Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 21, Issue 11, 2021

Anticancer is a high priority research area for scientists as cancer is one of the leading causes of death globally. It is pertinent to mention here that conventional anticancer drugs such as methotrexate, vincristine, cyclophosphamide, etoposide, doxorubicin, cisplatin, etc. are not much efficient for the treatment of different types of cancer; also these suffer from serious side effects leading to therapy failure. A large variety of cancerrelated receptors such as carbonic anhydrase, tyrosine kinase, topoisomerase, protein kinase, histone deacetylase, etc. have been identified which can be targeted by anticancer drugs. Heterocycles like oxadiazole, thiazole, thiadiazole, indole, pyridine, pyrimidine, benzimidazole, etc. play a pivotal role in modern medicinal chemistry because they have a broad spectrum of pharmacological activities including prominent anticancer activity. Therefore, it was considered significant to explore heterocyclic compounds reported in recent most literature which can bind effectively with the cancer-related receptors. This will not only provide a targeted approach to deal with cancer but also the safety profile of the drugs can be further improved. The information provided in this manuscript may be found useful for the design and development of anticancer drugs.

Background: Cancer is one of the major causes of human mortality worldwide. A number of existing antineoplastic medications and treatment regimens are already working in the field, and several new compounds are in different phases of clinical trials. An extensive series of anticancer drugs exist in the market, and studies suggest that these molecules are associated with different types of adverse side effects. The reduction of the cytotoxicity of drugs to normal cells is a major problem in anticancer therapy. Therefore, researchers around the globe are involved in the development of more efficient and safer anticancer drugs. The output of extensive research is that the quinazoline scaffold and its various derivatives can be explored further as a novel class of cancer chemotherapeutic agents that has already shown promising activities against different tumours. Quinazoline derivatives have already occupied a crucial place in modern medicinal chemistry. Various research has been performed on quinazoline and their derivatives for anticancer activity and pharmacological importance of this scaffold has been well established. Objective: The aim of this review is to compile and highlight the developments concerning the anticancer activity of quinazoline derivatives as well as to suggest some new aspects of the expansion of anticancer activity of novel quinazoline derivatives as anticancer agents in the near future. Methods: Recent literature related to quinazoline derivatives endowed with encouraging anticancer potential is reviewed. With a special focus on quinazoline moiety, this review offers a detailed account of multiple mechanisms of action of various quinazoline derivatives: inhibition of the DNA repair enzyme system, inhibition of EGFR, thymidylate enzyme inhibition and inhibitory effects for tubulin polymerization by which these derivatives have shown promising anticancer potential. Results: Exhaustive literature survey indicated that quinazoline derivatives are associated with properties of inhibiting EGFR and thymidylate enzymes. It was also found to be involved in disturbing tubulin assembly. Furthermore, quinazoline derivatives have been found to inhibit critical targets such as DNA repair enzymes. These derivatives have shown significant activity against cancer. Conclusion: In cancer therapy, Quinazoline derivatives seems to be quite promising and act through various mechanisms that are well established. This review has shown that quinazoline derivatives can further be explored for the betterment of chemotherapy. A lot of potentials are still hidden, which demands to be discovered for upgrading quinazoline derivatives efficacy.

