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Antitumor and Anti-HIV Agents from Natural Products
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Antitumor and Anti-HIV Agents from Natural Products

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 79243

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. Kyoko Nakagawa-Goto

E-Mail Website
Guest Editor
1. Associate Professor, School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences , Kakuma-machi, Kanazawa 920-1192, Japan
2. Adjunct Associate Professor, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hil, NC, USA
Interests: medicinal chemistry; drug discovery; natural products; antitumor; anti-virus; synthesis of bioactive compounds; chemical biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is the second leading cause of death worldwide and was accountable for an estimated 9.6 million deaths in 2018. Nowadays, about 1 in 6 deaths in the world is due to cancer. Another major global public health issue is HIV. Over 70 million people have been infected with the HIV virus and about 35 million people have died of HIV-related illness, since the start of the epidemic. We have been fighting against these two serious diseases by finding successful treatments. The discovery of effective drugs is important for fighting cancer and HIV.

Natural products, which are secondary metabolites produced by various living organisms, have been playing a principal role in drug discovery and developments because of the structural and biological diversity. Many clinically-used drugs have come from natural products, for an example, more than 60% of anticancer drugs currently in clinical use are derived from natural sources.

This Special Issue aims to collect the original research and review articles focusing on notable and recent contributions to the discovery and development of novel anticancer and anti-HIV drug candidates from natural sources. Up-to-date knowledge from various research fields is welcome. This could be of great interest for scientists working in different research areas, such as natural product chemistry, including isolation and structural elucidation; phytochemistry; medicinal chemistry, including chemically modified natural compounds with improved biological activity; pharmacology; molecular biology; mechanisms of action study using natural products or related compounds; pharmacognosy etc. Biological studies of natural extracts without an appropriate chemical characterization may not be considered.

Prof. Dr. Kyoko Nakagawa-Goto
Guest Editor

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Natural products
  • Natural product derivatives
  • Synthetic derivatives inspired by natural scaffolds
  • Phytochemistry
  • Pharmacognosy
  • Structure elucidation
  • Isolation and purification
  • Drug discovery and development
  • Antitumor/antiproliferative activity
  • Anti-HIV
  • Chemosensitizer
  • Cancer prevention
  • Structure–activity relationship
  • Mechanisms of action study

Published Papers (18 papers)

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15 pages, 5676 KiB  
Article
Quercetin Inhibits Cell Survival and Metastatic Ability via the EMT-Mediated Pathway in Oral Squamous Cell Carcinoma
by So Ra Kim, Eun Young Lee, Da Jeong Kim, Hye Jung Kim and Hae Ryoun Park
Molecules 2020, 25(3), 757; https://doi.org/10.3390/molecules25030757 - 10 Feb 2020
Cited by 21 | Viewed by 4226
Abstract
This study aimed to investigate whether quercetin exerts anticancer effects on oral squamous cell carcinoma (OSCC) cell lines and to elucidate its mechanism of action. These anticancer effects in OSCC cells were assessed using an MTT assay, flow cytometry (to assess the cell [...] Read more.
This study aimed to investigate whether quercetin exerts anticancer effects on oral squamous cell carcinoma (OSCC) cell lines and to elucidate its mechanism of action. These anticancer effects in OSCC cells were assessed using an MTT assay, flow cytometry (to assess the cell cycle), wound-healing assay, invasion assay, Western blot analysis, gelatin zymography, and immunofluorescence. To investigate whether quercetin also inhibits transforming growth factor β1 (TGF-β1)-induced epithelial–mesenchymal transition (EMT) in human keratinocyte cells, HaCaT cells were treated with TGF-β1. Overall, our results strongly suggest that quercetin suppressed the viability of OSCC cells by inducing cell cycle arrest at the G2/M phase. However, quercetin did not affect cell viability of human keratinocytes such as HaCaT (immortal keratinocyte) and nHOK (primary normal human oral keratinocyte) cells. Additionally, quercetin suppresses cell migration through EMT and matrix metalloproteinase (MMP) in OSCC cells and decreases TGF-β1-induced EMT in HaCaT cells. In conclusion, this study is the first, to our knowledge, to demonstrate that quercetin can inhibit the survival and metastatic ability of OSCC cells via the EMT-mediated pathway, specifically Slug. Quercetin may thus provide a novel pharmacological approach for the treatment of OSCCs. Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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15 pages, 3727 KiB  
Article
The Antiproliferative Activity of Oxypeucedanin via Induction of G2/M Phase Cell Cycle Arrest and p53-Dependent MDM2/p21 Expression in Human Hepatoma Cells
by So Hyun Park, Ji-Young Hong, Hyen Joo Park and Sang Kook Lee
Molecules 2020, 25(3), 501; https://doi.org/10.3390/molecules25030501 - 23 Jan 2020
Cited by 12 | Viewed by 2849
Abstract
Oxypeucedanin (OPD), a furocoumarin compound from Angelica dahurica (Umbelliferae), exhibits potential antiproliferative activities in human cancer cells. However, the underlying molecular mechanisms of OPD as an anticancer agent in human hepatocellular cancer cells have not been fully elucidated. Therefore, the present study investigated [...] Read more.
