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20 pages, 5610 KiB

Open AccessArticle

Novel Chrysin-De-Allyl PAC-1 Hybrid Analogues as Anticancer Compounds: Design, Synthesis, and Biological Evaluation

by Buthina A. Al-Oudat, Hariteja Ramapuram, Saloni Malla, Suaad A. Audat, Noor Hussein, Jenna M. Len, Shikha Kumari, Mel F. Bedi, Charles R. Ashby, Jr. and Amit K. Tiwari

Molecules 2020, 25(13), 3063; https://doi.org/10.3390/molecules25133063 - 04 Jul 2020

Cited by 10 | Viewed by 3662

Abstract

New chrysin-De-allyl-Pac-1 hybrid analogues, tethered with variable heterocyclic systems (4a–4o), were rationally designed and synthesized. The target compounds were screened for in vitro antiproliferative efficacy in the triple-negative breast cancer (TNBC) cell line, MDA-MB-231, and normal human mammary epithelial [...] Read more.

New chrysin-De-allyl-Pac-1 hybrid analogues, tethered with variable heterocyclic systems (4a–4o), were rationally designed and synthesized. The target compounds were screened for in vitro antiproliferative efficacy in the triple-negative breast cancer (TNBC) cell line, MDA-MB-231, and normal human mammary epithelial cells (HMECs). Two compounds, 4g and 4i, had the highest efficacy and selectivity towards MDA-MB-231 cells, and thus, were further evaluated by mechanistic experiments. The results indicated that both compounds 4g and 4i induced apoptosis by (1) inducing cell cycle arrest at the G2 phase in MDA-MB-231 cells, and (2) activating the intrinsic apoptotic pathways in a concentration-dependent manner. Physicochemical characterizations of these compounds suggested that they can be further optimized as potential anticancer compounds for TNBC cells. Overall, our results suggest that 4g and 4i could be suitable leads for developing novel compounds to treat TNBC. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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24 pages, 6464 KiB

Open AccessArticle

Phenylpyrazalopyrimidines as Tyrosine Kinase Inhibitors: Synthesis, Antiproliferative Activity, and Molecular Simulations

by Bhupender S. Chhikara, Sajda Ashraf, Saghar Mozaffari, Nicole St. Jeans, Dindyal Mandal, Rakesh Kumar Tiwari, Zaheer Ul-Haq and Keykavous Parang

Molecules 2020, 25(9), 2135; https://doi.org/10.3390/molecules25092135 - 02 May 2020

Cited by 16 | Viewed by 4299

Abstract

N1-(α,β-Alkene)-substituted phenylpyrazolopyrimidine derivatives with acetyl and functionalized phenyl groups at α- and β-positions, respectively, were synthesized by the reaction of 3-phenylpyrazolopyrimidine (PhPP) with bromoacetone, followed by a chalcone reaction with differently substituted aromatic aldehydes. The Src kinase enzyme assay revealed modest inhibitory [...] Read more.

N1-(α,β-Alkene)-substituted phenylpyrazolopyrimidine derivatives with acetyl and functionalized phenyl groups at α- and β-positions, respectively, were synthesized by the reaction of 3-phenylpyrazolopyrimidine (PhPP) with bromoacetone, followed by a chalcone reaction with differently substituted aromatic aldehydes. The Src kinase enzyme assay revealed modest inhibitory activity (half maximal inhibitory concentration, IC₅₀ = 21.7–192.1 µM) by a number of PhPP derivatives. Antiproliferative activity of the compounds was evaluated on human leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), breast carcinoma (MDA-MB-231), and colon adenocarcinoma (HT-29) cells in vitro. 4-Chlorophenyl carbo-enyl substituted 3-phenylpyrazolopyrimidine (10) inhibited the cell proliferation of HT-29 and SK-OV-3 by 90% and 79%, respectively, at a concentration of 50 µM after 96 h incubation. The compound showed modest inhibitory activity against c-Src (IC₅₀ = 60.4 µM), Btk (IC₅₀ = 90.5 µM), and Lck (IC₅₀ = 110 µM), while it showed no activity against Abl1, Akt1, Alk, Braf, Cdk2, and PKCa. In combination with target selection and kinase profiling assay, extensive theoretical studies were carried out to explore the selectivity behavior of compound 10. Specific interactions were also explored by examining the changing trends of interactions of tyrosine kinases with the phenylpyrazolopyrimidine derivative. The results showed good agreement with the experimental selectivity pattern among c-Src, Btk, and Lck. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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18 pages, 5555 KiB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of Proteolysis Targeting Chimeras (PROTACs) for the Dual Degradation of IGF-1R and Src

by Sudhakar Manda, Na Keum Lee, Dong-Chan Oh and Jeeyeon Lee

Molecules 2020, 25(8), 1948; https://doi.org/10.3390/molecules25081948 - 23 Apr 2020

Cited by 17 | Viewed by 5993

Abstract

A focused PROTAC library was developed to degrade both IGF-1R and Src proteins, which are associated with various cancers. PROTACs with IGF-1R and Src degradation potentials were synthesized by tethering different inhibitor warhead units and the E3 ligase (CRBN) recruiting-pomalidomide with various linkers. [...] Read more.

A focused PROTAC library was developed to degrade both IGF-1R and Src proteins, which are associated with various cancers. PROTACs with IGF-1R and Src degradation potentials were synthesized by tethering different inhibitor warhead units and the E3 ligase (CRBN) recruiting-pomalidomide with various linkers. The designed PROTACs 12a–b inhibited the proliferation and migration of MCF7 and A549 cancer cells with low micromolar potency (1–5 μM) in various cellular assays. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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31 pages, 48910 KiB

Open AccessArticle

Synthesis, Antiproliferative Activity and Molecular Docking Studies of Novel Doubly Modified Colchicine Amides and Sulfonamides as Anticancer Agents

by Julia Krzywik, Witold Mozga, Maral Aminpour, Jan Janczak, Ewa Maj, Joanna Wietrzyk, Jack A. Tuszyński and Adam Huczyński

Molecules 2020, 25(8), 1789; https://doi.org/10.3390/molecules25081789 - 14 Apr 2020

Cited by 32 | Viewed by 4524

Abstract

Colchicine is a well-known compound with strong antiproliferative activity that has had limited use in chemotherapy because of its toxicity. In order to create more potent anticancer agents, a series of novel colchicine derivatives have been obtained by simultaneous modification at C7 (amides [...] Read more.

Colchicine is a well-known compound with strong antiproliferative activity that has had limited use in chemotherapy because of its toxicity. In order to create more potent anticancer agents, a series of novel colchicine derivatives have been obtained by simultaneous modification at C7 (amides and sulfonamides) and at C10 (methylamino group) positions and characterized by spectroscopic methods. All the synthesized compounds have been tested in vitro to evaluate their cytotoxicity toward A549, MCF-7, LoVo, LoVo/DX and BALB/3T3 cell lines. Additionally, the activity of the studied compounds was investigated using computational methods involving molecular docking of the colchicine derivatives to β-tubulin. The majority of the obtained derivatives exhibited higher cytotoxicity than colchicine, doxorubicin or cisplatin against tested cancer cell lines. Furthermore, molecular modeling studies of the obtained compounds revealed their possible binding modes into the colchicine binding site of tubulin. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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14 pages, 2765 KiB

Open AccessArticle

Organosilicon Compounds, SILA-409 and SILA-421, as Doxorubicin Resistance-Reversing Agents in Human Colon Cancer Cells

by Olga Wesołowska, Krystyna Michalak, Maria Błaszczyk, Joseph Molnár and Kamila Środa-Pomianek

Molecules 2020, 25(7), 1654; https://doi.org/10.3390/molecules25071654 - 03 Apr 2020

Cited by 6 | Viewed by 2601

Abstract

Multidrug resistance (MDR) that occurs in cancer cells constitutes one of the major reasons for chemotherapy failure. The main molecular mechanism of MDR is overexpression of protein transporters from the ATP-binding cassette (ABC) superfamily, such as ABCB1 (multidrug resistance protein 1 (MDR1), P-glycoprotein). [...] Read more.

