Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 21, Issue 4, 2021

Quinacrine (QC) is a tricyclic compound and a derivative of 9-aminoacridine. It has been widely used to treat malaria and other parasitic diseases since the last century. Interestingly, studies have revealed that it also displays anti-cancer activities. Here, we have discussed the anti-cancer mechanism of QC along with its potentiality to specifically target cancer stem cells. The anti-cancer action of this drug includes DNA intercalation, inhibition of DNA repair mechanism, prevention of cellular growth, cell cycle arrest, inhibition of DNA and RNA polymerase activity, induction of autophagy, promotion of apoptosis, deregulation of cell signaling in cancer cells and cancer stem cells, inhibition of metastasis and angiogenesis. In addition, we have also emphasized on the synergistic effect of this drug with other potent chemotherapeutic agents and mentioned its different applications in anti-cancer therapy.

Cancer is one of the most lethal diseases in the world. Because of the high death rate associated with cancer and the side effects of chemotherapy and radiation therapy, patients require alternative strategies for its treatment. Ginger (Zingiber officinale) has enormous medicinal properties and health benefits. In this review, we discuss the basic mechanism by which gingerol (an active component of ginger) modulates a variety of cell signaling pathways linked to cancer, including Nuclear Factors (NF-ΚB), Signal Transducer and Activator of Transcription 3 (STAT3), Activator Protein-1 (AP-1), β-catenin, Growth Factors Receptors (EGFR, VEGFR); Mitogen-Activated Protein Kinases (MAPK) and pro-inflammatory mediators (TNF-α and COX-2). Both in vitro and in vivo studies support the role of gingerol in cancer. The efficacy of gingerol by clinical trials has also been reported. Importantly, natural agents are already in clinical trials against various kinds of cancer. An effort has been made through this comprehensive review to highlight the recent developments and milestones achieved in cancer therapies via studies based on different cell lines using gingerol.

Background: The currently available anti breast cancer agents as well as conventional drug delivery methods have some limitations. Objective: In view of these limitations, researchers used phytochemicals/herbal extracts as anti-breast cancer agents together with the polymeric nanoparticles to provide an effective way of targeted drug delivery with lesser /no side effects. Methods: The literature for this review was searched during the year 2015 to 2019, using the keywords, ‘ ‘breast cancer’, ‘breast cancer and its current treatments’, ‘plants against the breast cancer’, ‘polymeric nanoparticles’, ‘herbal based polymeric nanoparticles’. The databases i.e., PubMed, Science Direct, and Google Scholar, were used for collecting the information. Results: In the present review, an attempt was made to summarize the potential of herbal-based nanoformulation as a specific and high efficacy therapeutic strategy in order to pave the way for future research involving screening and use of herbal nanoparticles for the treatment of breast cancer. Conclusion: The encapsulation of the herbal extract in the polymeric nanoparticles is the prominent, effective, and emerging way of targeted drug delivery for cancer. It may serve as a safer way of targeted drug delivery and maybe the answer to the complications related to the currently available anti-breast cancer agents as well as limitations of the conventional method of drug delivery.

Aim: The rapid growth, morbidity and mortality of prostate cancer, and the lack of effective treatment have attracted great interest of researchers to find novel cancer therapies aiming at the effect of gossypin on cell proliferation and apoptosis of PC-3 cells. Methods: The effect of gossypin on cell viability was determined using MTT assay at 5-100μg/ml and cisplatin (50μM) in a time-dependent manner in PC-3 cell lines. The expression levels of caspase-3 (CASP3) and caspase-9 (CASP9) for apoptosis and Nuclear Factor Kappa B (NFKB1) for survival, inflammation, and growth were evaluated by real-time PCR. Hoechst staining was used to analyze apoptosis. Results: Gossypin showed an anti-proliferative effect on PC3 cell line in a time- and dose-dependent manner. In addition, gossypin led to a significant increase in apoptosis genes (CASP3, CASP9) when compared to control while it caused a decrease in the level of NFKB1, which is accepted as apoptosis inhibitor (p<0.05) (cisplatin-like). Gossypin 50 and 100μM significantly induced apoptotic mechanism in PC-3 cells. However, no apoptotic or commonly stained nuclei have been observed in control group cells. Conclusion: The results indicated that gossypin can be defined as a promising anticancer agent for PC-3 human prostate cancer cell line.