Oxypeucedanin (OPD), a furocoumarin compound from Angelica dahurica (Umbelliferae), exhibits potential antiproliferative activities in human cancer cells. However, the underlying molecular mechanisms of OPD as an anticancer agent in human hepatocellular cancer cells have not been fully elucidated. Therefore, the present study investigated the antiproliferative effect of OPD in SK-Hep-1 human hepatoma cells. OPD effectively inhibited the growth of SK-Hep-1 cells. Flow cytometric analysis revealed that OPD was able to induce G2/M phase cell cycle arrest in cells. The G2/M phase cell cycle arrest by OPD was associated with the downregulation of the checkpoint proteins cyclin B1, cyclin E, cdc2, and cdc25c, and the up-regulation of p-chk1 (Ser345) expression. The growth-inhibitory activity of OPD against hepatoma cells was found to be p53-dependent. The p53-expressing cells (SK-Hep-1 and HepG2) were sensitive, but p53-null cells (Hep3B) were insensitive to the antiproliferative activity of OPD. OPD also activated the expression of p53, and thus leading to the induction of MDM2 and p21, which indicates that the antiproliferative activity of OPD is in part correlated with the modulation of p53 in cancer cells. In addition, the combination of OPD with gemcitabine showed synergistic growth-inhibitory activity in SK-Hep-1 cells. These findings suggest that the anti-proliferative activity of OPD may be highly associated with the induction of G2/M phase cell cycle arrest and upregulation of the p53/MDM2/p21 axis in SK-HEP-1 hepatoma cells. Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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17 pages, 3943 KiB  
Article
Caffeic Acid Attenuates Multi-Drug Resistance in Cancer Cells by Inhibiting Efflux Function of Human P-Glycoprotein
by Yu-Ning Teng, Charles C.N. Wang, Wei-Chieh Liao, Yu-Hsuan Lan and Chin-Chuan Hung
Molecules 2020, 25(2), 247; https://doi.org/10.3390/molecules25020247 - 07 Jan 2020
Cited by 30 | Viewed by 4327
Abstract
Multidrug resistance (MDR) is a complicated ever-changing problem in cancer treatment, and P-glycoprotein (P-gp), a drug efflux pump, is regarded as the major cause. In the way of developing P-gp inhibitors, natural products such as phenolic acids have gotten a lot of attention [...] Read more.
Multidrug resistance (MDR) is a complicated ever-changing problem in cancer treatment, and P-glycoprotein (P-gp), a drug efflux pump, is regarded as the major cause. In the way of developing P-gp inhibitors, natural products such as phenolic acids have gotten a lot of attention recently. The aim of the present study was to investigate the modulating effects and mechanisms of caffeic acid on human P-gp, as well as the attenuating ability on cancer MDR. Calcein-AM, rhodamine123, and doxorubicin were used to analyze the interaction between caffeic acid and P-gp, and the ATPase activity of P-gp was evaluated as well. Resistance reversing effects were revealed by SRB and cell cycle assay. The results indicated that caffeic acid uncompetitively inhibited rhodamine123 efflux and competitively inhibited doxorubicin efflux. In terms of P-gp ATPase activity, caffeic acid exhibited stimulation in both basal and verapamil-stimulated activity. The combination of chemo drugs and caffeic acid resulted in decreased IC50 in ABCB1/Flp-InTM-293 and KB/VIN, indicating that the resistance was reversed. Results of molecular docking suggested that caffeic acid bound to P-gp through GLU74 and TRY117 residues. The present study demonstrated that caffeic acid is a promising candidate for P-gp inhibition and cancer MDR attenuation. Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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15 pages, 4170 KiB  
Article
Pterostilbene Suppresses both Cancer Cells and Cancer Stem-Like Cells in Cervical Cancer with Superior Bioavailability to Resveratrol
by Hee Jeong Shin, Jang Mi Han, Ye Seul Choi and Hye Jin Jung
Molecules 2020, 25(1), 228; https://doi.org/10.3390/molecules25010228 - 06 Jan 2020
Cited by 48 | Viewed by 5378
Abstract
Increasing studies have reported that cancer stem cells (CSCs) play critical roles in therapeutic resistance, recurrence, and metastasis of tumors, including cervical cancer. Pterostilbene, a dimethylated derivative of resveratrol, is a plant polyphenol compound with potential chemopreventive activity. However, the therapeutic effect of [...] Read more.
