Molecules

Research

Jump to: Review

10 pages, 1546 KiB

Open AccessArticle

Baicalein Induces G₂/M Cell Cycle Arrest Associated with ROS Generation and CHK2 Activation in Highly Invasive Human Ovarian Cancer Cells

by Tzu-Chao Chuang, Wei-Syun Shao, Shih-Chung Hsu, Shou-Lun Lee, Ming-Ching Kao and Vinchi Wang

Molecules 2023, 28(3), 1039; https://doi.org/10.3390/molecules28031039 - 20 Jan 2023

Cited by 5 | Viewed by 1636

Abstract

Ovarian cancer is a lethal gynecological cancer because drug resistance often results in treatment failure. The CHK2, a tumor suppressor, is considered to be an important molecular target in ovarian cancer due to its role in DNA repair. Dysfunctional CHK2 impairs DNA damage-induced [...] Read more.

Ovarian cancer is a lethal gynecological cancer because drug resistance often results in treatment failure. The CHK2, a tumor suppressor, is considered to be an important molecular target in ovarian cancer due to its role in DNA repair. Dysfunctional CHK2 impairs DNA damage-induced checkpoints, reduces apoptosis, and confers resistance to chemotherapeutic drugs and radiation therapy in ovarian cancer cells. This provides a basis for finding new effective agents targeting CHK2 upregulation or activation to treat or prevent the progression of advanced ovarian cancer. Here, the results show that baicalein (5,6,7-trihydroxyflavone) treatment inhibits the growth of highly invasive ovarian cancer cells, and that baicalein-induced growth inhibition is mediated by the cell cycle arrest in the G₂/M phase. Baicalein-induced G₂/M phase arrest is associated with an increased reactive oxygen species (ROS) production, DNA damage, and CHK2 upregulation and activation. Thus, baicalein modulates the expression of DNA damage response proteins and G₂/M phase regulatory molecules. Blockade of CHK2 activation by CHK2 inhibitors protects cells from baicalein-mediated G₂/M cell cycle arrest. All the results suggest that baicalein has another novel growth inhibitory effect on highly invasive ovarian cancer cells, which is partly related to G₂/M cell cycle arrest through the ROS-mediated DNA breakage damage and CHK2 activation. Collectively, our findings provide a molecular basis for the potential of baicalein as an adjuvant therapeutic agent in the treatment of metastatic ovarian cancer. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Figure 1

16 pages, 1054 KiB

Open AccessFeature PaperArticle

New Class of Benzodiazepinone Derivatives as Pro-Death Agents Targeting BIR Domains in Cancer Cells

by Michele Fiore, Michele Mosconi, Francesco Bonì, Alice Parodi, Annalisa Salis, Bruno Tasso, Eloise Mastrangelo, Enrico Millo and Federica Cossu

Molecules 2023, 28(1), 446; https://doi.org/10.3390/molecules28010446 - 03 Jan 2023

Viewed by 2036

Abstract

Inhibitor of Apoptosis Proteins (IAPs) are validated targets for cancer therapy, and the deregulation of their activities within the NF-κB pathway correlates with chemoresistance events, even after treatment with IAPs-antagonists in the clinic (Smac-mimetics). The molecule FC2 was identified as a NF-κB pathway [...] Read more.

Inhibitor of Apoptosis Proteins (IAPs) are validated targets for cancer therapy, and the deregulation of their activities within the NF-κB pathway correlates with chemoresistance events, even after treatment with IAPs-antagonists in the clinic (Smac-mimetics). The molecule FC2 was identified as a NF-κB pathway modulator in MDA-MB-231 adenocarcinoma cancer cells after virtual screening of the Chembridge library against the Baculoviral IAP Repeat 1 (BIR1) domain of cIAP2 and XIAP. An improved cytotoxic effect is observed when FC2 is combined with Smac-mimetics or with the cytokine Tumor Necrosis Factor (TNF). Here, we propose a library of 22 derivatives of FC2, whose scaffold was rationally modified starting from the position identified as R₁. The cytotoxic effect of FC2 derivatives was evaluated in MDA-MB-231 and binding to the cIAP2- and XIAP-BIR1 domains was assessed in fluorescence-based techniques and virtual docking. Among 22 derivatives, 4m and 4p display improved efficacy/potency in MDA-MB-231 cells and low micromolar binding affinity vs the target proteins. Two additional candidates (4b and 4u) display promising cytotoxic effects in combination with TNF, suggesting the connection between this class of molecules and the NF-κB pathway. These results provide the rationale for further FC2 modifications and the design of novel IAP-targeting candidates supporting known therapies. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Graphical abstract

18 pages, 5160 KiB

Open AccessArticle

Dual Topoisomerase I/II Inhibition-Induced Apoptosis and Necro-Apoptosis in Cancer Cells by a Novel Ciprofloxacin Derivative via RIPK1/RIPK3/MLKL Activation

by Rania Alaaeldin, Islam M. Abdel-Rahman, Fares E. M. Ali, Amany Abdlrehim Bekhit, Eyad Y. Elhamadany, Qing-Li Zhao, Zheng-Guo Cui and Moustafa Fathy

Molecules 2022, 27(22), 7993; https://doi.org/10.3390/molecules27227993 - 17 Nov 2022

Cited by 9 | Viewed by 2125

Abstract

Fluoroquinolones (FQs) are synthetic broad-spectrum antimicrobial agents that have been recently repurposed to anticancer candidates. Designing new derivatives of FQs with different moieties to target DNA topoisomerases could improve their anticancer efficacy. The present study aimed to synthesize a novel ciprofloxacin derivative, examine [...] Read more.

Fluoroquinolones (FQs) are synthetic broad-spectrum antimicrobial agents that have been recently repurposed to anticancer candidates. Designing new derivatives of FQs with different moieties to target DNA topoisomerases could improve their anticancer efficacy. The present study aimed to synthesize a novel ciprofloxacin derivative, examine its anticancer activity against HepG2 and A549 cancer cells, and investigate the possible molecular mechanism underlying this activity by examining its ability to inhibit the topo I/II activity and to induce the apoptotic and necro-apoptotic pathways. Molecular docking, cell viability, cell migration, colony formation, cell cycle, Annexin V, lactate dehydrogenase (LDH) release, ELISA, and western blotting assays were utilized. Molecular docking results showed that this novel ciprofloxacin derivative exerted dual topo I and topo II binding and inhibition. It significantly inhibited the proliferation of A549 and HepG2 cancer cells and decreased their cell migration and colony formation abilities. In addition, it significantly increased the % of apoptotic cells, caused cell cycle arrest at G2/M phase, and elevated the LDH release levels in both cancer cells. Furthermore, it increased the expression of cleaved caspase 3, RIPK1, RIPK3, and MLKL proteins. This novel ciprofloxacin derivative exerted substantial dual inhibition of topo I/II enzyme activities, showed antiproliferative activity, suppressed the cell migration and colony formation abilities for A549 and HepG2 cancer cells and activated the apoptotic pathway. In addition, it initiated another backup deadly pathway, necro-apoptosis, through the activation of the RIPK1/RIPK3/MLKL pathway. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Figure 1