Background: The abnormal signaling from tyrosine kinase causes many types of cancers, including breast cancer, non-small cell lung cancer, and chronic myeloid leukemia. This research reports the in silico, synthesis, and in vitro study of novel pyrimidine derivatives as EGFR inhibitors. Objective: The objective of the research study is to discover more promising lead compounds using the drug discovery process, in which a rational drug design is achieved by molecular docking and virtual pharmacokinetic studies. Methods: The molecular docking studies were carried out using discovery studio 3.5-version software. The molecules with good docking and binding energy score were synthesized, and their structures were confirmed by FT-IR, NMR, Mass and elemental analysis. Subsequently, molecules were evaluated for their anti-cancer activity using MDA-MB-231, MCF-7, and A431 breast cancer cell lines by MTT and tyrosine kinase assay methodology. Results: Pyrimidine derivatives displayed anti-cancer activity. Particularly, compound R8 showed significant cytotoxicity against MDA-MB-231 with an IC50 value of 18.5±0.6μM. Molecular docking studies proved that the compound R8 has good binding fitting by forming hydrogen bonds with amino acid residues at ATP binding sites of EGFR. Conclusion: Eight pyrimidine derivatives were designed, synthesized, and evaluated against breast cancer cell lines. Compound R8 significantly inhibited the growth of MDA-MB-231 and MCF-7. Molecular docking studies revealed that compound R8 has good fitting by forming different Hydrogen bonding interactions with amino acids at the ATP binding site of epidermal growth factor receptor target. Compound R8 was a promising lead molecule that showed better results as compared to other compounds in in vitro studies.

Background: Although Mycophenolic Acid (MPA) is applied as prodrugs in clinic as an immunosuppressant, it also possesses anticancer activity. MPA acts as Inosine-5’-Monophosphate Dehydrogenase (IMPDH) inhibitor, where the carboxylic group at the end of the side chain interacts with Ser 276 of the enzyme via hydrogen bonds. Therefore, MPA derivatives with other polar groups indicated high inhibition too. On the other hand, potent anticancer agents like dacarbazine and cisplatin give numerous side-effects. Objective: Based on the literature data, MPA derivatives should be explored towards anticancer properties. Conversion of the carboxylic group of MPA to amide could maintain antiproliferative activity. Therefore, we decided to investigate several amino acid and peptide derivatives of MPA against chosen cancer cell lines in vitro. Methods: Amides of MPA hold threonine and arginine amino acid unit. These amino acid derivatives were tested as L and D enantiomers and both in free acid and methyl esters forms. Additionally, MPA was modified with tuftsin or retro-tuftsin as biologically active peptides, which could act as a drug carrier. Results: Amino acid and peptide derivatives of MPA were investigated in vitro as potential anticancer agents on cell lines: Ab melanoma, A375 melanoma and SHSY5Y neuroblastoma. The activity of the tested compounds was compared to parent MPA and known chemotherapeutics: dacarbazine and cisplatin. Conclusion: Amino acid moiety and the sequence of amino acids in the peptide part influenced observed activity. The most active amino acid MPA analogues occurred to be D and L-threonine derivatives as methyl esters, probably due to better cell membrane penetration.

Background: Recentlty, pyrazoloquinazoline derivatives acquired a special attention due to their wide range of pharmacological activities, especially therapeutic. Through the market, it was found that many pharmacological drugs containing the quinazoline nucleus were known. Objective: The aim of this work is to synthesize target molecules possessing not only anti-tumor activities but also kinase inhibitors. The target molecules were obtained through the synthesis of a series of 5,6,8,9- tetrahydropyrazolo[5,1-b]quinazolin-7(3H)-one derivatives 4a-i using the multi-component reactions of cyclohexane- 1,4-dione (1), the 5-amino-4-(2-arylhydrazono)-4H-pyrazol-3-ol derivatives 2a-c, the aromatic aldehydes 3a-c, respectively. The synthesized compounds were evaluated against c-Met kinase, PC-3 cell line, and different kinds of cancer cell lines together with normal cell line, tyrosine kinases, and Pim-1 kinase. Methods: Multi-component reactions were adopted using compound 1 to get different 5,6,8,9- tetrahydropyrazolo[5,1-b]quinazolin-7(3H)-one derivatives which underwent further heterocyclization reactions. The c-Met kinase activity of all compounds was evaluated using Homogeneous Time-Resolved Fluorescence (HTRF) assay, taking foretinib as the positive control. The anti-proliferative activity of all target compounds against the human prostatic cancer PC-3 cell line was measured using MTT assay using SGI-1776 as the reference drug. All the synthesized compounds were assessed for inhibitory activities against A549 (non-small cell lung cancer), H460 (human lung cancer), HT-29 (human colon cancer), and MKN-45 (human gastric cancer) cancer cell lines together with foretinib as the positive control by an MTT assay. Results: Antiproliferative evaluations and c-Met kinase, Pim-1 kinase inhibitions were performed for the synthesized compounds, where the varieties of substituents through the aryl ring and the thiophene moiety afforded compounds with high activities. Conclusion: The compounds with high antiproliferative activity were tested towards c-Met and the results showed that compounds 4e, 4f, 4g, 4i, 6i, 6k, 6l, 8f, 8i, 10d, 10e, 10f, 10h, 12e, 12f, 12g, 12h, 12i, 14f, 14g, 14h, and 14i were the most potent compounds. A further selection of compounds for the Pim-1 kinase inhibition activity showed that compounds 4f, 6i, 6l, 8h, 8i, 8g, 10d, 12i, and 14f were the most active compounds to inhibit Pim-1.