Increasing studies have reported that cancer stem cells (CSCs) play critical roles in therapeutic resistance, recurrence, and metastasis of tumors, including cervical cancer. Pterostilbene, a dimethylated derivative of resveratrol, is a plant polyphenol compound with potential chemopreventive activity. However, the therapeutic effect of pterostilbene against cervical CSCs remains unclear. In this study, we compared the anticancer effects of resveratrol and pterostilbene using both HeLa cervical cancer adherent and stem-like cells. Pterostilbene more effectively inhibited the growth and clonogenic survival, as well as metastatic ability of HeLa adherent cells than those of resveratrol. Moreover, the superior inhibitory effects of pterostilbene compared to resveratrol were associated with the enhanced activation of multiple mechanisms, including cell cycle arrest at S and G2/M phases, induction of ROS-mediated caspase-dependent apoptosis, and inhibition of matrix metalloproteinase (MMP)-2/-9 expression. Notably, pterostilbene exhibited a greater inhibitory effect on the tumorsphere-forming and migration abilities of HeLa cancer stem-like cells compared to resveratrol. This greater effect was achieved through more potent inhibition of the expression levels of stemness markers, such as CD133, Oct4, Sox2, and Nanog, as well as signal transducer and activator of transcription 3 signaling. These results suggest that pterostilbene might be a potential anticancer agent targeting both cancer cells and cancer stem-like cells of cervical cancer via the superior bioavailability to resveratrol. Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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16 pages, 2913 KiB  
Article
Isolation, Structure Elucidation, and Antiproliferative Activity of Butanolides and Lignan Glycosides from the Fruit of Hernandia nymphaeifolia
by Simayijiang Aimaiti, Yohei Saito, Shuichi Fukuyoshi, Masuo Goto, Katsunori Miyake, David J. Newman, Barry R. O’Keefe, Kuo-Hsiung Lee and Kyoko Nakagawa-Goto
Molecules 2019, 24(21), 4005; https://doi.org/10.3390/molecules24214005 - 05 Nov 2019
Cited by 9 | Viewed by 2967
Abstract
Seven new butanolides, peltanolides A–G (1–7), and two lignan glucosides, peltasides A (8) and B (9), along with eleven known compounds, 10–20, were isolated from a crude CH3OH/CH2Cl [...] Read more.
Seven new butanolides, peltanolides A–G (1–7), and two lignan glucosides, peltasides A (8) and B (9), along with eleven known compounds, 10–20, were isolated from a crude CH3OH/CH2Cl2 (1:1) extract of the fruit of Hernandia nymphaeifolia (Hernandiaceae). The structures of 1–9 were characterized by extensive 1D and 2D NMR spectroscopic and HRMS analysis. The absolute configurations of newly isolated compounds 1–9 were determined from data obtained by optical rotation and electronic circular dichroism (ECD) exciton chirality methods. Butanolides and lignan glucosides have not been isolated previously from this genus. Several isolated compounds were evaluated for antiproliferative activity against human tumor cell lines. Lignans 15 and 16 were slightly active against chemosensitive tumor cell lines A549 and MCF-7, respectively. Furthermore, both compounds displayed significant activity (IC50 = 5 µM) against a P-glycoprotein overexpressing multidrug-resistant tumor cell line (KB-VIN) but were less active against its parent chemosensitive cell line (KB). Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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10 pages, 3276 KiB  
Article
Ivalin Induces Mitochondria-Mediated Apoptosis Associated with the NF-κB Activation in Human Hepatocellular Carcinoma SMMC-7721 Cells
by Zhuo Han, Fang-yuan Liu, Shi-qi Lin, Cai-yun Zhang, Jia-hui Ma, Chao Guo, Fu-juan Jia, Qian Zhang, Wei-dong Xie and Xia Li
Molecules 2019, 24(20), 3809; https://doi.org/10.3390/molecules24203809 - 22 Oct 2019
Cited by 3 | Viewed by 2346
Abstract
Ivalin, a natural compound isolated from Carpesium divaricatum, showed excellent microtubule depolymerization activities among human hepatocellular carcinoma in our previous work. Here, we investigated its functions on mitochondria-mediated apoptosis in hepatocellular carcinoma SMMC-7721 cells. DAPI (4′,6-diamidino-2-phenylindole) staining, annexin V-fluorexcein isothiocyanate (FITC) apoptosis [...] Read more.
