Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 21, Issue 3, 2021

Background: Quinoline is considered to be a privileged heterocyclic ring owing to its presence in diverse scaffolds endowed with promising activity profiles. In particular, quinoline containing compounds have exhibited substantial antiproliferative effects through the diverse mechanism of actions, which indicates that the heteroaryl unit is flexible as well as accessible to subtle structural changes that enable its inclusion in chemically distinct anti-tumor constructs. Methods: Herein, we describe a medicinal chemistry perspective on quinolines as anticancer agents by digging into the peer-reviewed literature as well as patents published in the past few years. Results: This review will serve as a guiding tool for medicinal chemists and chemical biologists to gain insights about the benefits of quinoline ring installation to tune the chemical architectures for inducing potent anticancer effects. Conclusion: Quinoline ring containing anticancer agents presents enough optimism and promise in the field of drug discovery to motivate the researchers towards the continued explorations on such scaffolds. It is highly likely that adequate efforts in this direction might yield some potential cancer therapeutics in the future.

Background: The use of nanoparticles synthesized by the green method to treat cancer is fairly recent. The aim of this study was to evaluate cytotoxicity, apoptotic and anti-angiogenic effects and the expression of involved genes, of Zinc Oxide Nanoparticles (ZnO-NPs) synthesized with Carob extracts on different human breast cancer cell lines. Methods: ZnO-NPs were synthesized using the extracts of Carob and characterized with various analytical techniques. The MCF-7 and MDA-MB231 cells were treated at different times and concentrations of ZnO-NPs. The cytotoxicity, apoptosis, and anti-angiogenic effects were examined using a series of cellular assays. Expression of apoptotic genes (Bax and Bcl2) and anti-angiogenic genes, Vascular Endothelial Growth Factor (VEGF) and its Receptor (VEGF-R) in cancer cells treated with ZnO-NPs were examined with Reverse Transcriptionquantitative Polymerase Chain Reaction (RT-qPCR). The anti-oxidant activities of ZnO-NPs were evaluated by ABTS and DPPH assay. Results: Exposure of cells to ZnO-NPs resulted in a dose-dependent loss of cell viability. The IC50 values at 24, 48, and 72 hours were 125, 62.5, and 31.2μg/ml, respectively (p<0.001). ZnO-NPs treated cells showed, in fluorescent microscopy, that ZnO-NPs are able to upregulate apoptosis and RT-qPCR revealed the upregulation of Bax (p<0.001) and downregulation of Bcl-2 (p<0.05). ZnO-NPs increased VEGF gene expression while decreasing VEGF-R (p<0.001). The anti-oxidant effects of ZnO-NPs were higher than the control group and were dose-dependent (p<0.001). Conclusion: ZnO-NPs synthetized using Carob extract have the ability to eliminate breast cancer cells and inhibit angiogenesis, therefore, they could be used as an anticancer agent.

Background: Benzo[d]imidazoles are highly biologically active, in addition, they are considered as a class of heterocyclic compounds with many pharmaceutical applications. Objective: We are aiming in this work to synthesize target molecules that possess not only anti-tumor activities but also kinase inhibitors. The target molecules were obtained starting from the benzo[d]imidazole derivatives followed by their heterocyclization reactions to produce anticancer target molecules. Methods: The 1-(1H-benzo[d]imidazol-2-yl)propan-2-one (3) and the ethyl 2-(1H-benzo[d]imidazol-2- yl)acetate (16) were used as the key starting material which reacted with salicylaldehyde to give the corresponding benzo[4,5]imidazo[1,2-a]quinoline derivatives. On the other hand, both of them were reacted with different reagents to give thiophene, pyran and benzo[4,5]imidazo[1,2-c]pyrimidine derivatives. The synthesized compounds were evaluated against the six cancer cell lines A549, HT-29, MKN-45, U87MG, SMMC-7721, and H460 together with inhibitions toward tyrosine kinases, c-Met kinase and prostate cancer cell line PC-3 using the standard MTT assay in vitro, with foretinib as the positive control. Results: Most of the synthesized compounds exhibited high inhibitions toward the tested cancer cell lines. In addition, tyrosine and Pim-1 kinases inhibitions were performed for the most active compounds where the variation of substituent through the aryl ring and heterocyclic ring afforded compounds with high activities. Our analysis showed that there is a strong correlation between the structure of the compound and the substituents of target molecules. Conclusion: Our present research proved that the synthesized heterocyclic compounds with varieties of substituents have a strong impact on the activity of compounds. The evaluations through different cell lines and tyrosine kinases indicated that the compounds were the excellent candidates as anticancer agents. This could encourage doing further research within this field for the building of compounds with high inhibitions.