19 pages, 4526 KiB

Open AccessArticle

Inhibition of NF-kB/IL-6/JAK2/STAT3 Pathway and Epithelial-Mesenchymal Transition in Breast Cancer Cells by Azilsartan

by Rania Alaaeldin, Fares E. M. Ali, Amany Abdlrehim Bekhit, Qing-Li Zhao and Moustafa Fathy

Molecules 2022, 27(22), 7825; https://doi.org/10.3390/molecules27227825 - 13 Nov 2022

Cited by 16 | Viewed by 2340

Abstract

Metastatic breast cancer is an incurable form of breast cancer that exhibits high levels of epithelial-mesenchymal transition (EMT) markers. Angiotensin II has been linked to various signaling pathways involved in tumor cell growth and metastasis. The aim of this study is to investigate, [...] Read more.

Metastatic breast cancer is an incurable form of breast cancer that exhibits high levels of epithelial-mesenchymal transition (EMT) markers. Angiotensin II has been linked to various signaling pathways involved in tumor cell growth and metastasis. The aim of this study is to investigate, for the first time, the anti-proliferative activity of azilsartan, an angiotensin II receptor blocker, against breast cancer cell lines MCF-7 and MDA-MB-231 at the molecular level. Cell viability, cell cycle, apoptosis, colony formation, and cell migration assays were performed. RT-PCR and western blotting analysis were used to explain the molecular mechanism. Azilsartan significantly decreased the cancer cells survival, induced apoptosis and cell cycle arrest, and inhibited colony formation and cell migration abilities. Furthermore, azilsartan reduced the mRNA levels of NF-kB, TWIST, SNAIL, SLUG and bcl2, and increased the mRNA level of bax. Additionally, azilsartan inhibited the expression of IL-6, JAK2, STAT3, MMP9 and bcl2 proteins, and increased the expression of bax, c-PARP and cleaved caspase 3 protein. Interestingly, it reduced the in vivo metastatic capacity of MDA-MBA-231 breast cancer cells. In conclusion, the present study revealed, for the first time, the anti-proliferative, apoptotic, anti-migration and EMT inhibition activities of azilsartan against breast cancer cells through modulating NF-kB/IL-6/JAK2/STAT3/MMP9, TWIST/SNAIL/SLUG and apoptosis signaling pathways. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Figure 1

27 pages, 8214 KiB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of Novel Dihydropyridine and Pyridine Analogs as Potent Human Tissue Nonspecific Alkaline Phosphatase Inhibitors with Anticancer Activity: ROS and DNA Damage-Induced Apoptosis

by Nazeer Ahmad Khan, Faisal Rashid, Muhammad Siraj Khan Jadoon, Saquib Jalil, Zulfiqar Ali Khan, Raha Orfali, Shagufta Perveen, Areej Al-Taweel, Jamshed Iqbal and Sohail Anjum Shahzad

Molecules 2022, 27(19), 6235; https://doi.org/10.3390/molecules27196235 - 22 Sep 2022

Cited by 5 | Viewed by 1763

Abstract

Small molecules with nitrogen-containing scaffolds have gained much attention due to their biological importance in the development of new anticancer agents. The present paper reports the synthesis of a library of new dihydropyridine and pyridine analogs with diverse pharmacophores. All compounds were tested [...] Read more.

Small molecules with nitrogen-containing scaffolds have gained much attention due to their biological importance in the development of new anticancer agents. The present paper reports the synthesis of a library of new dihydropyridine and pyridine analogs with diverse pharmacophores. All compounds were tested against the human tissue nonspecific alkaline phosphatase (h-TNAP) enzyme. Most of the compounds showed excellent enzyme inhibition against h-TNAP, having IC₅₀ values ranging from 0.49 ± 0.025 to 8.8 ± 0.53 µM, which is multi-fold higher than that of the standard inhibitor (levamisole = 22.65 ± 1.60 µM) of the h-TNAP enzyme. Furthermore, an MTT assay was carried out to evaluate cytotoxicity against the HeLa and MCF-7 cancer cell lines. Among the analogs, the most potent dihydropyridine-based compound 4d was selected to investigate pro-apoptotic behavior. The further analysis demonstrated that compound 4d played a significant role in inducing apoptosis through multiple mechanisms, including overproduction of reactive oxygen species, mitochondrial dysfunction, DNA damaging, and arrest of the cell cycle at the G1 phase by inhibiting CDK4/6. The apoptosis-inducing effect of compound 4d was studied through staining agents, microscopic, and flow cytometry techniques. Detailed structure–activity relationship (SAR) and molecular docking studies were carried out to identify the core structural features responsible for inhibiting the enzymatic activity of the h-TNAP enzyme. Moreover, fluorescence emission studies corroborated the binding interaction of compound 4d with DNA through a fluorescence titration experiment. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Graphical abstract

21 pages, 9594 KiB

Open AccessArticle

Halogenated Flavonoid Derivatives Display Antiangiogenic Activity

by Mai Khater, Kimberly A. Watson, Samuel Y. Boateng, Francesca Greco and Helen M. I. Osborn

Molecules 2022, 27(15), 4757; https://doi.org/10.3390/molecules27154757 - 25 Jul 2022

Cited by 3 | Viewed by 1691

Abstract

Antiangiogenic agents attenuate tumours’ growth and metastases and are therefore beneficial as an adjuvant or standalone cancer regimen. Drugs with dual antiproliferative and antiangiogenic activities can achieve anticancer efficacy and overcome acquired resistance. In this study, synthetic flavones (5a,b) [...] Read more.