Ivalin, a natural compound isolated from Carpesium divaricatum, showed excellent microtubule depolymerization activities among human hepatocellular carcinoma in our previous work. Here, we investigated its functions on mitochondria-mediated apoptosis in hepatocellular carcinoma SMMC-7721 cells. DAPI (4′,6-diamidino-2-phenylindole) staining, annexin V-fluorexcein isothiocyanate (FITC) apoptosis detection, and western blotting were applied to explore the apoptotic effect of Ivalin. Next, the induction effect of Ivalin on the mitochondrial pathway was also confirmed via a series of phenomena including the damage of mitochondria membrane potential, mitochondria cytochrome c escape, cleaved caspase-3 induction, and the reactive oxygen species generation. In this connection, we understood that Ivalin induced apoptosis through the mitochondrial pathway and the overload of reactive oxygen species. Furthermore, we found that the activation of nuclear factor-κB (NF-κB) and subsequent p53 induction were associated with the apoptotic effect of Ivalin. These data confirmed that Ivalin might be a promising pro-apoptotic compound that can be utilized as a potential drug for clinical treatment. Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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16 pages, 3012 KiB  
Article
Apple Peel Flavonoid Fraction 4 Suppresses Breast Cancer Cell Growth by Cytostatic and Cytotoxic Mechanisms
by Chao-Yu Loung, Wasundara Fernando, H.P. Vasantha Rupasinghe and David W. Hoskin
Molecules 2019, 24(18), 3335; https://doi.org/10.3390/molecules24183335 - 13 Sep 2019
Cited by 13 | Viewed by 4020
Abstract
Many dietary flavonoids possess anti-cancer activities. Here, the effect of apple peel flavonoid fraction 4 (AF4) on the growth of triple-negative (MDA-MB-231, MDA-MB-468), estrogen receptor-positive (MCF-7), and HER2-positive (SKBR3) breast cancer cells was determined and compared with the effect of AF4 on normal [...] Read more.
Many dietary flavonoids possess anti-cancer activities. Here, the effect of apple peel flavonoid fraction 4 (AF4) on the growth of triple-negative (MDA-MB-231, MDA-MB-468), estrogen receptor-positive (MCF-7), and HER2-positive (SKBR3) breast cancer cells was determined and compared with the effect of AF4 on normal mammary epithelial cells and dermal fibroblasts. AF4 inhibited breast cancer cell growth in monolayer cultures, as well as the growth of MCF-7 spheroids, without substantially affecting the viability of non-malignant cells. A sub-cytotoxic concentration of AF4 suppressed the proliferation of MDA-MB-231 cells by inhibiting passage through the G0/G1 phase of the cell cycle. AF4-treated MDA-MB-231 cells also exhibited reduced in vitro migration and invasion, and decreased Akt (protein kinase B) signaling. Higher concentrations of AF4 were selectively cytotoxic for MDA-MB-231 cells. AF4 cytotoxicity was associated with the intracellular accumulation of reactive oxygen species. Importantly, intratumoral administration of AF4 suppressed the growth of MDA-MB-231 xenografts in non-obese diabetic severe combined immunodeficient (NOD-SCID) female mice. The selective cytotoxicity of AF4 for breast cancer cells, combined with the capacity of sub-cytotoxic AF4 to inhibit breast cancer cell proliferation, migration, and invasion suggests that flavonoid-rich AF4 (and its constituents) has potential as a natural therapeutic agent for breast cancer treatment. Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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21 pages, 2762 KiB  
Article
Romanian Wormwood (Artemisia absinthium L.): Physicochemical and Nutraceutical Screening
by Elena-Alina Moacă, Ioana Zinuca Pavel, Corina Danciu, Zorin Crăiniceanu, Daliana Minda, Florina Ardelean, Diana Simona Antal, Roxana Ghiulai, Andreea Cioca, Mihnea Derban, Sebastian Simu, Raul Chioibaş, Camelia Szuhanek and Cristina-Adriana Dehelean
Molecules 2019, 24(17), 3087; https://doi.org/10.3390/molecules24173087 - 25 Aug 2019
Cited by 29 | Viewed by 6096
Abstract
Artemisia species are used worldwide for their antioxidant, antimicrobial and anti-inflammatory properties. This research was designed to investigate the phytochemical profile of two ethanolic extracts obtained from leaves and stems of A. absinthium L. as well as the biological potential (antioxidant activity, cytotoxic, [...] Read more.