Multidrug resistance (MDR) that occurs in cancer cells constitutes one of the major reasons for chemotherapy failure. The main molecular mechanism of MDR is overexpression of protein transporters from the ATP-binding cassette (ABC) superfamily, such as ABCB1 (multidrug resistance protein 1 (MDR1), P-glycoprotein). At the expense of ATP hydrolysis, ABCB1 pumps a diverse range of substrates (including anticancer drugs) out of the cell, thereby reducing their intracellular concentration. In the present study, the ability of two patented disiloxanes (SILA-409 and SILA-421) to reverse drug resistance in human colon adenocarcinoma cell lines LoVo and LoVo/Dx was investigated. It was demonstrated that both compounds in concentrations of 0.5–1 µM strongly increased the sensitivity of LoVo/Dx cells to doxorubicin. By means of an accumulation test in which rhodamine 123 was used as an ABCB1 substrate analogue, both organosilicon compounds were also shown to inhibit ABCB1 transport activity. The intracellular accumulation of doxorubicin was also increased, and more drug entered the cellular nuclei of resistant cells in the presence of the studied compounds. In conclusion, both SILA-409 and SILA-421 were demonstrated to be effective MDR reversal agents in resistant human colon cancer cells. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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15 pages, 3574 KiB

Open AccessArticle

Synthesis, Docking Studies and Biological Activity of New Benzimidazole- Triazolothiadiazine Derivatives as Aromatase Inhibitor

by Ulviye Acar Çevik, Betül Kaya Çavuşoğlu, Begüm Nurpelin Sağlık, Derya Osmaniye, Serkan Levent, Sinem Ilgın, Yusuf Özkay and Zafer Asım Kaplancıklı

Molecules 2020, 25(7), 1642; https://doi.org/10.3390/molecules25071642 - 02 Apr 2020

Cited by 30 | Viewed by 4048

Abstract

In the last step of estrogen biosynthesis, aromatase enzyme catalyzes the conversion of androgens to estrogens. Aromatase inhibition is an important way to control estrogen-related diseases and estrogen levels. In this study, sixteen of benzimidazole-triazolothiadiazine derivatives have been synthesized and studied as potent [...] Read more.

In the last step of estrogen biosynthesis, aromatase enzyme catalyzes the conversion of androgens to estrogens. Aromatase inhibition is an important way to control estrogen-related diseases and estrogen levels. In this study, sixteen of benzimidazole-triazolothiadiazine derivatives have been synthesized and studied as potent aromatase inhibitors. First, these compounds were tested for their anti-cancer properties against human breast cancer cell line (MCF-7). The most active compounds 5c, 5e, 5k, and 5m on MCF-7 cell line were subject to further in vitro aromatase enzyme inhibition assays to determine the possible mechanisms of action underlying their activity. Compound 5e showed slight less potent aromatase inhibitory activity than that of letrozole with IC₅₀ = 0.032 ± 0.042 µM, compared to IC₅₀ = 0.024 ± 0.001 µM for letrozole. Furthermore, compound 5e and reference drug letrozole were docked into human placental aromatase enzyme to predict their possible binding modes with the enzyme. Finally, ADME parameters (absorption, distribution, metabolism, and excretion) of synthesized compounds (5a–5p) were calculated by QikProp 4.8 software. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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24 pages, 1947 KiB

Open AccessFeature PaperArticle

Synthesis, Characterization and Biological Evaluation of Novel Dihydropyranoindoles Improving the Anticancer Effects of HDAC Inhibitors

by Murat Bingul, Greg M. Arndt, Glenn M. Marshall, Belamy B. Cheung, Naresh Kumar and David StC. Black

Molecules 2020, 25(6), 1377; https://doi.org/10.3390/molecules25061377 - 18 Mar 2020

Cited by 4 | Viewed by 3618

Abstract

The dihydropyranoindole scaffold was identified as a promising target for improving the anti-cancer activity of HDAC inhibitors from the preliminary screening of a library of compounds. A suitable methodology has been developed for the preparation of novel dihydropyranoindoles via the Hemetsberger indole synthesis [...] Read more.

The dihydropyranoindole scaffold was identified as a promising target for improving the anti-cancer activity of HDAC inhibitors from the preliminary screening of a library of compounds. A suitable methodology has been developed for the preparation of novel dihydropyranoindoles via the Hemetsberger indole synthesis using azido-phenylacrylates, derived from the reaction of corresponding alkynyl-benzaldehydes with methyl azidoacetate, followed by thermal cyclization in high boiling solvents. Anti-cancer activity of all the newly synthesized compounds was evaluated against the SH-SY5Y and Kelly neuroblastoma cells as well as the MDA-MB-231 and MCF-7 breast adenocarcinoma cell lines. Biological studies showed that the tetracyclic systems had significant cytotoxic activity at higher concentration against the neuroblastoma cancer cells. More importantly, these systems, at the lower concentration, considerably enhanced the SAHA toxicity. In addition to that, the toxicity of designated systems on the healthy human cells was found to be significantly less than the cancer cells. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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12 pages, 1314 KiB

Open AccessArticle

Synthesis and Antiproliferative Screening Of Novel Analogs of Regioselectively Demethylated Colchicine and Thiocolchicine

by Dominika Czerwonka, Szymon Sobczak, Ewa Maj, Joanna Wietrzyk, Andrzej Katrusiak and Adam Huczyński

Molecules 2020, 25(5), 1180; https://doi.org/10.3390/molecules25051180 - 05 Mar 2020

Cited by 10 | Viewed by 3906

Abstract

Colchicine, a pseudoalkaloid isolated from Colchicum autumnale, has been identified as a potent anticancer agent because of its strong antimitotic activity. It was shown that colchicine modifications by regioselective demethylation affected its biological properties. For demethylated colchicine analogs, 10-demethylcolchicine (colchiceine, 1) [...] Read more.

Colchicine, a pseudoalkaloid isolated from Colchicum autumnale, has been identified as a potent anticancer agent because of its strong antimitotic activity. It was shown that colchicine modifications by regioselective demethylation affected its biological properties. For demethylated colchicine analogs, 10-demethylcolchicine (colchiceine, 1) and 1-demethylthiocolchicine (3), a series of 12 colchicine derivatives including 5 novel esters (2b–c and 4b–d) and 4 carbonates (2e–f and 4e–f) were synthesized. The antiproliferative activity assay, together with in silico evaluation of physicochemical properties, confirmed attractive biological profiles for all obtained compounds. The substitutions of H-donor and H-acceptor sites at C1 in thiocolchicine position provide an efficient control of the hydration affinity and solubility, as demonstrated for anhydrate 3, hemihydrate 4e and monohydrate 4a. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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16 pages, 2180 KiB

Open AccessArticle

Overcoming Resistance to Platinum-Based Drugs in Ovarian Cancer by Salinomycin and Its Derivatives—An In Vitro Study

by Marcin Michalak, Michał Stefan Lach, Michał Antoszczak, Adam Huczyński and Wiktoria Maria Suchorska

Molecules 2020, 25(3), 537; https://doi.org/10.3390/molecules25030537 - 26 Jan 2020

Cited by 20 | Viewed by 6341

Abstract

Polyether ionophore salinomycin (SAL) and its semi-synthetic derivatives are recognized as very promising anticancer drug candidates due to their activity against various types of cancer cells, including multidrug-resistant populations. Ovarian cancer is the deadliest among gynecologic malignancies, which is connected with the development [...] Read more.