Antiangiogenic agents attenuate tumours’ growth and metastases and are therefore beneficial as an adjuvant or standalone cancer regimen. Drugs with dual antiproliferative and antiangiogenic activities can achieve anticancer efficacy and overcome acquired resistance. In this study, synthetic flavones (5a,b) with reported anticancer activity, and derivatives (4b and 6a), exhibited significant inhibition of endothelial cell tube formation (40–55%, 12 h) at 1 µM, which is comparable to sunitinib (50% inhibition at 1 µM, 48 h). Flavones (4b, 5a,b and 6a) also showed 25–37% reduction in HUVECs migration at 10 µM. In a Western blotting assay, 5a and 5b subdued VEGFR2 phosphorylation by 37% and 57%, respectively, suggesting that VEGFR2 may be their main antiangiogenic target. 5b displayed the best docking fit with VEGFR2 in an in silico study, followed by 5a, emphasizing the importance of the 7-hydroxyl group accompanied by a 4−C=S for activity. Conversely, derivatives with a 4-carbonyl moiety fitted poorly into the target’s binding pocket, suggesting that their antiangiogenic activity depends on a different target. This study provides valuable insight into the Structure Activity Relationships (SAR) and modes of action of halogenated flavones with VEGFR2 and highlights their therapeutic potential as antiangiogenic/anticancer lead compounds. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Figure 1

26 pages, 2021 KiB

Open AccessArticle

α-Hydroxylactams as Efficient Entries to Diversely Functionalized Ferrociphenols: Synthesis and Antiproliferative Activity Studies

by Pascal Pigeon, Marie Gaschard, Mohamed Othman, Michèle Salmain and Gérard Jaouen

Molecules 2022, 27(14), 4549; https://doi.org/10.3390/molecules27144549 - 16 Jul 2022

Cited by 3 | Viewed by 1580

Abstract

The [ferrocene-ene-phenol] motif has been identified as the pharmacophore responsible for the anticancer activity of the family of ferrocene-based molecules coined ferrocifens, owing to its unique redox properties. The addition of imide entities to the historical ferrociphenol scaffold tremendously enhanced the cytotoxic activity [...] Read more.

The [ferrocene-ene-phenol] motif has been identified as the pharmacophore responsible for the anticancer activity of the family of ferrocene-based molecules coined ferrocifens, owing to its unique redox properties. The addition of imide entities to the historical ferrociphenol scaffold tremendously enhanced the cytotoxic activity of a large panel of cancer cell cultures and preliminary studies showed that the reduction of one of the carbonyl groups of the imide groups to the corresponding α-hydroxylactams only slightly affected the antiproliferative activity. As a continuation to these studies, we took advantage of the facile conversion of α-hydroxylactams to highly electrophilic N-acyliminium ions to graft various substituents to the imide motif of phthalimido ferrocidiphenol. Cell viability studies showed that the newly synthesized compounds showed diverse cytotoxic activities on two breast cancer cell lines, while only one compound was significantly less active on the non-tumorigenic cell line hTERT-RPE1. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Figure 1

15 pages, 2359 KiB

Open AccessArticle

Antioxidant Properties and Aldehyde Reactivity of PD-L1 Targeted Aryl-Pyrazolone Anticancer Agents

by Natascha Leleu-Chavain, Romain Regnault, Hania Ahouari, Raphaël Le Biannic, Mostafa Kouach, Frédérique Klupsch, Romain Magnez, Hervé Vezin, Xavier Thuru, Christian Bailly, Jean-François Goossens and Régis Millet

Molecules 2022, 27(10), 3316; https://doi.org/10.3390/molecules27103316 - 21 May 2022

Cited by 3 | Viewed by 1872

Abstract

Small molecules targeting the PD-1/PD-L1 checkpoint are actively searched to complement the anticancer arsenal. Different molecular scaffolds have been reported, including phenyl-pyrazolone derivatives which potently inhibit binding of PD-L1 to PD-1. These molecules are structurally close to antioxidant drug edaravone (EDA) used to [...] Read more.

Small molecules targeting the PD-1/PD-L1 checkpoint are actively searched to complement the anticancer arsenal. Different molecular scaffolds have been reported, including phenyl-pyrazolone derivatives which potently inhibit binding of PD-L1 to PD-1. These molecules are structurally close to antioxidant drug edaravone (EDA) used to treat amyotrophic lateral sclerosis. For this reason, we investigated the capacity of five PD-L1-binding phenyl-pyrazolone compounds (1–5) to scavenge the formation of oxygen free radicals using electron spin resonance spectroscopy with DPPH/DMPO probes. In addition, the reactivity of the compounds toward the oxidized base 5-formyluracil (5fU) was assessed using chromatography coupled to mass spectrometry and photodiode array detectors. The data revealed that the phenyl-pyrazolone derivatives display antioxidant properties and exhibit a variable reactivity toward 5fU. Compound 2 with a N-dichlorophenyl-pyrazolone moiety cumulates the three properties, being a potent PD-L1 binder, a robust antioxidant and an aldehyde-reactive compound. On the opposite, the adamantane derivative 5 is a potent PD-L1 binding with a reduced antioxidant potential and no aldehyde reactivity. The nature of the substituent on the phenyl-pyrazolone core modulates the antioxidant capacity and reactivity toward aromatic aldehydes. The molecular signature of the compound can be adapted at will, to confer additional properties to these PD-L1 binders. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Graphical abstract

17 pages, 3724 KiB

Open AccessArticle

nurP28, a New-to-Nature Zein-Derived Peptide, Enhances the Therapeutic Effect of Docetaxel in Breast Cancer Monolayers and Spheroids

by Plinio Alejandro Trinidad-Calderón, Laura Margarita López-Castillo, Salvador Gallegos-Martínez, Grissel Trujillo-de Santiago, Silverio García-Lara and Mario Moisés Álvarez

Molecules 2022, 27(9), 2824; https://doi.org/10.3390/molecules27092824 - 29 Apr 2022

Cited by 6 | Viewed by 2645

Abstract

The development of novel cancer therapeutic strategies has garnered increasing interest in cancer research. Among the therapeutic choices, chemosensitizers have shown exciting prospects. Peptides are an attractive alternative among the molecules that may be used as chemosensitizers. We rationally designed a new-to-nature peptide, [...] Read more.

The development of novel cancer therapeutic strategies has garnered increasing interest in cancer research. Among the therapeutic choices, chemosensitizers have shown exciting prospects. Peptides are an attractive alternative among the molecules that may be used as chemosensitizers. We rationally designed a new-to-nature peptide, nurP28, derived from the 22-kDa α-zein protein sequence (entry Q00919_MAIZE). The resultant sequence of the nurP28 peptide after the addition of arginine residues was LALLALLRLRRRATTAFIIP, and we added acetyl and amide groups at the N- and C-terminus, respectively, for capping. We evaluated the cytotoxicity of the nurP28 peptide alone and in combination with docetaxel in fibroblast monolayers and breast cancer monolayers and spheroids. Our results indicated that nurP28 is not cytotoxic to human fibroblasts or cancer cells. Nevertheless, when combined with 1 µM docetaxel, 3 ng/mL nurP28 induced equivalent (in MCF7 monolayers) and higher (in MCF7 spheroids) cytotoxic effects than 10-fold higher doses of docetaxel alone. These findings suggest that nurP28 may act as a chemosensitizer in breast cancer treatment. This study describes the enhancing “anti-cancer” effects of nurP28 in breast cancer 2D and 3D cultures treated with docetaxel. Further studies should explore the mechanisms underlying these effects and assess the clinical potential of our findings using animal models. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Graphical abstract