Artemisia species are used worldwide for their antioxidant, antimicrobial and anti-inflammatory properties. This research was designed to investigate the phytochemical profile of two ethanolic extracts obtained from leaves and stems of A. absinthium L. as well as the biological potential (antioxidant activity, cytotoxic, anti-migratory and anti-inflammatory properties). Both plant materials showed quite similar thermogravimetric, FT-IR phenolic profile (high chlorogenic acid) with mild antioxidant capacity [ascorbic acid (0.02–0.1) > leaves (0.1–2.0) > stem (0.1–2.0)]. Alcoholic extracts from these plant materials showed a cytotoxic effect against A375 (melanoma) and MCF7 (breast adenocarcinoma) and affected less the non-malignant HaCaT cells (human keratinocytes) at 72 h post-stimulation and this same trend was observed in the anti-migratory (A375, MCF7 > HaCat) assay. Lastly, extracts ameliorated the pro-inflammatory effect of TPA (12-O-tetradecanoylphorbol-13-acetate) in mice ears, characterized by a diffuse neutrophil distribution with no exocytosis or micro-abscesses. Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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17 pages, 3834 KiB  
Article
Evaluating the Anti-cancer Efficacy of a Synthetic Curcumin Analog on Human Melanoma Cells and Its Interaction with Standard Chemotherapeutics
by Krishan Parashar, Siddhartha Sood, Ali Mehaidli, Colin Curran, Caleb Vegh, Christopher Nguyen, Christopher Pignanelli, Jianzhang Wu, Guang Liang, Yi Wang and Siyaram Pandey
Molecules 2019, 24(13), 2483; https://doi.org/10.3390/molecules24132483 - 06 Jul 2019
Cited by 14 | Viewed by 4243
Abstract
Melanoma is the leading cause of skin-cancer related deaths in North America. Metastatic melanoma is difficult to treat and chemotherapies have limited success. Furthermore, chemotherapies lead to toxic side effects due to nonselective targeting of normal cells. Curcumin is a natural product of [...] Read more.
Melanoma is the leading cause of skin-cancer related deaths in North America. Metastatic melanoma is difficult to treat and chemotherapies have limited success. Furthermore, chemotherapies lead to toxic side effects due to nonselective targeting of normal cells. Curcumin is a natural product of Curcuma longa (turmeric) and has been shown to possess anti-cancer activity. However, due to its poor bioavailability and stability, natural curcumin is not an effective cancer treatment. We tested synthetic analogs of curcumin that are more stable. One of these derivatives, Compound A, has shown significant anti-cancer efficacy in colon, leukemia, and triple-negative inflammatory breast cancer cells. However, the effects of Compound A against melanoma cells have not been studied before. In this study, for the first time, we demonstrated the efficacy of Compound A for the selective induction of apoptosis in melanoma cells and its interaction with tamoxifen, taxol, and cisplatin. We found that Compound A induced apoptosis selectively in human melanoma cells by increasing oxidative stress. The anti-cancer activity of Compound A was enhanced when combined with tamoxifen and the combination treatment did not result in significant toxicity to noncancerous cells. Additionally, Compound A did not interact negatively with the anti-cancer activity of taxol and cisplatin. These results indicate that Compound A could be developed as a selective and effective melanoma treatment either alone or in combination with other non-toxic agents like tamoxifen. Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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15 pages, 4290 KiB  
Article
Essential Oil of Mentha aquatica var. Kenting Water Mint Suppresses Two-Stage Skin Carcinogenesis Accelerated by BRAF Inhibitor Vemurafenib
by Chih-Ting Chang, Wen-Ni Soo, Yu-Hsin Chen and Lie-Fen Shyur
Molecules 2019, 24(12), 2344; https://doi.org/10.3390/molecules24122344 - 25 Jun 2019
Cited by 7 | Viewed by 4147
Abstract
The v-raf murine sarcoma viral homolog B1 (BRAF) inhibitor drug vemurafenib (PLX4032) is used to treat melanoma; however, epidemiological evidence reveals that it could cause cutaneous keratoacanthomas and squamous cell carcinoma in cancer patients with the most prevalent HRASQ61L mutation. In a [...] Read more.