Polyether ionophore salinomycin (SAL) and its semi-synthetic derivatives are recognized as very promising anticancer drug candidates due to their activity against various types of cancer cells, including multidrug-resistant populations. Ovarian cancer is the deadliest among gynecologic malignancies, which is connected with the development of chemoresistant forms of the disease in over 70% of patients after initial treatment regimen. Thus, we decided to examine the anticancer properties of SAL and selected SAL derivatives against a series of drug-sensitive (A2780, SK-OV-3) and derived drug-resistant (A2780 CDDP, SK-OV-3 CDDP) ovarian cancer cell lines. Although SAL analogs showed less promising IC₅₀ values than SAL, they were identified as the antitumor agents that significantly overcome the resistance to platinum-based drugs in ovarian cancer, more potent than unmodified SAL and commonly used anticancer drugs—5-fluorouracil, gemcitabine, and cisplatin. Moreover, when compared with SAL used alone, our experiments proved for the first time increased selectivity of SAL-based dual therapy with 5-fluorouracil or gemcitabine, especially towards A2780 cell line. Looking closer at the results, SAL acted synergistically with 5-fluorouracil towards the drug-resistant A2780 cell line. Our results suggest that combinations of SAL with other antineoplastics may become a new therapeutic option for patients with ovarian cancer. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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14 pages, 2349 KiB

Open AccessArticle

Design, Synthesis, and In Vitro Evaluation of the Photoactivatable Prodrug of the PARP Inhibitor Talazoparib

by Jiaguo Li, Dian Xiao, Lianqi Liu, Fei Xie, Wei Li, Wei Sun, Xiaohong Yang and Xinbo Zhou

Molecules 2020, 25(2), 407; https://doi.org/10.3390/molecules25020407 - 18 Jan 2020

Cited by 4 | Viewed by 4677

Abstract

In this article, we report the design, synthesis, photodynamic properties, and in vitro evaluation of photoactivatable prodrug for the poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor Talazoparib. In order to yield a photoactivatable, inactive prodrug, photoactivatable protecting groups (PPGs) were employed to mask the [...] Read more.

In this article, we report the design, synthesis, photodynamic properties, and in vitro evaluation of photoactivatable prodrug for the poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor Talazoparib. In order to yield a photoactivatable, inactive prodrug, photoactivatable protecting groups (PPGs) were employed to mask the key pharmacophore of Talazoparib. Our study confirmed the good stability and photolytic effect of prodrugs. A PARP-1 enzyme inhibition assay and PARylation experiment showed that the inhibitory activity of the prodrug was reduced 380 times and more than 658 times, respectively, which proved that the prodrug’s expected activity was lost after PPG protection. In BRCA1- and BRCA2-deficient cell lines, the inhibitory activity of the compound was significantly restored after ultraviolet (UV) irradiation. The results indicate that the photoactivatable prodrug strategy is an interesting approach for studying PARP inhibitors. Meanwhile, the described photoactivatable prodrug also provided a new biological tool for the mechanism research of PARP. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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16 pages, 2533 KiB

Open AccessArticle

New Zampanolide Mimics: Design, Synthesis, and Antiproliferative Evaluation

by Guanglin Chen, Ziran Jiang, Qiang Zhang, Guangdi Wang and Qiao-Hong Chen

Molecules 2020, 25(2), 362; https://doi.org/10.3390/molecules25020362 - 15 Jan 2020

Cited by 8 | Viewed by 3323

Abstract

Zampanolide is a promising microtubule-stabilizing agent (MSA) with a unique chemical structure. It is superior to the current clinically used MSAs due to the covalent nature of its binding to β-tubulin and high cytotoxic potency toward multidrug-resistant cancer cells. However, its further [...] Read more.

Zampanolide is a promising microtubule-stabilizing agent (MSA) with a unique chemical structure. It is superior to the current clinically used MSAs due to the covalent nature of its binding to β-tubulin and high cytotoxic potency toward multidrug-resistant cancer cells. However, its further development as a viable drug candidate is hindered by its limited availability. More importantly, conversion of its chemically fragile side chain into a stabilized bioisostere is envisioned to enable zampanolide to possess more drug-like properties. As part of our ongoing project aiming to develop its mimics with a stable side chain using straightforward synthetic approaches, 2-fluorobenzyl alcohol was designed as a bioisosteric surrogate for the side chain based on its binding conformation as confirmed by the X-ray structure of tubulin complexed with zampanolide. Two new zampanolide mimics with the newly designed side chain have been successfully synthesized through a 25-step chemical transformation for each. Yamaguchi esterification and intramolecular Horner–Wadsworth–Emmons condensation were used as key reactions to construct the lactone core. The chiral centers at C17 and C18 were introduced by the Sharpless asymmetric dihydroxylation. Our WST-1 cell proliferation assay data in both docetaxel-resistant and docetaxel-naive prostate cancer cell lines revealed that compound 6 is the optimal mimic and the newly designed side chain can serve as a bioisostere for the chemically fragile N-acetyl hemiaminal side chain in zampanolide. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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23 pages, 4083 KiB

Open AccessArticle

P-MAPA and Interleukin-12 Reduce Cell Migration/Invasion and Attenuate the Toll-Like Receptor-Mediated Inflammatory Response in Ovarian Cancer SKOV-3 Cells: A Preliminary Study

by Luiz Antonio Lupi, Flávia Karina Delella, Maira Smaniotto Cucielo, Graziela Gorete Romagnoli, Ramon Kaneno, Iseu da Silva Nunes, Raquel Fantin Domeniconi, Marcelo Martinez, Francisco Eduardo Martinez, Wagner José Fávaro and Luiz Gustavo de Almeida Chuffa

Molecules 2020, 25(1), 5; https://doi.org/10.3390/molecules25010005 - 18 Dec 2019

Cited by 9 | Viewed by 3237

Abstract

Immunotherapies have emerged as promising complementary treatments for ovarian cancer (OC), but its effective and direct role on OC cells is unclear. This study examined the combinatory effects of the protein aggregate magnesium–ammonium phospholinoleate–palmitoleate anhydride, known as P-MAPA, and the human recombinant interleukin-12 [...] Read more.

Immunotherapies have emerged as promising complementary treatments for ovarian cancer (OC), but its effective and direct role on OC cells is unclear. This study examined the combinatory effects of the protein aggregate magnesium–ammonium phospholinoleate–palmitoleate anhydride, known as P-MAPA, and the human recombinant interleukin-12 (hrIL-12) on cell migration/invasion, apoptosis, toll-like receptor (TLR)-mediated inflammation, and cytokine/chemokine profile in human OC cell line SKOV-3. P-MAPA and IL-12 showed cancer cell toxicity under low doses after 48 h. Although apoptosis/necrosis and the cell cycle were unchanged by the treatments, P-MAPA enhanced the sensitivity to paclitaxel (PTX) and P-MAPA associated with IL-12 significantly reduced the migratory potential and invasion capacity of SKOV-3 cells. P-MAPA therapy reduced TLR2 immunostaining and the myeloid differentiation factor 88 (MyD88), but not the TLR4 levels. Moreover, the combination of P-MAPA with IL-12 attenuated the levels of MyD88, interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-kB p65). The IL-12 levels were increased and P-MAPA stimulated the secretion of cytokines IL-3, IL-9, IL-10, and chemokines MDC/CCL22 and, regulated on activation, normal T cells expressed and secreted (RANTES)/CCL5. Conversely, combination therapy reduced the levels of IL-3, IL-9, IL-10, MDC/CCL22, and RANTES/CCL5. Collectively, P-MAPA and IL-12 reduce cell dynamics and effectively target the TLR-related downstream molecules, eliciting a protective effect against chemoresistance. P-MAPA also stimulates the secretion of anti-inflammatory molecules, possibly having an immune response in the OC microenvironment. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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16 pages, 3019 KiB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of Pyridineamide Derivatives Containing a 1,2,3-Triazole Fragment as Type II c-Met Inhibitors

by Hehua Xiong, Jianxin Cheng, Jianqing Zhang, Qian Zhang, Zhen Xiao, Han Zhang, Qidong Tang and Pengwu Zheng

Molecules 2020, 25(1), 10; https://doi.org/10.3390/molecules25010010 - 18 Dec 2019

Cited by 8 | Viewed by 2914

Abstract

A series of 4-(pyridin-4-yloxy)benzamide derivatives containing a 1,2,3-triazole fragment were designed, synthesized, and their inhibitory activity against A549, HeLa, and MCF-7 cancer cell lines was evaluated. Most compounds exhibited moderate to potent antitumor activity against the three cell lines. Among them, the promising [...] Read more.