Background: Recently, the Notch signaling pathway has gained attention as a potential therapeutic target for chemotherapeutic intervention. However, the efficacy of previously known Notch inhibitors in colon cancer is still unclear. The purpose of this study was to investigate the effect of andrographolide on aberrantly activated Notch signaling in SW-480 cells in vitro. Methods: The cytostatic potential of andrographolide on SW-480 cells was evaluated by 3-(4,5-dimethylthiazol- 2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay, morphology assessment, and colony formation assay. The apoptotic activity was evaluated by FITC Annexin V assay, 4′,6-diamidino-2-phenylindole (DAPI), Hoechst, Rhodamine 123, and Mito Tracker CMXRos staining. Scratch assay was conducted for migratory potential assessment. 7’-Dichlorodihydrofluorescein Diacetate (DCFH-DA) staining was used to evaluate the Reactive Oxygen Species (ROS) generation. Relative mRNA expression of Bax, Bcl2, NOTCH 1, and JAGGED 1 was estimated by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). Cell cycle phase distribution was evaluated by Annexin V-FITC/PI staining. Results: MTT assay demonstrated the dose and time-dependent cytotoxicity of andrographolide on SW-480 cells. It also inhibited the migratory and colony forming potential of SW-480 cells. Furthermore, andrographolide also showed disruption of mitochondrial membrane potential and induced apoptosis through nuclear condensation. Flow cytometric evaluation showed that andrographolide enhanced early and late apoptotic cells and induced upregulation of pro-apoptotic (Bax and Bad) and downregulation of anti-apoptotic Bcl2 in treated SW- 480 cells. Andrographolide augmented intracellular ROS generation and induced G0/G1 phase cell cycle arrest in colon cancer SW-480 cells. Furthermore, andrographolide repressed the Notch signaling by decreasing the expression of NOTCH 1 and JAGGED 1. Conclusion: The findings suggested that andrographolide constraint the growth of SW-480 cells through the inhibition of the Notch signaling pathway.

Background and Purpose: Leukemia is considered a top-listed ailment, according to WHO, which contributes to the death of a major population of the world every year. Paris Saponin VII (PS), a saponin which was isolated from the roots of Trillium kamtschaticum, from our group, was reported to provide hemostatic, cytotoxic and antimicrobial activities. However, its molecular mechanism underlying the anti-proliferative effects remains unclear. Thus, this study hypothesized to assess that mechanism in PS treated HEL cells. Methods: The MTT assay was used to analyze the PS inhibited cell viability in the HEL cells. We further found that PS could induce S phase cell cycle arrest through flow cytometry as well as the western blot analysis of intrinsic and extrinsic apoptotic molecules. Results: The MTT assay showed the IC50 concentration of PS as 0.667μM. The study revealed that PS treatment inhibits cell proliferation dose-dependently. It further caused mitochondrial membrane potential changes by PS treatment. Mechanistic protein expression revealed a dose-dependent upsurge for Bid and Bim molecules, while Bcl2 and PARP expression levels were significantly (P<0.05) down-regulated in PS treated HEL cells resulting in caspase -3 release and increased the Bim levels upon 24h of incubation. Conclusion: These findings indicate that PS possesses an excellent anti-leukemic activity via the regulation of the mitochondrial pathway, leading to S phase cell cycle arrest and caspase-dependent apoptosis, suggesting it as a potential alternative chemotherapeutic agent for leukemia patients.