The v-raf murine sarcoma viral homolog B1 (BRAF) inhibitor drug vemurafenib (PLX4032) is used to treat melanoma; however, epidemiological evidence reveals that it could cause cutaneous keratoacanthomas and squamous cell carcinoma in cancer patients with the most prevalent HRASQ61L mutation. In a two-stage skin carcinogenesis mouse model, the skin papillomas induced by 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) (DT) resemble the lesions in BRAF inhibitor-treated patients. In this study, we investigated the bioactivity of Mentha aquatica var. Kenting Water Mint essential oil (KWM-EO) against PDV cells, mouse keratinocytes bearing HRASQ61L mutation, and its effect on inhibiting papilloma formation in a two-stage skin carcinogenesis mouse model with or without PLX4032 co-treatment. Our results revealed that KWM-EO effectively attenuated cell viability, colony formation, and the invasive and migratory abilities of PDV cells. Induction of G2/M cell-cycle arrest and apoptosis in PDV cells was also observed. KWM-EO treatment significantly decreased the formation of cutaneous papilloma further induced by PLX4032 in DT mice (DTP). Immunohistochemistry analyses showed overexpression of keratin14 and COX-2 in DT and DTP skin were profoundly suppressed by KWM-EO treatment. This study demonstrates that KWM-EO has chemopreventive effects against PLX4032-induced cutaneous side-effects in a DMBA/TPA-induced two-stage carcinogenesis model and will be worth further exploration for possible application in melanoma patients. Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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19 pages, 2597 KiB  
Article
Synthesis and Cytotoxicity Evaluation of DOTA-Conjugates of Ursolic Acid
by Michael Kahnt, Sophie Hoenke, Lucie Fischer, Ahmed Al-Harrasi and René Csuk
Molecules 2019, 24(12), 2254; https://doi.org/10.3390/molecules24122254 - 17 Jun 2019
Cited by 16 | Viewed by 3896
Abstract
In this study, we report the synthesis of several amine-spacered conjugates of ursolic acid (UA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Thus, a total of 11 UA-DOTA conjugates were prepared holding various oligo-methylene diamine spacers as well as different substituents at the acetate units of [...] Read more.
In this study, we report the synthesis of several amine-spacered conjugates of ursolic acid (UA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Thus, a total of 11 UA-DOTA conjugates were prepared holding various oligo-methylene diamine spacers as well as different substituents at the acetate units of DOTA including tert-butyl, benzyl, and allyl esters. Furthermore, three synthetic approaches were compared for the ethylenediamine-spacered conjugate 29 regarding reaction steps, yields, and precursor availability. The prepared conjugates were investigated regarding cytotoxicity using SRB assays and a set of human tumor cell lines. The highest cytotoxicity was observed for piperazinyl spacered compound 22. Thereby, EC50 values of 1.5 µM (for A375 melanoma) and 1.7 µM (for A2780 ovarian carcinoma) were determined. Conjugates 22 and 24 were selected for further cytotoxicity investigations including fluorescence microscopy, annexin V assays and cell cycle analysis. Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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10 pages, 3129 KiB  
Article
Antiproliferative Aspidosperma-Type Monoterpenoid Indole Alkaloids from Bousigonia mekongensis Inhibit Tubulin Polymerization
by Yu Zhang, Masuo Goto, Akifumi Oda, Pei-Ling Hsu, Ling-Li Guo, Yan-Hui Fu, Susan L. Morris-Natschke, Ernest Hamel, Kuo-Hsiung Lee and Xiao-Jiang Hao
Molecules 2019, 24(7), 1256; https://doi.org/10.3390/molecules24071256 - 31 Mar 2019
Cited by 15 | Viewed by 3287
Abstract
Monoterpenoid indole alkaloids are structurally diverse natural products found in plants of the family Apocynaceae. Among them, vincristine and its derivatives are well known for their anticancer activity. Bousigonia mekongensis, a species in this family, contains various monoterpenoid indole alkaloids. In the [...] Read more.
Monoterpenoid indole alkaloids are structurally diverse natural products found in plants of the family Apocynaceae. Among them, vincristine and its derivatives are well known for their anticancer activity. Bousigonia mekongensis, a species in this family, contains various monoterpenoid indole alkaloids. In the current study, fourteen known aspidosperma-type monoterpenoid indole alkaloids (1–14) were isolated and identified from a methanol extract of the twigs and leaves of B. mekongensis for the first time. Among them, compounds 3, 6, 9, and 13 exhibited similar antiproliferative activity spectra against A549, KB, and multidrug-resistant (MDR) KB subline KB-VIN cells with IC50 values ranging from 0.5–0.9 μM. The above alkaloids efficiently induced cell cycle arrest at the G2/M phase by inhibiting tubulin polymerization as well as mitotic bipolar spindle formation. Computer modeling studies indicated that compound 7 likely forms a hydrogen bond (H-bond) with α- or β-tubulin at the colchicine site. Evaluation of the antiproliferative effects and SAR analysis suggested that a 14,15-double bond or 3α-acetonyl group is critical for enhanced antiproliferative activity. Mechanism of action studies demonstrated for the first time that compounds 3, 4, 6, 7, and 13 efficiently induce cell cycle arrest at G2/M by inhibiting tubulin polymerization by binding to the colchicine site. Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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9 pages, 613 KiB  
Article
Synthesis and Biological Evaluation of Phaeosphaeride A Derivatives as Antitumor Agents
by Victoria Abzianidze, Petr Beltyukov, Sofya Zakharenkova, Natalia Moiseeva, Jennifer Mejia, Alvin Holder, Yuri Trishin, Alexander Berestetskiy and Victor Kuznetsov
Molecules 2018, 23(11), 3043; https://doi.org/10.3390/molecules23113043 - 21 Nov 2018
Cited by 8 | Viewed by 3218
Abstract
New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor activity studies were carried out on the HCT-116, PC3, MCF-7, A549, К562, NCI-Н929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All of the compounds synthesized were found [...] Read more.