A series of 4-(pyridin-4-yloxy)benzamide derivatives containing a 1,2,3-triazole fragment were designed, synthesized, and their inhibitory activity against A549, HeLa, and MCF-7 cancer cell lines was evaluated. Most compounds exhibited moderate to potent antitumor activity against the three cell lines. Among them, the promising compound B26 showed stronger inhibitory activity than Golvatinib, with IC₅₀ values of 3.22, 4.33, and 5.82 μM against A549, HeLa, and MCF-7 cell lines, respectively. The structure–activity relationships (SARs) demonstrated that the modification of the terminal benzene ring with a single electron-withdrawing substituent (fluorine atom) and the introduction of a pyridine amide chain with a strong hydrophilic group (morpholine) to the hinge region greatly improved the antitumor activity. Meanwhile, the optimal compound B26 showed potent biological activity in some pharmacological experiments in vitro, such as cell morphology study, dose-dependent test, kinase activity assay, and cell cycle experiment. Finally, the molecular docking simulation was performed to further explore the binding mode of compound B26 with c-Met. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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24 pages, 3790 KiB

Open AccessArticle

Novel Homo-Bivalent and Polyvalent Compounds Based on Ligustrazine and Heterocyclic Ring as Anticancer Agents

by Jiawen Wang, Ge Hong, Guoliang Li, Wenzhi Wang and Tianjun Liu

Molecules 2019, 24(24), 4505; https://doi.org/10.3390/molecules24244505 - 09 Dec 2019

Cited by 12 | Viewed by 2793

Abstract

Bivalent and polyvalent inhibitors can be used as antitumor agents. In this experiment, eight ligustrazine dimers and seven ligustrazine tetramers linked by alkane diamine with different lengths of carbon chain lengths were synthesized. After screening their antiproliferation activities against five cancer cell lines, [...] Read more.

Bivalent and polyvalent inhibitors can be used as antitumor agents. In this experiment, eight ligustrazine dimers and seven ligustrazine tetramers linked by alkane diamine with different lengths of carbon chain lengths were synthesized. After screening their antiproliferation activities against five cancer cell lines, most ligustrazine derivatives showed better cytotoxicity than the ligustrazine monomer. In particular, ligustrazine dimer 8e linked with decane-1,10-diamine exhibited the highest cytotoxicity in FaDu cells with an IC₅₀ (50% inhibiting concentration) value of 1.36 nM. Further mechanism studies suggested that 8e could induce apoptosis of FaDu cells through the depolarization of mitochondrial membrane potential and S-phase cell cycle arrest. Inspired by these results, twenty-seven additional small molecule heterocyclic dimers linked with decane-1,10-diamine and nine cinnamic acid dimers bearing ether chain were synthesized and screened. Most monocyclic and bicyclic aromatic systems showed highly selective anti-proliferation activity to FaDu cells and low toxicity to normal MCF 10A cells. The structure-activity relationship revealed that the two terminal amide bonds and the alkyl linker with a chain length of 8–12 carbon were two important factors to maintain its antitumor activity. In addition, the ADMET calculation predicted that most of the potent compounds had good oral bioavailability. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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14 pages, 3596 KiB

Open AccessArticle

Synthesis and Evaluation of Novel 2H-Benzo[e]-[1,2,4]thiadiazine 1,1-Dioxide Derivatives as PI3Kδ Inhibitors

by Ya-Ping Gong, Long-Qian Tang, Tong-Shen Liu and Zhao-Peng Liu

Molecules 2019, 24(23), 4299; https://doi.org/10.3390/molecules24234299 - 25 Nov 2019

Cited by 2 | Viewed by 2600

Abstract

In previous work, we applied the rotation-limiting strategy and introduced a substituent at the 3-position of the pyrazolo [3,4-d]pyrimidin-4-amine as the affinity element to interact with the deeper hydrophobic pocket, discovered a series of novel quinazolinones as potent PI3Kδ inhibitors. Among [...] Read more.

In previous work, we applied the rotation-limiting strategy and introduced a substituent at the 3-position of the pyrazolo [3,4-d]pyrimidin-4-amine as the affinity element to interact with the deeper hydrophobic pocket, discovered a series of novel quinazolinones as potent PI3Kδ inhibitors. Among them, the indole derivative 3 is one of the most selective PI3Kδ inhibitors and the 3,4-dimethoxyphenyl derivative 4 is a potent and selective dual PI3Kδ/γ inhibitor. In this study, we replaced the carbonyl group in the quinazolinone core with a sulfonyl group, designed a series of novel 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives as PI3Kδ inhibitors. After the reduction of nitro group in N-(2,6-dimethylphenyl)-2-nitrobenzenesulfonamide 5 and N-(2,6-dimethylphenyl)-2-nitro-5-fluorobenzenesulfonamide 6, the resulting 2-aminobenzenesulfonamides were reacted with trimethyl orthoacetate to give the 3-methyl-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives. After bromination of the 3-methyl group, the nucleophilic substitution with the 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine provided the respective iodide derivatives, which were further reacted with a series of arylboronic acids via Suzuki coupling to furnish the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives 15a–J and 16a–d. In agreement with the quinazolinone derivatives, the introduction of a 5-indolyl or 3,4-dimethoxyphenyl at the affinity pocket generated the most potent analogues 15a and 15b with the IC₅₀ values of 217 to 266 nM, respectively. In comparison with the quinazolinone lead compounds 3 and 4, these 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives exhibited much decreased PI3Kδ inhibitory potency, but maintained the high selectivity over other PI3K isoforms. Unlike the quinazolinone lead compound 4 that was a dual PI3Kδ/γ inhibitor, the benzthiadiazine 1,1-dioxide 15b with the same 3,4-dimethoxyphenyl moiety was more than 21-fold selective over PI3Kγ. Moreover, the introducing of a fluorine atom at the 7-position of the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide core, in general, was not favored for the PI3Kδ inhibitory activity. In agreement with their high PI3Kδ selectivity, 15a and 15b significantly inhibited the SU-DHL-6 cell proliferation. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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18 pages, 10732 KiB

Open AccessArticle

Potent Cytotoxicity of Novel L-Shaped Ortho-Quinone Analogs through Inducing Apoptosis

by Sheng-You Li, Ze-Kun Sun, Xue-Yi Zeng, Yue Zhang, Meng-Ling Wang, Sheng-Cao Hu, Jun-Rong Song, Jun Luo, Chao Chen, Heng Luo and Wei-Dong Pan

Molecules 2019, 24(22), 4138; https://doi.org/10.3390/molecules24224138 - 15 Nov 2019

Cited by 4 | Viewed by 2739

Abstract

Twenty-seven L-shaped ortho-quinone analogs were designed and synthesized using a one pot double-radical synthetic strategy followed by removing methyl at C-3 of the furan ring and introducing a diverse side chain at C-2 of the furan ring. The synthetic derivatives were investigated for [...] Read more.