Background: A Chinese folk medicine plant Pleurospermum lindleyanum possesses pharmacological activities of heat-clearing, detoxifying and preventing from hepatopathy, coronary heart disease, hypertension, and high altitude sickness. We isolated and characterized its constituents to investigate its synergistic effects against human hepatoma SMMC-7721 cells. Objective: The aim of this study was to explore the synergistic anti-cancer activities of isolates from P. lindleyanum with 5-FU on hepatoma SMMC-7721 cells in vitro and their primary mechanisms. Methods: Sequential chromatographic techniques were conducted for the isolation studies. The isolate's structures were established by spectroscopic analysis as well as X-ray crystallographic diffraction. Growth inhibition was detected by MTT assay. The isobologram method was used to assess the effect of drug combinations. Flow cytometry and western blot were used to examine apoptosis and protein expression. Results: A new coumarin (16), along with sixteen known compounds, were isolated from the whole plant of P. lindleyanum and their structures were elucidated by spectroscopic methods. Four coumarins (2, 3, 5, and 16), two flavonoids (8 and 9) and three phytosterols and triterpenes (12-14) were found to synergistically enhance the inhibitory effect of 5-FU against SMMC-7721 cells. Among them, compounds 3 and 16 exhibited the best synergistic effects with IC50 of 5-FU reduced by 16-fold and 22-fold possessing the minimum Combination Index (CI) 0.34 and 0.27. The mechanism of action of combinations might be through synergistic arresting for the cell cycle at G1 phases and the induction of apoptosis. Moreover, western blotting and molecular docking revealed that compounds 3 or 5 might promote 5-FU-induced apoptosis by regulating the expression of Caspase 9 and PARP. Conclusion: Constituents from P. lindleyanum may improve the treatment effectiveness of 5-FU against hepatocellular carcinoma cells.

Background: Compounds with biological activities had been reported in the jackfruit. These compounds are susceptible to structural changes such as isomerization and/or loss of bonds due to environmental factors. Then, the encapsulation for protecting is a necessary process. Objective: In this study, encapsulation of High-Value Biological Compounds (HVBC) was performed using High Degree of Polymerization Agave Fructans (HDPAF) and Whey Protein (WP) as encapsulating materials to preserve the biological properties of the HVBC. Methods: The extract was characterized by HPLC-MS in order to show the presence of compounds with preventive or therapeutic effects on chronic degenerative diseases such as cancer. The micrographs by Scanning Electron Microscopy (SEM), Thermal Analysis (TGA and DSC), photostabilization and antiproliferation of M12.C3.F6 cell line of capsules were evaluated. Results: The micrographs of the nanocapsules obtained by Scanning Electron Microscopy (SEM) showed spherical capsules with sizes between 700 and 800nm. No cracks, dents or deformations were observed. The Thermogravimetric Analysis (TGA) evidenced the decomposition of the unencapsulated extract ranging from 154 to 221°C. On the other hand, the fructan-whey protein mixture demonstrated that nanocapsules have a thermoprotective effect because the decomposition temperature of the encapsulated extract increased 32.1°C. Differential Scanning Calorimetry (DSC) exhibited similar values of the glass transition temperature (Tg) between the capsules with and without extract; which indicates that the polymeric material does not interact with the extract compounds. The photoprotection study revealed that nanocapsules materials protect the jackfruit extract compounds from the UV radiation. Finally, the cell viability on the proliferation of M12.C3.F6 cell line was not affected by powder nanocapsules without jackfruit extract, indicating that capsules are not toxic for these cells. However, microcapsules with jackfruit extract (50μg/ml) were able to inhibit significantly the proliferation cells. Conclusion: The encapsulation process provides thermoprotection and photostability, and the antiproliferative activity of HVBC from jackfruit extract was preserved.

Aim: The aim of this study is to explore the therapeutic potential of S-allylcysteine (SAC) organosulphur compound as a potent immune checkpoint inhibitor PD-L1. Background: Natural compounds have been showing tremendous anticancerous potential via suppressing the expression of genes involved in the development and progression of several carcinomas. This has further motivated us to explore the therapeutic potential of organosulphur compounds as potent immune checkpoint inhibitors. Objective: Our study was designed to elucidate the potential of S-allylcysteine (SAC) as significant PD-L1 (immune checkpoint) inhibitor in human lung cancer A549 cancer cell line by using both the in vitro and in silico approaches. Methods: Anticancerous effect of the SAC on lung cancer cells was determined by using the MTT cell viability. Apoptotic induction was confirmed by Hoechst staining, percent caspase-3 activity as well as gene expression analysis by real time PCR. Reactive Oxygen Species (ROS) was estimated by DCFDA method. Additionally, ligand-target protein interaction was analysed by molecular docking. Result: Cell growth and proliferation was significantly reduced in SAC treated A549 cells in a concentration and time dependent manner. The effect of SAC on apoptotic induction was analyzed by enhanced nuclear condensation, increased percent caspase-3 activity as well as modulation of apoptotic genes. Furthermore, SAC treatment also resulted in reduced expression of PD-L1 and HIF-1α. Additionally, in silico analysis also supported the in vitro findings by showing efficient docking with PD-L1 immune checkpoint target. Conclusion: Therefore, our results clearly suggested that SAC could serve as a novel chemotherapeutic candidate for the treatment of lung cancer by inhibiting immune checkpoint target PD-L1 in human lung cancer cells. Additionally, our study also explained a novel molecular mechanism of its antitumor activity.