New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor activity studies were carried out on the HCT-116, PC3, MCF-7, A549, К562, NCI-Н929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All of the compounds synthesized were found to have better efficacy than PPA towards the tumor cell lines mentioned. Compound 6 was potent against six cancer cell lines, HCT-116, PC-3, K562, NCI-H929, Jurkat, and RPMI8226, showing a 47, 13.5, 16, 4, 1.5, and 7-fold increase in anticancer activity comparative to those of etoposide, respectively. Compound 1 possessed selectivity toward the NCI-H929 cell line (IC50 = 1.35 ± 0.69 μM), while product 7 was selective against three cancer cell lines, HCT-116, MCF-7, and NCI-H929, each having IC50 values of 1.65 μM, 1.80 μM and 2.00 μM, respectively. Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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Review

Jump to: Research

22 pages, 3389 KiB  
Review
Anticancer Potential of Resveratrol, β-Lapachone and Their Analogues
by Danielly C. Ferraz da Costa, Luciana Pereira Rangel, Mafalda Maria Duarte da Cunha Martins-Dinis, Giulia Diniz da Silva Ferretti, Vitor F. Ferreira and Jerson L. Silva
Molecules 2020, 25(4), 893; https://doi.org/10.3390/molecules25040893 - 18 Feb 2020
Cited by 40 | Viewed by 5369
Abstract
This review aims to explore the potential of resveratrol, a polyphenol stilbene, and beta-lapachone, a naphthoquinone, as well as their derivatives, in the development of new drug candidates for cancer. A brief history of these compounds is reviewed along with their potential effects [...] Read more.
This review aims to explore the potential of resveratrol, a polyphenol stilbene, and beta-lapachone, a naphthoquinone, as well as their derivatives, in the development of new drug candidates for cancer. A brief history of these compounds is reviewed along with their potential effects and mechanisms of action and the most recent attempts to improve their bioavailability and potency against different types of cancer. Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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22 pages, 658 KiB  
Review
Molecular Mechanisms of the Anti-Cancer Effects of Isothiocyanates from Cruciferous Vegetables in Bladder Cancer
by Tomhiro Mastuo, Yasuyoshi Miyata, Tsutomu Yuno, Yuta Mukae, Asato Otsubo, Kensuke Mitsunari, Kojiro Ohba and Hideki Sakai
Molecules 2020, 25(3), 575; https://doi.org/10.3390/molecules25030575 - 29 Jan 2020
Cited by 39 | Viewed by 5144
Abstract
Bladder cancer (BC) is a representative of urological cancer with a high recurrence and metastasis potential. Currently, cisplatin-based chemotherapy and immune checkpoint inhibitors are used as standard therapy in patients with advanced/metastatic BC. However, these therapies often show severe adverse events, and prolongation [...] Read more.
Bladder cancer (BC) is a representative of urological cancer with a high recurrence and metastasis potential. Currently, cisplatin-based chemotherapy and immune checkpoint inhibitors are used as standard therapy in patients with advanced/metastatic BC. However, these therapies often show severe adverse events, and prolongation of survival is unsatisfactory. Therefore, a treatment strategy using natural compounds is of great interest. In this review, we focused on the anti-cancer effects of isothiocyanates (ITCs) derived from cruciferous vegetables, which are widely cultivated and consumed in many regions worldwide. Specifically, we discuss the anti-cancer effects of four ITC compounds—allyl isothiocyanate, benzyl isothiocyanate, sulforaphane, and phenethyl isothiocyanate—in BC; the molecular mechanisms underlying their anti-cancer effects; current trends and future direction of ITC-based treatment strategies; and the carcinogenic potential of ITCs. We also discuss the advantages and limitations of each ITC in BC treatment, furthering the consideration of ITCs in treatment strategies and for improving the prognosis of patients with BC. Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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19 pages, 1081 KiB  
Review
Antiangiogenic Effects of Coumarins against Cancer: From Chemistry to Medicine
by Mohammad Bagher Majnooni, Sajad Fakhri, Antonella Smeriglio, Domenico Trombetta, Courtney R. Croley, Piyali Bhattacharyya, Eduardo Sobarzo-Sánchez, Mohammad Hosein Farzaei and Anupam Bishayee
Molecules 2019, 24(23), 4278; https://doi.org/10.3390/molecules24234278 - 24 Nov 2019
Cited by 40 | Viewed by 6566
Abstract
Angiogenesis, the process of formation and recruitment of new blood vessels from pre-existing vessels, plays an important role in the development of cancer. Therefore, the use of antiangiogenic agents is one of the most critical strategies for the treatment of cancer. In addition, [...] Read more.