Twenty-seven L-shaped ortho-quinone analogs were designed and synthesized using a one pot double-radical synthetic strategy followed by removing methyl at C-3 of the furan ring and introducing a diverse side chain at C-2 of the furan ring. The synthetic derivatives were investigated for their cytotoxicity activities against human leukemia cells K562, prostate cancer cells PC3, and melanoma cells WM9. Compounds TB1, TB3, TB4, TB6, TC1, TC3, TC5, TC9, TC11, TC12, TC14, TC15, TC16, and TC17 exhibited a better broad-spectrum cytotoxicity on three cancer cells. TB7 and TC7 selectively displayed potent inhibitory activities on leukemia cells K562 and prostate cancer cells PC3, respectively. Further studies indicated that TB3, TC1, TC3, TC7, and TC17 could significantly induce the apoptosis of PC3 cells. TC1 and TC17 significantly induced apoptosis of K562 cells. TC1, TC11, and TC14 induced significant apoptosis of WM9 cells. The structure-activity relationships evaluation showed that removing methyl at C-3 of the furan ring and introducing diverse side chains at C-2 of the furan ring is an effective strategy for improving the anticancer activity of L-shaped ortho-quinone analogs. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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19 pages, 3086 KiB

Open AccessArticle

Synthesis, Antiproliferative, and Antioxidant Evaluation of 2-Pentylquinazolin-4(3H)-one(thione) Derivatives with DFT Study

by Amira A. El-Sayed, Mahmoud F. Ismail, Abd El-Galil E. Amr and Ahmed M. Naglah

Molecules 2019, 24(20), 3787; https://doi.org/10.3390/molecules24203787 - 21 Oct 2019

Cited by 20 | Viewed by 3698

Abstract

The current study was chiefly designed to examine the antiproliferative and antioxidant activities of some novel quinazolinone(thione) derivatives 6–14. The present work focused on two main points; firstly, comparing between quinazolinone and quinazolinthione derivatives. Whereas, antiproliferative (against two cell lines [...] Read more.

The current study was chiefly designed to examine the antiproliferative and antioxidant activities of some novel quinazolinone(thione) derivatives 6–14. The present work focused on two main points; firstly, comparing between quinazolinone and quinazolinthione derivatives. Whereas, antiproliferative (against two cell lines namely, HepG2 and MCF-7) and antioxidant (by two methods; ABTS and DPPH) activities of the investigated compounds, the best quinazolinthione derivatives were 6 and 14, which exhibited excellent potencies comparable to quinazolinone derivatives 5 and 9, respectively. Secondly, we compared the activity of four series of Schiff bases which included the quinazolinone moiety (11a–d). In addition, the antiproliferative and antioxidant activities of the compounds with various aryl aldehyde hydrazone derivatives (11a–d) analogs were studied. The compounds exhibited potency that increased with increasing electron donating group in p-position (OH > OMe > Cl) due to extended conjugated systems. Noteworthy, most of antiproliferative and antioxidant activities results for the tested compounds are consistent with the DFT calculations. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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14 pages, 3148 KiB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of Novel Thienopyrimidine Derivatives as PI3Kα Inhibitors

by Lide Yu, Qinqin Wang, Caolin Wang, Binliang Zhang, Zunhua Yang, Yuanying Fang, Wufu Zhu and Pengwu Zheng

Molecules 2019, 24(19), 3422; https://doi.org/10.3390/molecules24193422 - 20 Sep 2019

Cited by 4 | Viewed by 2690

Abstract

Three series of novel thienopyrimidine derivatives 9a–l, 15a–l, and 18a–h were designed and synthesized, and their IC₅₀ values against four cancer cell lines HepG-2, A549, PC-3, and MCF-7 were evaluated. Most compounds show moderate [...] Read more.

Three series of novel thienopyrimidine derivatives 9a–l, 15a–l, and 18a–h were designed and synthesized, and their IC₅₀ values against four cancer cell lines HepG-2, A549, PC-3, and MCF-7 were evaluated. Most compounds show moderate cytotoxicity against the tested cancer cell lines. The most promising compound 9a showed moderate activity with IC₅₀ values of 12.32 ± 0.96, 11.30 ± 1.19, 14.69 ± 1.32, and 9.80 ± 0.93 µM, respectively. The inhibitory activities of compounds 9a and 15a against PI3Kα and mTOR kinase were further evaluated. Compound 9a exhibited PI3Kα kinase inhibitory activity with IC₅₀ of 9.47 ± 0.63 µM. In addition, docking studies of compounds 9a and 15a were also investigated. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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20 pages, 6895 KiB

Open AccessArticle

Synthesis, Anti-Cancer and Anti-Migratory Evaluation of 3,6-Dibromocarbazole and 5-Bromoindole Derivatives

by Krystal M. Butler-Fernández, Zulma Ramos, Adela M. Francis-Malavé, Joseph Bloom, Suranganie Dharmawardhane and Eliud Hernández

Molecules 2019, 24(15), 2686; https://doi.org/10.3390/molecules24152686 - 24 Jul 2019

Cited by 8 | Viewed by 3606

Abstract

In this study, a new series of N-alkyl-3,6-dibromocarbazole and N-alkyl-5-bromoindole derivatives have been synthesized and evaluated in vitro as anti-cancer and anti-migration agents. Cytotoxic and anti-migratory effects of these compounds were evaluated in MCF-7 and MDA-MB-231 breast cancer cell lines and [...] Read more.

In this study, a new series of N-alkyl-3,6-dibromocarbazole and N-alkyl-5-bromoindole derivatives have been synthesized and evaluated in vitro as anti-cancer and anti-migration agents. Cytotoxic and anti-migratory effects of these compounds were evaluated in MCF-7 and MDA-MB-231 breast cancer cell lines and an insight on the structure-activity relationship was developed. Preliminary investigations of their anti-cancer activity demonstrated that several compounds have moderate antiproliferative effects on cancer cell lines with GI₅₀ values in the range of 4.7–32.2 µM. Moreover, carbazole derivatives 10, 14, 15, 23, and 24 inhibit migration activity of metastatic cell line MDA-MB-231 in the range of 18–20%. The effect of compounds 10, 14, and 15 in extension of invadopodia and filopodia was evaluated by fluorescence microscopy and results demonstrated a reduction in actin-based cell extensions by compounds 10 and 15. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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14 pages, 6674 KiB

Open AccessArticle

A Comparative Study of the Anticancer Activity and PARP-1 Inhibiting Effect of Benzofuran–Pyrazole Scaffold and Its Nano-Sized Particles in Human Breast Cancer Cells

by Manal M. Anwar, Somaia S. Abd El-Karim, Ahlam H. Mahmoud, Abd El-Galil E. Amr and Mohamed A. Al-Omar

Molecules 2019, 24(13), 2413; https://doi.org/10.3390/molecules24132413 - 29 Jun 2019

Cited by 36 | Viewed by 3407

Abstract

Breast cancer is considered the most common and deadly cancer among women worldwide. Nanomedicine has become extremely attractive in the field of cancer treatment. Due to the high surface to volume ratio and other unique properties, nanomaterials can be specifically targeted to certain [...] Read more.