15 pages, 2143 KiB

Open AccessArticle

The Polyphenols α-Mangostin and Nordihydroguaiaretic Acid Induce Oxidative Stress, Cell Cycle Arrest, and Apoptosis in a Cellular Model of Medulloblastoma

by Alberto Rojas-Ochoa, Emilio J. Córdova, Adela Carrillo-García, Marcela Lizano, José Pedraza-Chaverri, Nelly Patiño, Alfredo Cruz-Gregorio and Norma Osnaya

Molecules 2021, 26(23), 7230; https://doi.org/10.3390/molecules26237230 - 29 Nov 2021

Cited by 4 | Viewed by 1671

Abstract

Medulloblastoma is a common malignant brain tumor in the pediatric age. The current therapeutics present serious collateral effects. Polyphenols

α

-mangostin and nordihydroguaiaretic acid (NDGA) exert potent antitumoral activity in different cancer models, although their antitumoral effects have not been described in medulloblastoma [...] Read more.

Medulloblastoma is a common malignant brain tumor in the pediatric age. The current therapeutics present serious collateral effects. Polyphenols

α

-mangostin and nordihydroguaiaretic acid (NDGA) exert potent antitumoral activity in different cancer models, although their antitumoral effects have not been described in medulloblastoma cells yet. This study aimed to examine the proapoptotic effects of these polyphenols on human medulloblastoma cells. Medulloblastoma cell line Daoy was incubated with increasing concentrations of

α

-mangostin or NDGA for 24 h. The cell viability was analyzed using crystal violet and trypan blue dyes. Determination of the glutathione (GSH)/glutathione disulfide (GSSG) ratio and levels of carbonylated proteins was performed to evaluate the oxidative stress. Cell cycle progression and induction of cell death by fluorochrome-couple and TUNEL assays were evaluated using flow cytometry assays. Individual treatments with

α

-mangostin or NDGA decreased the viability of Daoy cells in a dose-dependent manner, inducing G2/M and S-G2/M cell cycle arrest, respectively. Both polyphenols induced cell death and increased oxidative stress. Very interestingly,

α

-mangostin showed more potent effects than NDGA. Our results indicate that

α

-mangostin and NDGA exert important cytostatic and cytotoxic effects in the Daoy cell line. These data highlight the potential usefulness of these compounds as an alternative strategy in medulloblastoma treatment. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Figure 1

18 pages, 2663 KiB

Open AccessArticle

New Series of Pyrazoles and Imidazo-Pyrazoles Targeting Different Cancer and Inflammation Pathways

by Maria Grazia Signorello, Federica Rapetti, Elda Meta, Adama Sidibè, Olga Bruno and Chiara Brullo

Molecules 2021, 26(19), 5735; https://doi.org/10.3390/molecules26195735 - 22 Sep 2021

Cited by 7 | Viewed by 1591

Abstract

(1) Background: different previously synthesized pyrazoles and imidazo-pyrazoles showed interesting anti-angiogenic action, being able to interfere with ERK1/2, AKT and p38MAPK phosphorylation in different manners and with different potency; (2) Methods: here, a new small compound library, endowed with the same differently decorated [...] Read more.

(1) Background: different previously synthesized pyrazoles and imidazo-pyrazoles showed interesting anti-angiogenic action, being able to interfere with ERK1/2, AKT and p38MAPK phosphorylation in different manners and with different potency; (2) Methods: here, a new small compound library, endowed with the same differently decorated chemical scaffolds, has been synthetized to obtain new agents able to inhibit different pathways involved in inflammation, cancer and human platelet aggregation. (3) Results: most of the new synthesized derivatives resulted able to block ROS production, platelet aggregation and p38MAPK phosphorylation both in platelets and Human Umbilical Vein Endothelial cells (HUVEC). This paves the way for the development of new agents with anti-angiogenic activity. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Graphical abstract

16 pages, 3615 KiB

Open AccessArticle

The Mitochondria-Independent Cytotoxic Effect of Leflunomide on RPMI-8226 Multiple Myeloma Cell Line

by Grzegorz Adamczuk, Ewelina Humeniuk, Magdalena Iwan, Dorota Natorska-Chomicka, Kamila Adamczuk and Agnieszka Korga-Plewko

Molecules 2021, 26(18), 5653; https://doi.org/10.3390/molecules26185653 - 17 Sep 2021

Cited by 2 | Viewed by 2330

Abstract

Leflunomide, an anti-inflammatory agent, has been shown to be effective in multiple myeloma (MM) treatment; however, the mechanism of this phenomenon has not been fully elucidated. The aim of the study was to assess the role of mitochondria and dihydroorotate dehydrogenase (DHODH) inhibition [...] Read more.

Leflunomide, an anti-inflammatory agent, has been shown to be effective in multiple myeloma (MM) treatment; however, the mechanism of this phenomenon has not been fully elucidated. The aim of the study was to assess the role of mitochondria and dihydroorotate dehydrogenase (DHODH) inhibition in the cytotoxicity of leflunomide in relation to the MM cell line RPMI 8226. The cytotoxic effect of teriflunomide—an active metabolite of leflunomide—was determined using MTT assay, apoptosis detection, and cell cycle analysis. To evaluate DHODH-dependent toxicity, the cultures treated with teriflunomide were supplemented with uridine. Additionally, the level of cellular thiols as oxidative stress symptom was measured as well as mitochondrial membrane potential and protein tyrosine kinases (PTK) activity. The localization of the compound in cell compartments was examined using HPLC method. Teriflunomide cytotoxicity was not abolished in uridine presence. Observed apoptosis occurred in a mitochondria-independent manner, there was also no decrease in cellular thiols level. Teriflunomide arrested cell cycle in the G2/M phase which is not typical for DHODH deficiency. PTK activity was decreased only at the highest drug concentration. Interestingly, teriflunomide was not detected in the mitochondria. The aforementioned results indicate DHODH- and mitochondria-independent mechanism of leflunomide toxicity against RPMI 8226 cell line. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Figure 1

11 pages, 1455 KiB

Open AccessArticle

KRIBB11 Induces Apoptosis in A172 Glioblastoma Cells via MULE-Dependent Degradation of MCL-1

by Kyunghyun Yoo, Hye-Hyeon Yun, Soon-Young Jung and Jeong-Hwa Lee

Molecules 2021, 26(14), 4165; https://doi.org/10.3390/molecules26144165 - 08 Jul 2021

Cited by 4 | Viewed by 2044

Abstract

KRIBB11, an HSF1 inhibitor, was shown to sensitize various types of cancer cells to treatment with several anticancer drugs. However, the exclusive effects of KRIBB11 in preventing the growth of glioblastoma cells and the related mechanisms have not been elucidated yet. Herein, we [...] Read more.