Head and Neck Squamous Cell Carcinoma (HNSCC) is an aggressive malignancy affecting more than 600,000 cases worldwide annually, associated with poor prognosis and significant morbidity. HNSCC tumors are dysplastic, with up to 80% fibroblasts. It has been reported that Cancer-Associated Fibroblasts (CAFs) facilitate HNSCC progression. Unlike normal cells, malignant cells often display increased glycolysis, even in the presence of oxygen; a phenomenon known as the Warburg effect. As a consequence, there is an increase in Lactic Acid (LA) production. Earlier, it has been reported that HNSCC tumors exhibit high LA levels that correlate with reduced survival. It has been reported that the activation of the receptor tyrosine kinase, c- MET, by CAF-secreted Hepatocyte Growth Factor (HGF) is a major contributing event in the progression of HNSCC. In nasopharyngeal carcinoma, c-MET inhibition downregulates the TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) and NADPH production resulting in apoptosis. Previously, it was demonstrated that HNSCC tumor cells are highly glycolytic. Further, CAFs show a higher capacity to utilize LA as a carbon source to fuel mitochondrial respiration than HNSCC. Earlier, we have reported that in admixed cultures, both cell types increase the expression of Monocarboxylate Transporters (MCTs) for a bidirectional LA transporter. Consequently, MCTs play an important role in signalling cross-talk between cancer cells and cancer associate fibroblast in head and neck cancer, and targeting MCTs would lead to the development of a potential therapeutic approach for head and neck cancer. In this review, we focus on the regulation of MCTs in head and neck cancer through signalling cross-talk between cancer cells and cancer-associated fibroblasts, and targeting this signalling cross talk would lead to the development of a potential therapeutic approach for head and neck cancer.

Background: Cancer is second leading disease after cardiovascular disease. Presently, Chemotherapy, Radiotherapy and use of chemicals are some treatments available these days. Thiazole and its hybrid compounds extensively used scaffolds in drug designing and development of novel anticancer agents due to their wide pharmacological profiles. Fused thiazole scaffold containing drugs are available in market as a promising group of anticancer agents. Methods: The detailed study has been done using different database that focused on potent thiazole hybrid compounds with anticancer activity. The literature included in this review is focused on novel fused thiazole derivatives exhibiting anticancer potency in last decade. Results: Literature suggested that thiazoles and its fused and linked congener serve excellent pharmacological profile as an anticancer agent. Various synthetic strategies for fused thiazole are also summarized in this article. Novel thiazole and its fused congener showed anticancer activity against various cancer cell lines. Interpretation: Thiazole is a promising scaffold reported in literature with broad range of biological activities. This article covers the thiazole compounds fused with other carbocyclic/heterocycle including benzene, imidazole, pyridine, pyrimidine, quinoline, phenothiazine, thiopyrano, steroids, pyrrole etc. with anticancer activity from last decades. Several inhibitors for breast cancer, colon cancer, melanoma cancer, ovarian cancer, tubulin cancer etc. were reported in this review. Thus, this review will definitely aid to develop a lead for the new selective anticancer agents in future.

Cancer is the foremost cause of death, and it supports the need for the identification of novel anticancer drugs to improve the efficacy of current-therapy. While the synthetic anticancer drug is associated with numerous side effects. Hence the plant active or phytoconstituents are in high demand for the treatment of cancer due to minimum side effects. But the polar nature of phytoconstituents hindered the absorption of the drug and lowered the therapeutic efficacy. The plant activity incorporated into Phyto-phospholipid Complexation can enhance bioavailability and improved therapeutic efficacy. In this review article, advantages, limitation and application of Phyto-phospholipid complexes have been illustrated. The article highlights the application of Phyto-phospholipid complexes as a promising drug carrier system to treat cancer.