Breast cancer is considered the most common and deadly cancer among women worldwide. Nanomedicine has become extremely attractive in the field of cancer treatment. Due to the high surface to volume ratio and other unique properties, nanomaterials can be specifically targeted to certain cells and tissues to interact with the living systems. The strategic planning of this study is based on using the nanoprecipitation method to prepare nanoparticles BZP-NPs (3.8–5.7 nm) of the previously prepared benzofuran–pyrazole compound (IV) BZP which showed promising cytotoxic activity. The capacity of BZP and BZP-NPs to suppress the growth of human breast tumor MCF-7 and MDA-MB-231 cells was evaluated using MTT assay. The IC₅₀ doses of BZP and BZP-NPs targeting normal breast cells MCF-12A exceeded those targeting the cancer cells by >1000-fold, demonstrating their reasonable safety profiles in normal cells. Furthermore, cell cycle analysis, apoptosis induction detection, assessment of p53, Bcl-2, caspase-3, and PARP-1 levels of BZP and its nano-sized-BZP-NPs particles were also evaluated. Although the obtained results were in the favor of compound IV in its normal-sized particles, BZP-NPs appeared as a hit compound which showed improved cytotoxicity against the tested human breast cancer cells associated with the induction of pre-G1 apoptosis as well as cell cycle arrest at G2/M phase. The increase in caspase-3 level, upregulation of p53, and downregulation of Bcl-2 protein expression levels confirmed apoptosis. Furthermore, ELISA results exhibited that BZP-NPs produced a more favorable impact as a PARP-1 enzyme inhibitor than the parent BZP. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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14 pages, 1226 KiB

Open AccessArticle

In Vitro and In Vivo Anti-Breast Cancer Activities of Some Newly Synthesized 5-(thiophen-2-yl)thieno-[2,3-d]pyrimidin-4-one Candidates

by Abd El-Galil E. Amr, Alhussein A. Ibrahimd, Mohamed F. El-Shehry, Hanaa M. Hosni, Ahmed A. Fayed and Elsayed A. Elsayed

Molecules 2019, 24(12), 2255; https://doi.org/10.3390/molecules24122255 - 17 Jun 2019

Cited by 6 | Viewed by 3284

Abstract

In this study, some of new thiophenyl thienopyrimidinone derivatives 2–15 were prepared and tested as anti-cancer agents by using thiophenyl thieno[2,3-d]pyrimidinone derivative 2 as a starting material, which was prepared from cyclization of ethyl ester derivative 1 with formamide. Treatment of [...] Read more.

In this study, some of new thiophenyl thienopyrimidinone derivatives 2–15 were prepared and tested as anti-cancer agents by using thiophenyl thieno[2,3-d]pyrimidinone derivative 2 as a starting material, which was prepared from cyclization of ethyl ester derivative 1 with formamide. Treatment of 2 with ethyl- chloroacetate gave thienopyrimidinone N-ethylacetate 3, which was reacted with hydrazine hydrate or anthranilic acid to afford acetohydrazide 4 and benzo[d][1,³]oxazin-4-one 5, respectively. Condensation of 4 with aromatic aldehydes or phenylisothiocyanate yielded Schiff base derivatives 6,7, and thiosemicarbazise 10, which were treated with 2-mercaptoacetic acid or chloroacetic acid to give the corresponding thiazolidinones 8, 9, and phenylimino-thiazolidinone 11, respectively. Treatment of 4 with ethylacetoacetate or acetic acid/acetic anhydride gave pyrazole 12 and acetyl acetohydrazide 13 derivatives, respectively. The latter compound 13 was reacted with ethyl cycno-acetate or malononitrile to give 14 and 15, respectively. In this work, we have studied the anti-cancer activity of the synthesized thienopyrimidinone derivatives against MCF-7 and MCF-10A cancer cells. Furthermore, in vivo experiments showed that the synthesized compounds significantly reduced tumor growth up to the 8^th day of treatment in comparison to control animal models. Additionally, the synthesized derivatives showed potential inhibitory effects against pim-1 kinase activities. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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23 pages, 1825 KiB

Open AccessArticle

Synthesis and Cytotoxicity of 7,9-O-Linked Macrocyclic C-Seco Taxoids

by Yu Zhao, Tian-En Wang, Alberto Mills, Federico Gago and Wei-Shuo Fang

Molecules 2019, 24(11), 2161; https://doi.org/10.3390/molecules24112161 - 08 Jun 2019

Cited by 2 | Viewed by 2941

Abstract

A series of novel 7,9-O-linked macrocyclic taxoids together with modification at the C2 position were synthesized, and their cytotoxicities against drug-sensitive and P-glycoprotein and βIII-tubulin overexpressed drug-resistant cancer cell lines were evaluated. It is demonstrated that C-seco taxoids conformationally constrained via [...] Read more.

A series of novel 7,9-O-linked macrocyclic taxoids together with modification at the C2 position were synthesized, and their cytotoxicities against drug-sensitive and P-glycoprotein and βIII-tubulin overexpressed drug-resistant cancer cell lines were evaluated. It is demonstrated that C-seco taxoids conformationally constrained via carbonate containing-linked macrocyclization display increased cytotoxicity on drug-resistant tumors overexpressing both βIII and P-gp, among which compound 22b, bearing a 2-m-methoxybenzoyl group together with a five-atom linker, was identified as the most potent. Molecular modeling suggested the improved cytotoxicity of 22b results from enhanced favorable interactions with the T7 loop region of βIII. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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27 pages, 11322 KiB

Open AccessArticle

Design and Synthesis of Indoleamine 2,3-Dioxygenase 1 Inhibitors and Evaluation of Their Use as Anti-Tumor Agents

by Hui Wen, Yuke Liu, Shufang Wang, Ting Wang, Gang Zhang, Xiaoguang Chen, Yan Li, Huaqing Cui, Fangfang Lai and Li Sheng

Molecules 2019, 24(11), 2124; https://doi.org/10.3390/molecules24112124 - 05 Jun 2019

Cited by 19 | Viewed by 4037

Abstract

Indoleamine 2,3-dioxygenase (IDO) 1 is the key enzyme for regulating tryptophan metabolism and is an important target for interrupting tumor immune escape. In this study, we designed four series of compounds as potential IDO1 inhibitors by attaching various fragments or ligands to indole [...] Read more.

Indoleamine 2,3-dioxygenase (IDO) 1 is the key enzyme for regulating tryptophan metabolism and is an important target for interrupting tumor immune escape. In this study, we designed four series of compounds as potential IDO1 inhibitors by attaching various fragments or ligands to indole or phenylimidazole scaffolds to improve binding to IDO1. The compounds were synthesized and their inhibitory activities against IDO1 and tryptophan 2,3-dioxygenase were evaluated. The cytotoxicities of the compounds against two tumor cell lines were also determined. Two compounds with a phenylimidazole scaffold (DX-03-12 and DX-03-13) showed potent IDO1 inhibition with IC₅₀ values of 0.3–0.5 μM. These two IDO1 inhibitors showed low cell cytotoxicity, which indicated that they may exert their anti-tumor effect via immune modulation. Compound DX-03-12 was investigated further by determining the in vivo pharmacokinetic profile and anti-tumor efficacy. The pharmacokinetic study revealed that DX-03-12 had satisfactory properties in mice, with rapid absorption, moderate plasma clearance (∼36% of hepatic blood flow), acceptable half-life (∼4.6 h), and high oral bioavailability (∼96%). Daily oral administration of 60 mg/kg of compound DX-03-12 decreased tumor growth by 72.2% after 19 days in a mouse melanoma cell B16-F10 xenograft model compared with the untreated control. Moreover, there was no obvious weight loss in DX-03-12-treated mice. In conclusion, compound DX-03-12 is a potent lead compound for developing IDO1 inhibitors and anti-tumor agents. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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18 pages, 14174 KiB

Open AccessArticle

Design, Synthesis and Biological Evaluation of a New Series of 1-Aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea Derivatives as Antiproliferative Agents

by Chuanming Zhang, Xiaoyu Tan, Jian Feng, Ning Ding, Yongpeng Li, Zhe Jin, Qingguo Meng, Xiaoping Liu and Chun Hu

Molecules 2019, 24(11), 2108; https://doi.org/10.3390/molecules24112108 - 04 Jun 2019

Cited by 5 | Viewed by 3513

Abstract

To discover new antiproliferative agents with high efficacy and selectivity, a new series of 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea derivatives (7a–7t) were designed, synthesized and evaluated for their antiproliferative activity against A549, HCT-116 and PC-3 cancer cell lines in vitro. Most of the [...] Read more.