KRIBB11, an HSF1 inhibitor, was shown to sensitize various types of cancer cells to treatment with several anticancer drugs. However, the exclusive effects of KRIBB11 in preventing the growth of glioblastoma cells and the related mechanisms have not been elucidated yet. Herein, we aimed to examine the potential of KRIBB11 as an anticancer agent for glioblastoma. Using MTT and colony formation assays and Western blotting for c-PARP, we demonstrated that KRIBB11 substantially inhibits the growth of A172 glioma cells by inducing apoptosis. At the molecular level, KRIBB11 decreased anti-apoptotic protein MCL-1 levels, which was attributable to the increase in MULE ubiquitin ligase levels. However, the constitutive activity of HSF1 in A172 cells was not influenced by the exclusive treatment with KRIBB11. Additionally, based on cycloheximide chase assay, we found that KRIBB11 markedly retarded the degradation of MULE. In conclusion, stabilization of MULE upon KRIBB11 treatment is apparently an essential step for degradation of MCL-1 and the subsequent induction of apoptosis in A172 cells. Our results have expanded the knowledge on molecular pathways controlled by KRIBB11 and could be potentially effective for developing an inhibitory therapeutic strategy for glioblastoma. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Figure 1

16 pages, 4317 KiB

Open AccessArticle

Synthesis, Biomacromolecular Interactions, Photodynamic NO Releasing and Cellular Imaging of Two [RuCl(qn)(Lbpy)(NO)]X Complexes

by Luna Song, Hehe Bai, Chenyang Liu, Wenjun Gong, Ai Wang, Li Wang, Yi Zhao, Xuan Zhao and Hongfei Wang

Molecules 2021, 26(9), 2545; https://doi.org/10.3390/molecules26092545 - 27 Apr 2021

Cited by 5 | Viewed by 1709

Abstract

Two light-activated NO donors [RuCl(qn)(Lbpy)(NO)]X with 8-hydroxyquinoline (qn) and 2,2′-bipyridine derivatives (Lbpy) as co-ligands were synthesized (Lbpy₁ = 4,4′-dicarboxyl-2,2′-dipyridine, X = Cl⁻ and Lbpy₂ = 4,4′-dimethoxycarbonyl-2,2′-dipyridine, X = NO₃⁻), and characterized using ultraviolet–visible (UV-vis) spectroscopy, Fourier transform [...] Read more.

Two light-activated NO donors [RuCl(qn)(Lbpy)(NO)]X with 8-hydroxyquinoline (qn) and 2,2′-bipyridine derivatives (Lbpy) as co-ligands were synthesized (Lbpy₁ = 4,4′-dicarboxyl-2,2′-dipyridine, X = Cl⁻ and Lbpy₂ = 4,4′-dimethoxycarbonyl-2,2′-dipyridine, X = NO₃⁻), and characterized using ultraviolet–visible (UV-vis) spectroscopy, Fourier transform infrared (FT-IR) spectroscopy, nuclear magnetic resonance (¹H NMR), elemental analysis and electrospray ionization mass spectrometry (ESI-MS) spectra. The [RuCl(qn)(Lbpy₂)(NO)]NO₃ complex was crystallized and exhibited distorted octahedral geometry, in which the Ru–N(O) bond length was 1.752(6) Å and the Ru–N–O angle was 177.6(6)°. Time-resolved FT-IR and electron paramagnetic resonance (EPR) spectra were used to confirm the photoactivated NO release of the complexes. The binding constant (K_b) of two complexes with human serum albumin (HSA) and DNA were quantitatively evaluated using fluorescence spectroscopy, Ru-Lbpy₁ (K_b~10⁶ with HSA and ~10⁴ with DNA) had higher affinity than Ru-Lbpy₂. The interactions between the complexes and HSA were investigated using matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS) and EPR spectra. HSA can be used as a carrier to facilitate the release of NO from the complexes upon photoirradiation. The confocal imaging of photo-induced NO release in living cells was successfully observed with a fluorescent NO probe. Moreover, the photocleavage of pBR322 DNA for the complexes and the effect of different Lbpy substituted groups in the complexes on their reactivity were analyzed. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Graphical abstract

17 pages, 5199 KiB

Open AccessFeature PaperArticle

Adlay Testa (Coix lachryma-jobi L. var. Ma-yuen Stapf.) Ethanolic Extract and Its Active Components Exert Anti-Proliferative Effects on Endometrial Cancer Cells via Cell Cycle Arrest

by Yun-Ju Huang, Chih-Chao Chang, Yun-Ya Wang, Wen-Chang Chiang, Yin-Hwa Shih, Tzong-Ming Shieh, Kai-Lee Wang, Mohamed Ali and Shih-Min Hsia

Molecules 2021, 26(7), 1966; https://doi.org/10.3390/molecules26071966 - 31 Mar 2021

Cited by 11 | Viewed by 2855

Abstract

Endometrial cancer is the most common malignant tumors of gynecologic neoplasms in Western society. In recent years, the incidence of endometrial cancer has increased, and it has become the third most common female gynecological cancer (after ovarian and cervical cancer) in Taiwan. Adlay [...] Read more.

Endometrial cancer is the most common malignant tumors of gynecologic neoplasms in Western society. In recent years, the incidence of endometrial cancer has increased, and it has become the third most common female gynecological cancer (after ovarian and cervical cancer) in Taiwan. Adlay (Coix lachryma-jobi L. var. Ma-yuen Stapf.) has been demonstrated to have bioactive polyphenols, flavonoids, phytosterols, and essential nutrients for health benefits, including anticancer effects in humans. However, little is known about the effect of adlay seeds on endometrial cancer. Our study aimed to investigate the potential growth inhibitory effects of several adlay seed fractions, including ethyl acetate (ATE-EA) and its bioactive constituents, separately on endometrial cancer cells—HEC-1A (phosphatase and tensin homolog-positive) and RL95-2 (phosphatase and tensin homolog-negative)—and identify related active ingredients. In addition, the potential active fractions and the phytochemical compounds were elucidated. The results demonstrate superior activity of ATE-EA with significant in vitro cell proliferation inhibitory capacity, particularly its C.D.E.F-subfraction. Moreover, HPLC- and GC/FID-based quantification of ATE-EA subfractions showed that phenolic compounds (caffeic acid, protocatechuic acid, and p-hydroxybenzaldehyde), flavonoids, steroids, and fatty acid compounds exert anti-proliferative effects in the cell model. Finally, it was shown that cell growth and cell cycle arrest most significantly occurred in the in G1 or G2/M phase under ATE-EA treatment. Collectively, our results demonstrate an antiproliferative effect of ATE-EA on endometrial cancer cells that suggest a positive health outcome for women from consumption of these compounds. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Figure 1

14 pages, 2121 KiB

Open AccessArticle

Bicyclic Basic Merbarone Analogues as Antiproliferative Agents

by Andrea Spallarossa, Matteo Lusardi, Chiara Caneva, Aldo Profumo, Camillo Rosano and Marco Ponassi

Molecules 2021, 26(3), 557; https://doi.org/10.3390/molecules26030557 - 21 Jan 2021

Cited by 1 | Viewed by 1778

Abstract

Pyrimido-pyrimidine derivatives have been developed as rigid merbarone analogues. In a previous study, these compounds showed potent antiproliferative activity and efficiently inhibited topoisomerase IIα. To further extend the structure–activity relationships on pyrimido-pyrimidines, a novel series of analogues was synthesized by a two-step procedure. [...] Read more.