Angiogenesis, the process of formation and recruitment of new blood vessels from pre-existing vessels, plays an important role in the development of cancer. Therefore, the use of antiangiogenic agents is one of the most critical strategies for the treatment of cancer. In addition, the complexity of cancer pathogenicity raises the need for multi-targeting agents. Coumarins are multi-targeting natural agents belonging to the class of benzopyrones. Coumarins have several biological and pharmacological effects, including antimicrobial, antioxidant, anti-inflammation, anticoagulant, anxiolytic, analgesic, and anticancer properties. Several reports have shown that the anticancer effect of coumarins and their derivatives are mediated through targeting angiogenesis by modulating the functions of vascular endothelial growth factor as well as vascular endothelial growth factor receptor 2, which are involved in cancer pathogenesis. In the present review, we focus on the antiangiogenic effects of coumarins and related structure-activity relationships with particular emphasis on cancer. Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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36 pages, 10590 KiB  
Review
Novel Antiretroviral Structures from Marine Organisms
by Karlo Wittine, Lara Saftić, Željka Peršurić and Sandra Kraljević Pavelić
Molecules 2019, 24(19), 3486; https://doi.org/10.3390/molecules24193486 - 26 Sep 2019
Cited by 18 | Viewed by 4503
Abstract
In spite of significant advancements and success in antiretroviral therapies directed against HIV infection, there is no cure for HIV, which scan persist in a human body in its latent form and become reactivated under favorable conditions. Therefore, novel antiretroviral drugs with different [...] Read more.
In spite of significant advancements and success in antiretroviral therapies directed against HIV infection, there is no cure for HIV, which scan persist in a human body in its latent form and become reactivated under favorable conditions. Therefore, novel antiretroviral drugs with different modes of actions are still a major focus for researchers. In particular, novel lead structures are being sought from natural sources. So far, a number of compounds from marine organisms have been identified as promising therapeutics for HIV infection. Therefore, in this paper, we provide an overview of marine natural products that were first identified in the period between 2013 and 2018 that could be potentially used, or further optimized, as novel antiretroviral agents. This pipeline includes the systematization of antiretroviral activities for several categories of marine structures including chitosan and its derivatives, sulfated polysaccharides, lectins, bromotyrosine derivatives, peptides, alkaloids, diterpenes, phlorotannins, and xanthones as well as adjuvants to the HAART therapy such as fish oil. We critically discuss the structures and activities of the most promising new marine anti-HIV compounds. Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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22 pages, 2152 KiB  
Review
Cytotoxic Effects of Diterpenoid Alkaloids Against Human Cancer Cells
by Koji Wada and Hiroshi Yamashita
Molecules 2019, 24(12), 2317; https://doi.org/10.3390/molecules24122317 - 22 Jun 2019
Cited by 36 | Viewed by 5886
Abstract
Diterpenoid alkaloids are isolated from plants of the genera Aconitum, Delphinium, and Garrya (Ranunculaceae) and classified according to their chemical structures as C18-, C19- or C20-diterpenoid alkaloids. The extreme toxicity of certain compounds, e.g., aconitine, [...] Read more.
Diterpenoid alkaloids are isolated from plants of the genera Aconitum, Delphinium, and Garrya (Ranunculaceae) and classified according to their chemical structures as C18-, C19- or C20-diterpenoid alkaloids. The extreme toxicity of certain compounds, e.g., aconitine, has prompted a thorough investigation of how structural features affect their bioactivities. Therefore, natural diterpenoid alkaloids and semi-synthetic alkaloid derivatives were evaluated for cytotoxic effects against human tumor cells [A549 (lung carcinoma), DU145 (prostate carcinoma), MDA-MB-231 (triple-negative breast cancer), MCF-7 (estrogen receptor-positive, HER2-negative breast cancer), KB (identical to cervical carcinoma HeLa derived AV-3 cell line), and multidrug-resistant (MDR) subline KB-VIN]. Among the tested alkaloids, C19-diterpenoid (e.g., lipojesaconitine, delcosine and delpheline derivatives) and C20-diterpenoid (e.g., kobusine and pseudokobusine derivatives) alkaloids exhibited significant cytotoxic activity and, thus, provide promising new leads for further development as antitumor agents. Notably, several diterpenoid alkaloids were more potent against MDR subline KB-VIN cells than the parental drug-sensitive KB cells. Full article
(This article belongs to the Special Issue Antitumor and Anti-HIV Agents from Natural Products)
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