To discover new antiproliferative agents with high efficacy and selectivity, a new series of 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea derivatives (7a–7t) were designed, synthesized and evaluated for their antiproliferative activity against A549, HCT-116 and PC-3 cancer cell lines in vitro. Most of the target compounds demonstrated significant antiproliferative effects on all the selective cancer cell lines. Among them, the target compound, 1-[4-chloro-3-(trifluoromethyl)phenyl]-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}thio}phenyl}urea (7i) was identified to be the most active one against three cell lines, which was more potent than the positive control with an IC₅₀ value of 1.53 ± 0.46, 1.11 ± 0.34 and 1.98 ± 1.27 μM, respectively. Further cellular mechanism studies confirmed that compound 7i could induce the apoptosis of A549 cells in a concentration-dependent manner and elucidated compound 7i arrests cell cycle at G1 phase by flow cytometry analysis. Herein, the studies suggested that the 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea skeleton might be regarded as new chemotypes for designing effective antiproliferative agents. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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15 pages, 1976 KiB

Open AccessArticle

Potent Anti-Ovarian Cancer with Inhibitor Activities on Both Topoisomerase II and ^V600EBRAF of Synthesized Substituted Estrone Candidates

by Mohamed El-Naggar, Abd El-Galil E. Amr, Ahmed A. Fayed, Elsayed A. Elsayed, Mohamed A. Al-Omar and Mohamed M. Abdalla

Molecules 2019, 24(11), 2054; https://doi.org/10.3390/molecules24112054 - 29 May 2019

Cited by 3 | Viewed by 2141

Abstract

A series of 16-(α-alkoxyalkane)-17-hydrazino-estra-1(10),2,4-trien[17,16-c]-3-ol (3a–l) and estra-1(10),2,4-trien-[17,16-c]pyrazoline-3-ol derivatives (4a–d) were synthesized from corresponding arylidines 2a,b which was prepared from estrone 1 as starting material. Condensation of 1 with aldehydes gave the corresponding arylidine derivatives 2a,b [...] Read more.

A series of 16-(α-alkoxyalkane)-17-hydrazino-estra-1(10),2,4-trien[17,16-c]-3-ol (3a–l) and estra-1(10),2,4-trien-[17,16-c]pyrazoline-3-ol derivatives (4a–d) were synthesized from corresponding arylidines 2a,b which was prepared from estrone 1 as starting material. Condensation of 1 with aldehydes gave the corresponding arylidine derivatives 2a,b which were treated with hydrazine derivatives in alcohols to give the corresponding derivatives 3a–l, respectively. Additionally, treatment of 2a,b with methyl- or phenylhydrazine in ethanolic potassium hydroxide afforded the corresponding N-substituted pyrazoline derivatives 4a–d, respectively. All these derivatives showed potent anti-ovarian cancer both in vitro and in vivo. The mechanism of anti-ovarian cancer was suggested to process via topoisomerase II and ^V600EBRAF inhibition. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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20 pages, 2725 KiB

Open AccessArticle

Synthesis, Biological Evaluation, and In Silico Studies of Novel Aminated Xanthones as Potential p53-Activating Agents

by Agostinho Lemos, Ana Sara Gomes, Joana B. Loureiro, Pedro Brandão, Andreia Palmeira, Madalena M. M. Pinto, Lucília Saraiva and Maria Emília Sousa

Molecules 2019, 24(10), 1975; https://doi.org/10.3390/molecules24101975 - 22 May 2019

Cited by 23 | Viewed by 4154

Abstract

Xanthone scaffold has been regarded as an attractive chemical tool in the search for bioactive molecules with antitumor activity, and in particular two xanthone derivatives, 12-hydroxy-2,2-dimethyl-3,4-dihydro-2H,6H-pyrano [3,2-b]xanthen-6-one (4) and 3,4-dimethoxy-9-oxo-9H-xanthene-1-carbaldehyde (5), [...] Read more.

Xanthone scaffold has been regarded as an attractive chemical tool in the search for bioactive molecules with antitumor activity, and in particular two xanthone derivatives, 12-hydroxy-2,2-dimethyl-3,4-dihydro-2H,6H-pyrano [3,2-b]xanthen-6-one (4) and 3,4-dimethoxy-9-oxo-9H-xanthene-1-carbaldehyde (5), were described as a murine double minute 2 (MDM2)-p53 inhibitor and a TAp73 activator, respectively. The xanthone 5 was used as a starting point for the construction of a library of 3,4-dioxygenated xanthones bearing chemical moieties of described MDM2-p53 inhibitors. Eleven aminated xanthones were successfully synthesized and initially screened for their ability to disrupt the MDM2-p53 interaction using a yeast cell-based assay. With this approach, xanthone 37 was identified as a putative p53-activating agent through inhibition of interaction with MDM2. Xanthone 37 inhibited the growth of human colon adenocarcinoma HCT116 cell lines in a p53-dependent manner. The growth inhibitory effect of xanthone 37 was associated with the induction of G1-phase cell cycle arrest and increased protein expression levels of p53 transcriptional targets. These results demonstrated the potential usefulness of coupling amine-containing structural motifs of known MDM2-p53 disruptors into a 3,4-dioxygenated xanthone scaffold in the design of novel and potent p53 activators with antitumor activity and favorable drug-like properties. Moreover, in silico docking studies were performed in order to predict the binding poses and residues involved in the potential MDM2-p53 interaction. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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14 pages, 1311 KiB

Open AccessArticle

Cytotoxic Effects of Newly Synthesized Heterocyclic Candidates Containing Nicotinonitrile and Pyrazole Moieties on Hepatocellular and Cervical Carcinomas

by Amira A. El-Sayed, Abd El-Galil E. Amr, Ahmed K. EL-Ziaty and Elsayed A. Elsayed

Molecules 2019, 24(10), 1965; https://doi.org/10.3390/molecules24101965 - 22 May 2019

Cited by 13 | Viewed by 2727

Abstract

In this study, a series of newly synthesized substituted pyridine 9, 11–18, naphthpyridine derivative 10 and substituted pyrazolopyridines 19–23 by using cycnopyridone 8 as a starting material. Some of the synthesized candidates are evaluated as anticancer agents against [...] Read more.

In this study, a series of newly synthesized substituted pyridine 9, 11–18, naphthpyridine derivative 10 and substituted pyrazolopyridines 19–23 by using cycnopyridone 8 as a starting material. Some of the synthesized candidates are evaluated as anticancer agents against different cancer cell lines. In vitro cytotoxic activities against hepatocellular and cervical carcinoma cell lines were evaluated using standard MTT assay. Different synthesized compounds exhibited potential in vitro cytotoxic activities against both HepG2 and HeLa cell lines. Furthermore, compared to standard positive control drugs, compounds 13 and 19 showed the most potent cytotoxic effect with IC₅₀ values of 8.78 ± 0.7, 5.16 ± 0.4 μg/mL, and 15.32 ± 1.2 and 4.26 ± 0.3 μg/mL for HepG2 and HeLa cells, respectively. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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10 pages, 869 KiB

Open AccessArticle

Design and Synthesis of Flavonoidal Ethers and Their Anti-Cancer Activity In Vitro

by Lu Jin, Meng-Ling Wang, Yao Lv, Xue-Yi Zeng, Chao Chen, Hai Ren, Heng Luo and Wei-Dong Pan

Molecules 2019, 24(9), 1749; https://doi.org/10.3390/molecules24091749 - 06 May 2019

Cited by 7 | Viewed by 2578

Abstract

Flavonoids are well-characterized polyphenolic compounds with pharmacological and therapeutic activities. However, most flavonoids have not been developed into clinical drugs, due to poor bioavailability. Herein, we report a strategy to increase the drugability of flavonoids by constructing C(sp²)-O bonds and stereo- [...] Read more.