Pyrimido-pyrimidine derivatives have been developed as rigid merbarone analogues. In a previous study, these compounds showed potent antiproliferative activity and efficiently inhibited topoisomerase IIα. To further extend the structure–activity relationships on pyrimido-pyrimidines, a novel series of analogues was synthesized by a two-step procedure. Analogues 3–6 bear small alky groups at positions 1 and 3 of the pyrimido-pyrimidine scaffold whereas at position 6a (4-chloro)phenyl substituent was inserted. The basic side chains introduced at position 7 were selected on the basis of the previously developed structure–activity relationships. The antiproliferative activity of the novel compounds proved to be affected by both the nature of the basic side chain and the substituents on the pyrimido-pyrimidine moiety. Derivatives 5d and 5e were identified as the most promising molecules still showing reduced antiproliferative activity in comparison with the previously prepared pyrimido-pyrimidine analogues. In topoisomerase IIα-5d docking complex, the ligand would poorly interact with the enzyme and assume a different orientation in comparison with 1d bioactive conformation. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Figure 1

26 pages, 13971 KiB

Open AccessArticle

Galeon: A Biologically Active Molecule with In Silico Metabolite Prediction, In Vitro Metabolic Profiling in Rat Liver Microsomes, and In Silico Binding Mechanisms with CYP450 Isoforms

by A. F. M. Motiur Rahman, Wencui Yin, Adnan A. Kadi and Yurngdong Jahng

Molecules 2020, 25(24), 5903; https://doi.org/10.3390/molecules25245903 - 13 Dec 2020

Cited by 1 | Viewed by 2618

Abstract

Galeon, a natural cyclic-diarylheptanoid (CDH), which was first isolated from Myrica gale L., is known to have potent cytotoxicity against A549 cell lines, anti-tubercular activity against Mycobacterium tuberculosis H37Rv, chemo-preventive potential, and moderate topoisomerase inhibitory activity. Here, in silico metabolism and toxicity prediction [...] Read more.

Galeon, a natural cyclic-diarylheptanoid (CDH), which was first isolated from Myrica gale L., is known to have potent cytotoxicity against A549 cell lines, anti-tubercular activity against Mycobacterium tuberculosis H37Rv, chemo-preventive potential, and moderate topoisomerase inhibitory activity. Here, in silico metabolism and toxicity prediction of galeon by CYP450, in vitro metabolic profiling study in rat liver microsomes (RLMs), and molecular interactions of galeon-CYP450 isoforms were performed. An in silico metabolic prediction study showed demethyl and mono-hydroxy galeon were the metabolites with the highest predictability. Among the predicted metabolites, mono-hydroxy galeon was found to have plausible toxicities such as skin sensitization, thyroid toxicity, chromosome damage, and carcinogenicity. An in vitro metabolism study of galeon, incubated in RLMs, revealed eighteen Phase-I metabolites, nine methoxylamine, and three glutathione conjugates. Identification of possible metabolites and confirmation of their structures were carried out using ion-trap tandem mass spectrometry. In silico docking analysis of galeon demonstrated significant interactions with active site residues of almost all CYP450 isoforms. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Figure 1

15 pages, 3277 KiB

Open AccessArticle

Development of a Bestatin-SAHA Hybrid with Dual Inhibitory Activity against APN and HDAC

by Jiangying Cao, Wei Zhao, Chunlong Zhao, Qian Liu, Shunda Li, Guozhen Zhang, C. James Chou and Yingjie Zhang

Molecules 2020, 25(21), 4991; https://doi.org/10.3390/molecules25214991 - 28 Oct 2020

Cited by 16 | Viewed by 3355

Abstract

With five histone deacetylase (HDAC) inhibitors approved for cancer treatment, proteolysis-targeting chimeras (PROTACs) for degradation of HDAC are emerging as an alternative strategy for HDAC-targeted therapeutic intervention. Herein, three bestatin-based hydroxamic acids (P1, P2 and P3) were designed, synthesized and [...] Read more.

With five histone deacetylase (HDAC) inhibitors approved for cancer treatment, proteolysis-targeting chimeras (PROTACs) for degradation of HDAC are emerging as an alternative strategy for HDAC-targeted therapeutic intervention. Herein, three bestatin-based hydroxamic acids (P1, P2 and P3) were designed, synthesized and biologically evaluated to see if they could work as HDAC degrader by recruiting cellular inhibitor of apoptosis protein 1 (cIAP1) E3 ubiquitin ligase. Among the three compounds, the bestatin-SAHA hybrid P1 exhibited comparable even more potent inhibitory activity against HDAC1, HDAC6 and HDAC8 relative to the approved HDAC inhibitor SAHA. It is worth noting that although P1 could not lead to intracellular HDAC degradation after 6 h of treatment, it could dramatically decrease the intracellular levels of HDAC1, HDAC6 and HDAC8 after 24 h of treatment. Intriguingly, the similar phenomenon was also observed in the HDAC inhibitor SAHA. Cotreatment with proteasome inhibitor bortezomib could not reverse the HDAC decreasing effects of P1 and SAHA, confirming that their HDAC decreasing effects were not due to protein degradation. Moreover, all three bestatin-based hydroxamic acids P1, P2 and P3 exhibited more potent aminopeptidase N (APN, CD13) inhibitory activities than the approved APN inhibitor bestatin, which translated to their superior anti-angiogenic activities. Taken together, a novel bestatin-SAHA hybrid was developed, which worked as a potent APN and HDAC dual inhibitor instead of a PROTAC. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Figure 1

12 pages, 21664 KiB

Open AccessArticle

Antitumor Activity and Mechanism of Robustic Acid from Dalbergia benthami Prain via Computational Target Fishing

by Juanjuan Huang, Ying Liang, Wenyu Tian, Jing Ma, Ling Huang, Benjie Li, Rui Chen and Dianpeng Li

Molecules 2020, 25(17), 3919; https://doi.org/10.3390/molecules25173919 - 27 Aug 2020

Cited by 8 | Viewed by 2700

Abstract

Dalbergia benthami Prain (D.benthami) is an important legume species of the Dalbergia family, due to the use of its trunk and root heart in traditional Chinese medicine (TCM). In the present study, we reported the isolation, characterization and pharmacological activities [...] Read more.