Background: Inflammation is a key element in tumor progression, over time, persistent inflammation causes damage to DNA and leads to cancer. The relationship between chronic inflammation and tumor development is well established, blocking of which can help in cancer prevention and treatment in the future. Objective: Hence, with this background, the present study aims to evaluate the anti-inflammatory and anticancer potential of Cassia auriculata (CA) solvent fractions through in silico and in vitro means, respectively. Methods: Generally, inflammatory mediators play a key task in chronic inflammation, following its inflection was chosen for their interactions with nine structurally varied phytoconstituents of CA identified through GCMS. The ethanolic extract of CA was assessed for its apoptotic effects on A549 lung cancer cells by 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, JC-10 staining, DNA fragmentation assay and quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Results: The interactions between bioactive components and target protein revealed that important molecules like 5,7-dihydroxy-2-[2-nethoxyphenyl]- 4H-1-Benzopyran-4-one, a flavonoid, and three other components can bind target interleukin 1-beta associated with lung cancer. In vitro data also confirmed that the diverse active components of CA extract might follow the intrinsic mitochondrial pathway to provoke cancer cell death. Conclusion: Hence, these findings strongly propose that Cassia auriculata (CA) solvent fractions could be exploited in the future to design ligands for obtaining novel leads for treating chronic inflammation linked with lung cancer, and also the extracts of CA can be recommended as a potential agent for lung cancer chemotherapy.

Background: Triple Negative Breast Cancer (TNBC) is an aggressive and highly heterogeneous subtype of breast cancer associated with poor prognosis. A better understanding of the biology of this complex cancer is needed to develop novel therapeutic strategies for the improvement of patient survival. We have previously demonstrated that Thymoquinone (TQ), the major phenolic compound found in Nigella sativa, induces anti-proliferative and anti-metastatic effects and inhibits in vivo tumor growth in orthotopic TNBC models in mice. Also, we have previously shown that Beclin-1 and LC3 autophagy genes contributes to TNBC cell proliferation, migration and invasion, suggesting that Beclin-1 and LC3 genes provide proto-oncogenic effects in TNBC. However, the role of Beclin-1 and LC3 in mediating TQ-induced anti-tumor effects in TNBC is not known. Objective: To investigate the effects of TQ on the major autophagy mediators, Beclin-1 and LC3 expression, as well as autophagic activity in TNBC cells. Methods: Cell proliferation, colony formation, migration and autophagy activity were evaluated using MTS cell viability, colony formation assay, wound healing and acridine orange staining assays, respectively. Western blotting and RT-PCR assays were used to investigate LC3 and Beclin-1 protein and gene expressions, respectively, in MDA-MB-231 TNBC cells in response to TQ treatments. Results: TQ treatment significantly inhibited cell proliferation, colony formation, migration and autophagic activity of MDA-MB-231 cells and suppressed LC3 and Beclin-1 expressions. Furthermore, TQ treatment led to the inhibition of Integrin-β1, VEGF, MMP-2 and MMP-9 in TNBC cells. Conclusion: TQ inhibits autophagic activity and expression of Beclin-1 and LC3 in TNBC cells and suppresses pathways related to cell migration/invasion and angiogenesis, including Integrin-β1, VEGF, MMP-2 and MMP- 9, suggesting that TQ may be used to control autophagic activity and oncogenic signaling in TNBC.

Background: Cancer is known to be the second significant cause of death worldwide. Chemotherapeutic agents such as platinum-based compounds are frequently used single-handedly or accompanied by additional chemotherapies to treat cancer patients. Chemotherapy-induced peripheral painful neuropathy is seen in around 40% of patients who are treated with platinum-based compounds, including cisplatin. This not only decreases the quality of life of patients but also patients’ compliance with cisplatin. Objectives: Nalbuphine, an opioid, is frequently used to treat acute and chronic pain, coupled with cisplatin in cancer patients. However, long term use of nalbuphine induces tolerance to its analgesic effects. We employed the same strategy to induce tolerance in mice. Methods: Here, we investigated analgesic effects of 2-[(pyrrolidin-1-yl) methyl]-1H-benzimidazole (BNZ), a benzimidazole derivative, on nalbuphine-induced tolerance during cisplatin-induced neuropathic pain using hot plate test, tail-flick tests and von Frey filament in mouse models. Furthermore, we investigated the effects of BNZ on the expression of Tumor Necrosis Factor-alpha (TNF-α) in the spinal cord. Results: The results showed that BNZ reduced tolerance to analgesic effects of nalbuphine and TNF-α expression in mice. Conclusion: BNZ could be a potential drug candidate for the management of nalbuphine-induced tolerance in cisplatin-induced neuropathic pain.

Background: Despite advances in the treatment of prostate cancer, side effects and the risks of developing drug resistance require new therapeutic agents. Eupatilin is a secondary metabolite of Artemisia asiatica and has shown potential anti-tumor activity in some cancers, but its potential in prostate cancer treatment has not yet been evaluated. Objective: The aim of the study was to investigate the effectiveness of eupatilin on prostate cancer cell proliferation and migration. Methods: Human prostate cancer PC3 and LNCaP cells were exposed to eupatilin and its efficacy on cell survival was determined by the MTT test. Apoptosis and cell cycle phases were evaluated by an image-based cytometer. Cell migration and invasion were evaluated by wound healing and matrigel migration assays; the expression of mRNA and protein was assessed by RT-qPCR and Western blot, respectively. Results: Eupatilin time- and dose-dependently reduced the viability of prostate cancer cells. Exposure of PC3 cells to 12.5μM-50μM eupatilin resulted in apoptosis by upregulating the expression of caspase 3, Bax and cytochrome c. Annexin V assessment also confirmed that eupatilin causes apoptosis. The treatment significantly upregulated the mRNA expression of p53, p21, and p27, causing cell cycle arrest in the G1 phase. Administration of eupatilin inhibited migration and invasion of the cells by downregulating the expression of Twist, Slug and MMP-2, -7. In addition, the agent increased protein expression of tumor suppressor PTEN, while transcription factor NF-ΚB expression was reduced. Conclusion: Eupatilin strongly prevents the proliferation of prostate cancer cells, and suppresses migration and invasion. Due to its therapeutic potential, the clinical use of eupatilin in prostate cancer should also be supported by in vivo studies.

Aims: In the present study, polymer-drug conjugates were synthesized based on azo-bond cleavage drug delivery approach for targeting erlotinib as an anticancer drug specifically to the colon for the proficient treatment of colon cancer. Background: Colon Cancer (CC) is the third commonly detected tumor worldwide and makes up about 10% of all cases of cancers. Most of the chemotherapeutic drugs available for treating colon cancer are not only toxic to cancerous cells but also to the normal healthy cells. Among the various approaches to get rid of the adverse effects of anticancer agents, prodrugs are one of the most imperative approaches. Objective: The objective of the study is to chemically modify the erlotinib drug through azo-bond linkage and suitable spacer which will be finally linked to the polymeric backbone to give the desired polymer linked prodrug. The azo reductase enzyme present in the colon is supposed to cleave the azo-bond specifically and augment the drug release at the colon. Methods: The synthesized conjugates were characterized by IR and ¹H-NMR spectroscopy. The cleavage of aromatic azo-bond resulted in a potential colon-specific liberation of drug from conjugate studied in rat fecal contents. In vitro release profiles of polyphosphazene-linked conjugates of erlotinib have been studied at pH 1.2, pH 6.8 and pH 7.4. The stability study was designed to exhibit that free drug was released proficiently and unmodified from polyphosphazene-erlotinib conjugates having aromatic azo-bond in artificial colon conditions. Results: The synthesized conjugates were demonstrated to be stable in simulated upper gastrointestinal tract conditions. The drug release kinetics shows that all the polymer-drug conjugates of erlotinib follow zero-order release kinetics which indicates that the drug release from the polymeric backbone is independent of its concentration. Kinetic study of conjugates with slope (n) shows the anomalous type of release with an exponent (n) > 0.89 indicating a super case II type of release. Conclusion: These studies indicate that polyphosphazene linked drug conjugates of erlotinib could be promising candidates for the site-specific treatment of colon cancer with the least detrimental side-effects.

Background: The quest for strong, safe and cost-effective natural antiproliferative agents that could reduce cancer has been the focus now a days. In this regard, the organosulfur compounds from garlic (Allium sativum L.), like Diallyl Sulfide (DAS) and Diallyl Disulfide (DADS), have been shown to exhibit potent antiproliferative and anticancer properties in many studies. However, the potential of these compounds against viral oncoproteins in cervical cancer has not been fully elucidated yet. Objective: The objective of this study was to analyze the antiproliferative and apoptotic properties of DADS and DAS in HPV16+ human cervical cancer Caski cell line. Methods: Caski (cervical cancer cells) were cultured and followed by the treatment of various concentrations of organosulphur compounds (DADS and DAS), cell viability was measured by MTT assay. The apoptotic assay was performed by DAPI and Hoechst3342 staining. Reactive Oxygen Species (ROS) was estimated by DCFDA staining protocol. The distributions of cell cycle and apoptosis (FITC-Annexin V assay) were analyzed by flow cytometry. Finally, gene expression analysis was performed via quantitative real time PCR. Results: Our results showed that DAS and DADS exerted a significant antiproliferative effect on Caski cells by reducing the cell viability and inducing a dose-related increment in intracellular ROS production along with apoptosis in Caski cells. DAS and DADS also induced cell cycle arrest in G0/G1 phase, which was supported by the downregulation of cyclin D1 and CDK4 and upregulation of CDK inhibitors p21WAF1/CIP1 and p27KIP1 in Caski cells. Additionally, DAS and DADS lead to the downregulation of viral oncogene E6 and E7 and restoration of p53 function. Conclusion: Thus, this study confirms the efficacy of both the organosulfur compounds DADS and DAS against cervical cancer cells.

Background: Defects in the physiological mechanisms of apoptosis are one of the pivotal factors implicated in carcinogenesis. Thus, the development of novel compounds that target various apoptotic pathways has provided promising anticancer therapeutic opportunities. Objective: This study explores the cytotoxic effects of a novel unsymmetrical azine against specific cancer cell lines and investigates the mechanism of cytotoxicity. Methods: Molecular modeling was used to test the binding affinity of four new unsymmetrical azines to a model of an apoptosis inhibitor protein (XIAP). The compound with the highest binding affinity, C4, was further tested on different cell lines. Real-time Polymerase Chain Reaction (PCR) and Transmission Electron Microscope (TEM) were used to study apoptosis induction biochemically and morphologically. Results: In comparison to cisplatin as a control, the compound C4 exhibited notable cytotoxicity against all tested cancer cell lines, especially the human colorectal carcinoma cell line (HCT-116). Furthermore, C4-treated cells demonstrated marked overexpression of the pro-apoptotic proteins Bax and caspase-3 as well as the tumor suppressor p53. On the other hand, the expression of the anti-apoptotic protein Bcl-2 was inhibited. On TEM examination, C4-treated HCT-116 cells showed classical structural signs of apoptosis. Conclusion: This study identifies a novel azine (C4), which induces remarkable cytotoxicity against the colorectal carcinoma cell line, mediated through apoptosis induction. These novel insights suggest C4 as a promising therapeutic agent in colorectal cancer.