Flavonoids are well-characterized polyphenolic compounds with pharmacological and therapeutic activities. However, most flavonoids have not been developed into clinical drugs, due to poor bioavailability. Herein, we report a strategy to increase the drugability of flavonoids by constructing C(sp²)-O bonds and stereo- as well as regioselective alkenylation of hydroxyl groups of flavonoids with ethyl-2,3-butadienoate allenes. Twenty-three modified flavonoid derivatives were designed, synthesized, and evaluated for their anti-cancer activities. The results showed that compounds 4b, 4c, 4e, 5e, and 6b exhibited better in vitro inhibitory activity against several cancer cell lines than their precursors. Preliminary structure–activity relationship studies indicated that, in most of the cancer cell lines evaluated, the substitution on position 7 was essential for increasing cytotoxicity. The results of this study might facilitate the preparation or late-stage modification of complex flavonoids as anti-cancer drug candidates. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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20 pages, 3786 KiB

Open AccessArticle

Design, Synthesis, and Mechanism of Dihydroartemisinin–Coumarin Hybrids as Potential Anti-Neuroinflammatory Agents

by Haonan Yu, Zhuang Hou, Xiaoguang Yang, Yanhua Mou and Chun Guo

Molecules 2019, 24(9), 1672; https://doi.org/10.3390/molecules24091672 - 28 Apr 2019

Cited by 13 | Viewed by 3319

Abstract

Cancer patients frequently suffer from cancer-related fatigue (CRF), which is a complex syndrome associated with weakness and depressed mood. Neuroinflammation is one of the major inducers of CRF. The aim of this study is to find a potential agent not only on the [...] Read more.

Cancer patients frequently suffer from cancer-related fatigue (CRF), which is a complex syndrome associated with weakness and depressed mood. Neuroinflammation is one of the major inducers of CRF. The aim of this study is to find a potential agent not only on the treatment of cancer, but also for reducing CRF level of cancer patients. In this study, total-thirty new Dihydroartemisinin–Coumarin hybrids (DCH) were designed and synthesized. The in vitro cytotoxicity against cancer cell lines (HT-29, MDA-MB-231, HCT-116, and A549) was evaluated. Simultaneously, we also tested the anti-neuroinflammatory activity of DCH. DCH could inhibit the activated microglia N9 release of NO, TNF-α, and IL-6. The docking analysis was shown that MD-2, the coreceptor of TLR4, might be one of the targets of DCH. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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16 pages, 2190 KiB

Open AccessArticle

Synthesis of New Derivatives of Benzofuran as Potential Anticancer Agents

by Mariola Napiórkowska, Marcin Cieślak, Julia Kaźmierczak-Barańska, Karolina Królewska-Golińska and Barbara Nawrot

Molecules 2019, 24(8), 1529; https://doi.org/10.3390/molecules24081529 - 18 Apr 2019

Cited by 26 | Viewed by 4030

Abstract

The results of our previous research indicated that some derivatives of benzofurans, particularly halogeno-derivatives, are selectively toxic towards human leukemia cells. Continuing our work with this group of compounds we here report new data on the synthesis as well as regarding the physico-chemical [...] Read more.

The results of our previous research indicated that some derivatives of benzofurans, particularly halogeno-derivatives, are selectively toxic towards human leukemia cells. Continuing our work with this group of compounds we here report new data on the synthesis as well as regarding the physico-chemical and biological characterization of fourteen new derivatives of benzofurans, including six brominated compounds. The structures of all new compounds were established by spectroscopic methods (¹H- and, ¹³C-NMR, ESI MS), and elemental analyses. Their cytotoxicity was evaluated against K562 (leukemia), MOLT-4 (leukemia), HeLa (cervix carcinoma), and normal cells (HUVEC). Five compounds (1c, 1e, 2d, 3a, 3d) showed significant cytotoxic activity against all tested cell lines and selectivity for cancer cell lines. The SAR analysis (structure-activity relationship analysis) indicated that the presence of bromine introduced to a methyl or acetyl group that was attached to the benzofuran system increased their cytotoxicity both in normal and cancer cells. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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Review

Jump to: Research

27 pages, 3996 KiB

Open AccessReview

Second-Generation Androgen Receptor Antagonists as Hormonal Therapeutics for Three Forms of Prostate Cancer

by Pravien Rajaram, Alyssa Rivera, Kevin Muthima, Nicholas Olveda, Hubert Muchalski and Qiao-Hong Chen

Molecules 2020, 25(10), 2448; https://doi.org/10.3390/molecules25102448 - 24 May 2020

Cited by 37 | Viewed by 8506

Abstract

Enzalutamide is the first second-generation nonsteroidal androgen receptor (AR) antagonist with a strong binding affinity to AR. Most significantly, enzalutamide can prolong not only overall survival time and metastatic free survival time for patients with lethal castration-resistant prostate cancer (CRPC), but also castration-resistant [...] Read more.

Enzalutamide is the first second-generation nonsteroidal androgen receptor (AR) antagonist with a strong binding affinity to AR. Most significantly, enzalutamide can prolong not only overall survival time and metastatic free survival time for patients with lethal castration-resistant prostate cancer (CRPC), but also castration-resistant free survival time for patients with castration-sensitive prostate cancer (CSPC). Enzalutamide has thus been approved by the US Food and Drug Administration (FDA) for the treatment of both metastatic (in 2012) and non-metastatic (in 2018) CRPC, as well as CSPC (2019). This is an inspiring drug discovery story created by an amazing interdisciplinary collaboration. Equally important, the successful clinical use of enzalutamide proves the notion that the second-generation AR antagonists can serve as hormonal therapeutics for three forms of advanced prostate cancer. This has been further verified by the recent FDA approval of the other two second-generation AR antagonists, apalutamide and darolutamide, for the treatment of prostate cancer. This review focuses on the rational design and discovery of these three second-generation AR antagonists, and then highlights their syntheses, clinical studies, and use. Strategies to overcome the resistance to the second-generation AR antagonists are also reviewed. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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14 pages, 806 KiB

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Mimicking Strategy for Protein–Protein Interaction Inhibitor Discovery by Virtual Screening

by Ke-Jia Wu, Pui-Man Lei, Hao Liu, Chun Wu, Chung-Hang Leung and Dik-Lung Ma

Molecules 2019, 24(24), 4428; https://doi.org/10.3390/molecules24244428 - 04 Dec 2019

Cited by 21 | Viewed by 5215

Abstract

As protein–protein interactions (PPIs) are highly involved in most cellular processes, the discovery of PPI inhibitors that mimic the structure of the natural protein partners is a promising strategy toward the discovery of PPI inhibitors. In this review, we discuss recent advances in [...] Read more.

As protein–protein interactions (PPIs) are highly involved in most cellular processes, the discovery of PPI inhibitors that mimic the structure of the natural protein partners is a promising strategy toward the discovery of PPI inhibitors. In this review, we discuss recent advances in the application of virtual screening for identifying mimics of protein partners. The classification and function of the mimicking protein partner inhibitor discovery by virtual screening are described. We anticipate that this review would be of interest to medicinal chemists and chemical biologists working in the field of protein–protein interaction inhibitors or probes. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)

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