Dalbergia benthami Prain (D.benthami) is an important legume species of the Dalbergia family, due to the use of its trunk and root heart in traditional Chinese medicine (TCM). In the present study, we reported the isolation, characterization and pharmacological activities of robustic acid (RA) from the ethyl acetate extract of D. benthami Prain. The SwissADME prediction showed that the RA satisfied the Lipinski’s rule of five (molecule weight (MW): 380.39 g/mol, lipid-water partition coefficient (log P): 3.72, hydrogen bond donors (Hdon): 1, hydrogen bond acceptors (Hacc): 6, rotatable bonds (Rbon): 3. Other chemical and pharmacological properties of this RA were also evaluated, including topological polar surface area (TPSA) = 78.13 Å and solubility (Log S) = −4.8. The probability values of the antineoplastic, anti-free radical activities and topoisomerase I (TopoI) inhibitory activity were found to be 0.784, 0.644 and 0.379, respectively. The molecular docking experiment using the Surflex-Dock showed that the Total Score and C Score of RNA binding with the human DNA-Topo I complex were 7.80 and 4. The MTS assay experiment showed that the inhibitory rates of RA on HL-60, MT4, Hela, HepG2, SK-OV-3 and MCF-7 cells were 37.37%, 97.41%, 81.22%, 34.4%, 32.68% and 51.4%, respectively. In addition, RA exhibited an inhibitory effect on the angiogenesis of zebrafish embryo, a good TopoI inhibitory activity at a 10 mM concentration and in a dose-dependent manner, excellent radical scavenging in the DPPH and ABTS assays, and the free radical scavenging rate was close to the positive control (BHT) at different concentrations (0.5–2.0 mg/mL). Furthermore, 18 potential targets were found for this RA by PharmMapper, including ANXA3, SRC, FGFR2, GSK3B, CSNK2B, YARS, LCK, EPHA2, MAPK14, RORA, CRABP2, PPP1CC, METAP2, MME, TTR, MET and KDR. The GO and KEGG pathway analysis revealed that the “protein tyrosine kinase activity”, “rap1 signaling pathway” and “PI3K-Akt signaling pathway” were significantly enriched by the RA target genes. Our results will provide new insights into the pharmaceutical use of this species. More importantly, our data will expand our understanding of the molecular mechanisms of RA functions. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Graphical abstract

9 pages, 552 KiB

Open AccessArticle

Synthesis and Biological Evaluation of Analogs of Didehydroepiandrosterone as Potential New Anticancer Agents

by Eirik J. Solum, Sandra Liekens and Trond Vidar Hansen

Molecules 2020, 25(13), 3052; https://doi.org/10.3390/molecules25133052 - 03 Jul 2020

Cited by 3 | Viewed by 2544

Abstract

The synthesis, cytotoxicity and inhibition of CDK8 by thirteen analogs of cortistatin A are reported. These efforts revealed that the analogs with either a 6- or 7-isoquinoline or 5-indole side chain in the 17-position are the most promising anti-proliferative agents. These compounds showed [...] Read more.

The synthesis, cytotoxicity and inhibition of CDK8 by thirteen analogs of cortistatin A are reported. These efforts revealed that the analogs with either a 6- or 7-isoquinoline or 5-indole side chain in the 17-position are the most promising anti-proliferative agents. These compounds showed potent cytotoxic effects in CEM, HeLa and HMEC-1 cells. All three compounds exhibited IC₅₀ values < 10µM. The most interesting 10l analog exhibited an IC₅₀ value of 0.59 µM towards the human dermal microvascular endothelial cell line (HMEC-1), significantly lower than the reference standard 2-methoxyestradiol. At a concentration at 50 nM the most potent 10h compound reduced the activity of CDK8 to 35%. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Graphical abstract

12 pages, 1443 KiB

Open AccessArticle

Effects of Pyrrole-Imidazole Polyamides Targeting Human TGF-β1 on the Malignant Phenotypes of Liver Cancer Cells

by Keiko Takagi, Yutaka Midorikawa, Tadatoshi Takayama, Hayato Abe, Kyoko Fujiwara, Masayoshi Soma, Hiroki Nagase, Toshio Miki and Noboru Fukuda

Molecules 2020, 25(12), 2883; https://doi.org/10.3390/molecules25122883 - 23 Jun 2020

Cited by 3 | Viewed by 2144

Abstract

Synthetic pyrrole-imidazole (PI) polyamides bind to the minor groove of double-helical DNA with high affinity and specificity, and inhibit the transcription of corresponding genes. In liver cancer, transforming growth factor (TGF)-β expression is correlated with tumor grade, and high-grade liver cancer tissues express [...] Read more.

Synthetic pyrrole-imidazole (PI) polyamides bind to the minor groove of double-helical DNA with high affinity and specificity, and inhibit the transcription of corresponding genes. In liver cancer, transforming growth factor (TGF)-β expression is correlated with tumor grade, and high-grade liver cancer tissues express epithelial-mesenchymal transition markers. TGF-β1 was reported to be involved in cancer development by transforming precancer cells to cancer stem cells (CSCs). This study aimed to evaluate the effects of TGF-β1-targeting PI polyamide on the growth of liver cancer cells and CSCs and their TGF-β1 expression. We analyzed TGF-β1 expression level after the administration of GB1101, a PI polyamide that targets human TGF-β1 promoter, and examined its effects on cell proliferation, invasiveness, and TGF-β1 mRNA expression level. GB1101 treatment dose-dependently decreased TGF-β1 mRNA levels in HepG2 and HLF cells, and inhibited HepG2 colony formation associated with downregulation of TGF-β1 mRNA. Although GB1101 did not substantially inhibit the proliferation of HepG2 cells compared to untreated control cells, GB1101 significantly suppressed the invasion of HLF cells, which displayed high expression of CD44, a marker for CSCs. Furthermore, GB1101 significantly inhibited HLF cell sphere formation by inhibiting TGF-β1 expression, in addition to suppressing the proliferation of HLE and HLF cells. Taken together, GB1101 reduced TGF-β1 expression in liver cancer cells and suppressed cell invasion; therefore, GB1101 is a novel candidate drug for the treatment of liver cancer. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Figure 1

17 pages, 3541 KiB

Open AccessArticle

Evaluation of the Anticancer Activities of Novel Transition Metal Complexes with Berenil and Nitroimidazole

by Robert Czarnomysy, Dominika Radomska, Anna Muszyńska, Justyna Magdalena Hermanowicz, Izabela Prokop, Anna Bielawska and Krzysztof Bielawski

Molecules 2020, 25(12), 2860; https://doi.org/10.3390/molecules25122860 - 21 Jun 2020

Cited by 18 | Viewed by 3248

Abstract

Novel transition metal complexes (Au, Pd, Pt) with berenil and 2-(1-methyl-5-nitroimidazol-2-yl)ethanol were obtained through two-step synthesis. The cytotoxicity assay against MCF-7 and MDA-MB-231 breast cancer cells revealed that novel platinum and palladium complexes cause a reduction on the viability of MCF-7 and MDA-MB-231 [...] Read more.