Background: The effect of cruciferous vegetable intake on breast cancer survival is controversial at present. Glucosinolates are the naturally occurring constituents found across the cruciferous vegetables. Isothiocyanates are produced from the hydrolysis of glucosinolates and this reaction is catalysed by the plant-derived enzyme myrosinase. The main Isothiocyanates (ITCs) from cruciferous vegetables are sulforaphane, benzyl ITC, and phenethyl ITC, which had been intensively investigated over the last decade for their anti-breast cancer effects. Objective: The aim of this article is to systematically review the evidence from all types of studies, which examined the protective effect of cruciferous vegetables and/or their isothiocyanate constituents on breast cancer. Methods: A systematic review was conducted in Pubmed, EMBASE, and the Cochrane Library from inception to 27 April 2020. Peer-reviewed studies of all types (in vitro studies, animal studies, and human studies) were selected. Results: The systematic literature search identified 16 human studies, 4 animal studies, and 65 in vitro studies. The effect of cruciferous vegetables and/or their ITCs intake on breast cancer survival was found to be controversial and varied greatly across human studies. Most of these trials were observational studies conducted in specific regions, mainly in the US and China. Substantial evidence from in vitro and animal studies was obtained, which strongly supported the protective effect of sulforaphane and other ITCs against breast cancer. Evidence from in vitro studies showed that sulforaphane and other ITCs reduced cancer cell viability and proliferation via multiple mechanisms and pathways. Isothiocyanates inhibited cell cycle, angiogenesis and epithelial mesenchymal transition, as well as induced apoptosis and altered the expression of phase II carcinogen detoxifying enzymes. These are the essential pathways that promote the growth and metastasis of breast cancer. Noticeably, benzyl ITC showed a significant inhibitory effect on breast cancer stem cells, a new dimension of chemo-resistance in breast cancer treatment. Sulforaphane and other ITCs displayed anti-breast cancer effects at variable range of concentrations and benzyl isothiocyanate appeared to have a relatively lower inhibitory concentration IC50. The mechanisms underlying the cancer protective effect of sulforaphane and other ITCs have also been highlighted in this article. Conclusion: Current preclinical evidence strongly supports the role of sulforaphane and other ITCs as potential therapeutic agents for breast cancer, either as adjunct therapy or combined therapy with current anti-breast cancer drugs, with sulforaphane displaying the greatest potential.

Background: Coumarin and benzophenone possess a vast sphere of biological activities, whereas thiazoles display various pharmacological properties. Hence, present study focused on the incorporation of coumarin and thiazole core to the benzophenone skeleton to enhance the bioactivity, anticipating their interesting biological properties. Objective: The objective of the current work is the synthesis and biological evaluation of a novel series of coumarin fused thiazole derivatives. Methods: A novel series of coumarin conjugated thiazolyl acetamide hybrid derivatives were synthesized by a multistep reaction sequence and were characterized by the FT-IR, LCMS, and NMR spectral techniques. The newly synthesized compounds were screened for anti-cancer activity by in silico and in vitro methods. The cytotoxicity of the synthesized unique compounds was executed for two different cancer cell lines, MCF-7 (Breast cancer) and KB (Oral cancer), in comparison with standard paclitaxel by MTT assay. Results: The compound 7f is a potent motif with an acceptable range of IC50 values, for anti-cancer activity, i.e., 63.54μg/ml and 55.67μg/ml, against the MCF-7 and KB cell lines, respectively. Molecule docking model revealed that this compound formed three conventional hydrogen bonds with the active sites of the amino acids, MET 769, ARG 817, and LYS 721. Conclusion: Compound 7f with two methyl groups on the phenoxy ring and one 4-position methoxy group on the benzoyl ring, showed a significant cytotoxic effect. An advantageous level of low toxicity against normal cell line (L292) by MTT assay was determined.

Aims: The purpose of this study was the synthesis of some new thienopyrimidine derivatives of 1,3-disubstituted benzimidazoles and the evaluation of their cytotoxicity against MDA-MB-231, MCF-7, and 3T3 cells lines. Background: An overexpression or mutational activation of TK receptors EGFR and HER2/neu is characteristic of tumors. It has been found that some thieno[2,3-d]pyrimidines exhibited better inhibitory activity against Epidermal Growth Factor Receptor (EGFR/ErbB-2) tyrosine kinase in comparison to aminoquinazolines. Breast cancer activity towards MDA-MB-231 and MCF-7 cell lines by inhibiting EGFR was revealed by a novel 2-arylbenzimidazole. This motivated the synthesis of new thienopyrimidines possessing benzimidazole fragments in order to evaluate their cytotoxicity to the above-mentioned cell lines. Objective: The objectives of the study were to design and synthesize a novel series of thieno[2,3-d]pyrimidines bearing biologically active moieties, such as 1,3-disubstituted-benzimidazole heterocycle, structurally similar to diaryl ureas in order to evaluate their cytotoxicity against MDA-MB-231, and MCF-7 breast cancer cell lines. Methods: N,N-disubstituted benzimidazole-2-one carbonitriles were synthesized by Aza-Michael addition and used as precursors to generate some of the new thieno[2,3-d]pyrimidines in acidic medium The interaction of chloroethyl-2-thienopyrimidines, 2-amino-benzimidazole and benzimidazol-2-one nitriles under solid-liquid transfer catalysis conditions led to new thienopyrimidines. MTT assay for cell survival was performed in order to evaluate the cytotoxicity of the tested compounds. A fluorescence study was conducted to elucidate some aspects of the mechanism of action. Results: The effects of nine synthesized compounds were investigated towards MDA-MB-231, MCF-7 and 3T3 cell lines. Thieno[2,3-d]pyirimidine-4-one 16 (IC50 - 0.058μM) and 21 (IC50 - 0.029μM) possess high cytotoxicity against MDA-MB-231 cells after 24h. The most cytotoxic compounds against breast cancer MCF-7 cells was compound 21 (IC50 - 0.074μM), revealing lower cytotoxicity against mouse fibroblast 3T3 cells with IC50 - 0.20μM. SAR analysis was performed. Fluorescence study of the treatment of MDA-MB cells with compound 21 was carried out in order to clarify some aspects of the mechanism of action. Conclusion: The relationship between cytotoxicity of compounds 14 and 20 against MCF-7 and 3T3 cells can suggest a similar mechanism of action. The antitumor potential of the tested compounds proves the necessity for further investigation to estimate the exact inhibition pathway in the cellular processes. The fluorescence study of the treatment of MDA-MB cells with compound 21 showed a rapid process of apoptosis.

Background and Objective: Histone Deacetylases (HDACs) are important therapeutic targets for many types of human cancers. A derivative of valproic acid, N-(2-hydroxyphenyl)-2-propylpentanamide (HOAAVPA), has antiproliferative properties on some cancer cell lines and inhibits the HDAC1 isoform. Materials and Methods: In this work, HO-AAVPA was tested as an antiproliferative agent in U87-MG (human glioblastoma) and U-2 OS cells (human osteosarcoma), which are types of cancer that are difficult to treat, and its antiangiogenic properties were explored. Results: HO-AAVPA had antiproliferative effects at 48h with an IC50=0.655mM in U87-MG cells and an IC50=0.453mM in U-2 OS cells. Additionally, in the colony formation assay, HO-AAVPA decreased the number of colonies by approximately 99% in both cell lines and induced apoptosis by 31.3% in the U-2 OS cell line and by 78.2% in the U87-MG cell line. Additionally, HO-AAVPA reduced the number of vessels in Chorioallantoic Membranes (CAMs) by approximately 67.74% and IL-6 levels in both cell lines suggesting that the biochemical mechanism on cancer cell of HO-AAVPA is different compared to VPA. Conclusion: HO-AAVPA has antiproliferative effects on glioblastoma and osteosarcoma and antiangiogenic properties.

Introduction: Inflammation is a vital reaction of the natural immune system that protects against encroaching agents. However, uncontrolled inflammation can lead to complications. Trigonella foenumgraecum is traditionally used as an anti-inflammatory herb. Objectives: The current study was conducted to explore the antioxidant, anti-inflammatory, and antiangiogenic potentials of Trigonella foenum-graecum seeds oil. Methods: Oil was extracted from seeds of Trigonella foenum-graecum by cold press method and labelled as TgSO. Phytochemical (GC-MS, Folin-Ciocalteu method) and metal analyses were conducted to evaluate the metalo-chemical profile of TgSO. In vitro antioxidant assays (2,2-diphenyl-1-picrylhydrazyl, 2,2'-azino-bis-3- ethylbenzothiazoline-6-sulfonic acid and ferric reducing antioxidant power) were performed to assess its antioxidant potential. In vitro antimicrobial activity was evaluated using agar disc diffusion method and the safety profile of TgSO was assessed in acute toxicological studies following OECD 425 guidelines. In vivo antiinflammatory activities of TgSO were assessed in carrageenan, serotonin, histamine, formalin, and cotton pelletinduced oedema models. Serum TNF-α, Superoxide Dismutase (SOD) and, Catalases (CAT) levels were assessed by ELISA kits. In vivo antiangiogenic activity of TgSO was screened in chick Chorioallantoic Membrane (CAM) assay. Histopathological studies using excised paws were conducted to observe the effects of TgSO treatment at the tissue level. In silico docking studies were conducted to screen the binding potentials of identified compounds with TNF-α. Results: Extraction by cold press method yielded 16% of TgSO. Phytochemical analysis of TgSO through GCMS showed the presence of eugenol, dihydrocoumairn, heptadecanoic acid, tri- and tetradecanoic acid, and hexadecanoic acid, respectively. Total phenolic contents of TgSO were found to be 0.30±0.01mg/g gallic acid equivalent in Folin-Ciocalteu method. Metal analysis indicated the presence of different metals in TgSO. Findings of antioxidant models showed the moderate antioxidant potential of TgSO. Findings of antimicrobial assays showed that TgSO was active against bacterial (S. aureus, S. epidermidis) and fungal (C. albicans, and A. niger) strains. In vivo toxicity study data showed that TgSO was safe up to the dose of 5000 mg/kg. Data of oedema models showed a significant (p<0.05) reduction in oedema development in TgSO treated animals in both acute and chronic models. Histopathological evaluations of paws showed minimum tissue infiltration with inflammatory cells in TgSO-treated animals. Treatment with TgSO also significantly (p<0.05) down-regulated TNF-α in serum while levels of SOD and CAT were up-regulated. Findings of the CAM assay revealed the antiangiogenic activity of TgSO. Findings of in silico docking studies showed that identified phytoconstituents can bind with culprit cytokine (TNF-α). Conclusion: Data obtained from the current study conclude that TgSO has antioxidant, anti-inflammatory, and antiangiogenic effects that validate its traditional uses. Synergistic actions of different phytoconstituents are proposed to be responsible for the observed effects.

Background: HSP70 is a survival factor for tumor cells in transformation and in tumor progression as well as in anti-apoptotic response. Objective: Several inhibitors targeting HSP70 ATPase function displayed off-target effects, but PES, which targets the HSP70 substrate binding domain, prevents tumor cell survival prominently. However, PES may not bind HSP70 in the absence of nucleotide. This research aimed to design a unique inhibitor molecule that works both in the presence and absence of nucleotides to amplify inhibition. Methods: A set of chimeric coumarine-pyrazole derivatives were determined by in silico techniques and synthesized to elucidate their inhibitory effects. Cell viability experiments displayed KBR1307 as the most efficient inhibitor. A set of characterization experiments were performed, and the results were compared to that of PES agent. Binding constant, ATP hydrolysis rate, and percent aggregation were determined in the presence and absence of inhibitors. Results: In silico docking experiments showed that only KBR1307 binds the HSP70 substrate binding domain and interacts with cochaperone interface. Binding experiments indicated that KBR1307 binds HSP70 both in the presence and absence of nucleotides, but PES does not. Both inhibitors significantly lower HSP70 ATPase activity and substrate protein disaggregation activity. However, KBR1307 displays a lower IC50 value at the MCF-7 cell line compared to PES. Both inhibitors do not alter HSP70 secondary structure composition and overall stability. Conclusion: KBR1307 effectively inhibits HSP70 compared to PES and provides a promising template for novel anticancer drug development.