Novel transition metal complexes (Au, Pd, Pt) with berenil and 2-(1-methyl-5-nitroimidazol-2-yl)ethanol were obtained through two-step synthesis. The cytotoxicity assay against MCF-7 and MDA-MB-231 breast cancer cells revealed that novel platinum and palladium complexes cause a reduction on the viability of MCF-7 and MDA-MB-231 breast cancer cells to a greater extent than cisplatin. The complexes showed lower cytotoxicity on normal MCF-10A human breast epithelial cells than on tumor cells. Furthermore, we observed that these complexes selectively concentrate in tumor cell mitochondria due to the characteristic for these cells increased membrane potential that may explain their increased proapoptotic activity. The activity of the synthesized compounds against topoisomerase type IIα and their increased impact on DNA defragmentation also were documented. The novel complexes also induced autophagosome changes and inhibited tumor growth in xenograft models (established using breast cancer cells). Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Figure 1

Review

Jump to: Research

34 pages, 5616 KiB

Open AccessReview

Marine Cyanobacteria as Sources of Lead Anticancer Compounds: A Review of Families of Metabolites with Cytotoxic, Antiproliferative, and Antineoplastic Effects

by Benjamín Robles-Bañuelos, Lorena María Durán-Riveroll, Edgar Rangel-López, Hugo Isidro Pérez-López and Leticia González-Maya

Molecules 2022, 27(15), 4814; https://doi.org/10.3390/molecules27154814 - 27 Jul 2022

Cited by 13 | Viewed by 3274

Abstract

The marine environment is highly diverse, each living creature fighting to establish and proliferate. Among marine organisms, cyanobacteria are astounding secondary metabolite producers representing a wonderful source of biologically active molecules aimed to communicate, defend from predators, or compete. Studies on these molecules’ [...] Read more.

The marine environment is highly diverse, each living creature fighting to establish and proliferate. Among marine organisms, cyanobacteria are astounding secondary metabolite producers representing a wonderful source of biologically active molecules aimed to communicate, defend from predators, or compete. Studies on these molecules’ origins and activities have been systematic, although much is still to be discovered. Their broad chemical diversity results from integrating peptide and polyketide synthetases and synthases, along with cascades of biosynthetic transformations resulting in new chemical structures. Cyanobacteria are glycolipid, macrolide, peptide, and polyketide producers, and to date, hundreds of these molecules have been isolated and tested. Many of these compounds have demonstrated important bioactivities such as cytotoxicity, antineoplastic, and antiproliferative activity with potential pharmacological uses. Some are currently under clinical investigation. Additionally, conventional chemotherapeutic treatments include drugs with a well-known range of side effects, making anticancer drug research from new sources, such as marine cyanobacteria, necessary. This review is focused on the anticancer bioactivities of metabolites produced by marine cyanobacteria, emphasizing the identification of each variant of the metabolite family, their chemical structures, and the mechanisms of action underlying their biological and pharmacological activities. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Graphical abstract

48 pages, 20033 KiB

Open AccessReview

Synthetic and Naturally Occurring Heterocyclic Anticancer Compounds with Multiple Biological Targets

by Richard Kwamla Amewu, Patrick Opare Sakyi, Dorcas Osei-Safo and Ivan Addae-Mensah

Molecules 2021, 26(23), 7134; https://doi.org/10.3390/molecules26237134 - 25 Nov 2021

Cited by 15 | Viewed by 3615

Abstract

Cancer is a complex group of diseases initiated by abnormal cell division with the potential of spreading to other parts of the body. The advancement in the discoveries of omics and bio- and cheminformatics has led to the identification of drugs inhibiting putative [...] Read more.

Cancer is a complex group of diseases initiated by abnormal cell division with the potential of spreading to other parts of the body. The advancement in the discoveries of omics and bio- and cheminformatics has led to the identification of drugs inhibiting putative targets including vascular endothelial growth factor (VEGF) family receptors, fibroblast growth factors (FGF), platelet derived growth factors (PDGF), epidermal growth factor (EGF), thymidine phosphorylase (TP), and neuropeptide Y4 (NY4), amongst others. Drug resistance, systemic toxicity, and drug ineffectiveness for various cancer chemo-treatments are widespread. Due to this, efficient therapeutic agents targeting two or more of the putative targets in different cancer cells are proposed as cutting edge treatments. Heterocyclic compounds, both synthetic and natural products, have, however, contributed immensely to chemotherapeutics for treatments of various diseases, but little is known about such compounds and their multimodal anticancer properties. A compendium of heterocyclic synthetic and natural product multitarget anticancer compounds, their IC₅₀, and biological targets of inhibition are therefore presented in this review. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Figure 1

24 pages, 10545 KiB

Open AccessReview

Continuous Flow Synthesis of Anticancer Drugs

by Mara Di Filippo and Marcus Baumann

Molecules 2021, 26(22), 6992; https://doi.org/10.3390/molecules26226992 - 19 Nov 2021

Cited by 5 | Viewed by 4891

Abstract

Continuous flow chemistry is by now an established and valued synthesis technology regularly exploited in academic and industrial laboratories to bring about the improved preparation of a variety of molecular structures. Benefits such as better heat and mass transfer, improved process control and [...] Read more.

Continuous flow chemistry is by now an established and valued synthesis technology regularly exploited in academic and industrial laboratories to bring about the improved preparation of a variety of molecular structures. Benefits such as better heat and mass transfer, improved process control and safety, a small equipment footprint, as well as the ability to integrate in-line analysis and purification tools into telescoped sequences are often cited when comparing flow to analogous batch processes. In this short review, the latest developments regarding the exploitation of continuous flow protocols towards the synthesis of anticancer drugs are evaluated. Our efforts focus predominately on the period of 2016–2021 and highlight key case studies where either the final active pharmaceutical ingredient (API) or its building blocks were produced continuously. It is hoped that this manuscript will serve as a useful synopsis showcasing the impact of continuous flow chemistry towards the generation of important anticancer drugs. Full article

(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Anticancer Compounds with Different Biological Targets

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (25 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI