Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 22, Issue 19, 2022

Cancer, a crucial global health problem, is characterized by abnormal cell division and uncontrolled growth. According to WHO, cancer is the second leading cause of global deaths and accounted for approximately 9.6 million deaths or one in six deaths in 2018. The National Cancer Registry Programme Report 2020, released by the ICMRIndia, estimated that there would be 13,90,000 cases of cancer in India in 2020 and that this number is likely to rise to 15,70,000 by 2025. In spite of several anti-cancer drugs, cancer cannot be cured completely, especially at late stages. In the current era, almost every person is suffering from some kind of disease. Thus, it is the necessity of time to develop novel, potent bioactive molecules. Many researchers are working on the development of new lead molecules or finding a new biological target for the betterment of human beings. However, heterocycles are constantly being used for the discovery of new lead molecules. Many of the clinically approved drugs contain the heterocyclic core as these molecules show exhilarating pharmaceutical properties, including anti-cancer agents such as methotrexate, vinblastine, vincristine, daunorubicin, 5-fluorouracil, doxorubicin, etc. Thus, heterocyclic compounds provide a fascinating research area for the design and development of anti-cancer drug(s). Herein, we focused on the natural as well as synthetic anti-cancer heterocyclic compounds. Furthermore, efforts have been made toward the mechanism of action of selected heterocyclic anti-cancer compounds.

Cancer is a leading cause of death worldwide. Proper efficient drugs are required to treat this deadly disease. Natural products have long been a vital source of anticancer agents and they have generated various “lead compounds” suitable for drug developments. With the recent advancement of chemical synthesis and bioevaluation techniques, these lead compounds of natural origins have been utilized for the production of useful anticancer drugs. Among the naturally occurring bioactive compounds, various O-heterocycles have been evaluated as remarkable cancer therapeutic agents. These compounds generally possess unique structures and novel mechanisms of action. In the present review article, some selected O-heterocycles as promoting anticancer agents have been discussed in brief. Various natural sources and chemistry, as well as bioactivities of these compounds, have been described. The development of improved analogues of these compounds through synthetic modifications and efficient bioevaluation, along with proper studies on structure-activity relationship and mechanism of actions, has been mentioned. The article has demonstrated the recent relevance of naturally occurring O-heterocyclic compounds in the current anticancer drug discovery and development scenario.

Mother Nature is an indispensable source of bioactive natural products. Bioactive secondary metabolites have played a crucial role in the drug development and discovery process; mainly, anticancer and antibiotic molecules are extensively enriched with molecules of natural origin. Anthocyanins are water-soluble secondary metabolites found in most species in the plant domain, especially flowers, fruits, and tubers. These natural vacuolar pigments belong to the chemical class of phenolic moieties, which are responsible for the shiny orange, red, blue, pink, and violet colors in the fruits, flowers, and vegetables. Chemically, anthocyanins comprise a core structure in the form of flavylium cation or 2-phenylbenzopyrylium, and these natural colorants are polyhydroxy and polymethoxy analouges of this flavylium cation and can have sugar moieties or acylated groups linked at different positions. Currently, these molecules have raised a growing interest because of their wide range of colors, innocuous and beneficial health effects, and commercial application in functional foods, nutraceuticals, pharmaceutical and cosmetic industries. However, interest in anthocyanin derivatives has noticeably enhanced in recent years due to their higher stability, improved bioavailability in biological matrices, and better use in food matrices and cosmetic products. Due to the enormous potential of natural anthocyanins and their derivatives, this review tries to cover syntheses of anthocyanins and their analogues, chemical derivatization of anthocyanins, and anticancer activities, such as breast, colorectal, leukemia, lung, prostate, and skin cancer of anthocyanins efficiently.

Heterocyclic compounds offer an enormous area for new lead molecules for drug discovery. Till today, efforts are being continuously made to find appropriate treatment for the management of the deadly disease of cancer. Amongst the large number of heterocycles that are found in nature, heterocycles having oxygen obtained noteworthy attention due to their distinctive and pharmacological activities.‘Pyran’ is one of the most significant non-aromatic, sixmembered ring composed of one oxygen atom and five carbon atoms. It is considered a privileged structure since pyran and its related derivatives exhibit a wide spectrum of biological activities. Pyran derivatives are found to have excellent anti-cancer properties against various types of cancer. The present review focussed on the current advances in different types of pyran-based derivatives as anti-cancer agents. Various in vitro (cell based testing), in vivo (animal based testing) models as well as molecular docking along with results are also covered. A subsection describing briefly natural pyran containing anticancer compounds is also incorporated in the review.

Background: In recent years, there has been a crucial need for the design and development of novel anticancer drugs that can lessen the serious health problems and unwanted side effects associated with currently used anticancer drugs. The triazole nucleus is well-recognized to possess numerous pharmacological activities, including anticancer, as revealed by various investigations on anticancer drugs and the latest research findings. Objective: The aim of this review article is to summarise the anticancer potential of 1, 2, 3-triazole, 1, 2, 4-triazole and heterocycle-fused triazole derivatives against several human cancer cell lines, compiling research articles published between 2010 and 2021. Methods: Data were collected from PubMed, Google scholar and Research Gate using keywords “anticancer activity of 1, 2, 3-triazole derivatives”, “anticancer activity of 1, 2, 4-triazole derivatives” and “anticancer activity of heterocycle- fused triazole derivatives” and reviewed comprehensively. Results: This review examines the anticancer potential of 1,2,3-triazole coupledoleanolic acid/dithiocarbamate/ pyrido[ 2,3-d] pyrimidine derivatives, 1,2,3-triazole linked pyrimidine/1,4-naphthoquinone hybrids, and 1,2,4-triazole substituted methanone derivatives, acridine-based 1,2,4-triazole derivatives, 1,2,4-thiadiazol coupled with 1,2,4- triazole and 5-ene-thiazolo[3,2-b][1,2,4]triazole-6(5H)-one derivatives against several human cancer cell lines. Conclusion: This review highlights the key findings in the area of cancer therapy. Triazole derivatives possess anticancer activity against various human cancer cell lines, and hence the triazole core may act as a lead molecule for the synthesis of novel anticancer drugs.

Background: Cancer is a life-threatening disease. Anti-cancer drugs are the focus of research. The heterocyclic molecules like benzimidazole occupy a central position in searching for novel and effective anti-cancer drugs. The medicinal chemists designed and synthesized several benzimidazole derivatives and conjugates to evaluate them as potential anti-cancer agents. Objective: The purpose of this compilation of literature is to cover the progress of benzimidazole-based anti-cancer agents, their synthesis, and their evaluation for cancer disease treatment. Methods: The recent literatures have been collected from various search engines and peer-reviewed journals. Results: The compounds like benzimidazole derivatives of dehydroabietic acid, piperidyl benzimidazole carboxamide, benzimidazole-quinazolinone hybrids, benzimidazole-thiazole conjugate, and benzimidazole pendant cyanopyrimidine derivatives have been discussed in detail. Conclusion: This review article will help the medicinal chemists to design and synthesize benzimidazole-based molecules and evaluate them as anti-cancer agents.

Heterocyclic compounds are that type of substances that are deeply intertwined with biological processes. Heterocycles are found in about 90% of commercially available medicines. In medicinal chemistry, finding new synthetic molecules with drug-like characteristics is a regular problem, which triggered the development of pharmacological molecules, the majority of which are based on N-heterocyclic motifs. Among the heterocycles, the pyrrole scaffold is the most commonly found heterocycle in both natural and synthetic bioactive compounds. Pyrrole has a fivemembered heterocyclic ring with a plethora of pharmacophores, resulting in a library of different lead compounds. Pyrrole derivatives are physiologically active heterocyclic compounds that can be used as scaffolds for antibacterial, antiviral, anticancer, antitubercular, anti-inflammatory, and as enzyme inhibitors. On account of their extensive pharmacological profile, pyrrole and its various synthetic derivatives have drawn much attention from researchers to explore it for the benefit of humankind. This review presents an overview of recent developments in the pyrrole derivatives against multiple therapeutic targets.

Background: Incidence rates and prevalence of cancer are substantially high globally. New safe therapeutic drugs are endorsed to overcome the high toxicity and poor safety profile of clinical anticancer agents. Objective: As antineoplastic Vosaroxin is a commercial fluoroquinolone (FQ), we hypothesize that superlative antiproliferation activity of lipophilic FQs/TFQs series correlates to their acidic groups and C8-C7 ethylene diamine Chelation Bridge along with bulky dual halogenations. Methods: We tested dual lipophilic- acidic chelating FQs with a genuine potential of antiproliferative propensities based on their dual DPPH- and NO- radicals scavenging biocapacities using cell based – and colorimetric assays vs. respective reference agents as their molecular action mechanism. Results: In this work, 9 lipophilic-acid chelating FQs and their cyclized TriazoloFQs (TFQs) designed to bear 7- dihaloanilino substituents with a special focus on dichlorosubstitutions have been prepared, characterized and screened against breast T47D and MCF7, Pancreatic PANC1, colorectal HT29, cervical HELA, lung A375, skin A549, and Leukaemia K562 cancer cell lines using sulforhodamine B colorimetric bioassay. Parameters including potency, toxicity, and selectivity (potency/toxicity) have been reported along with DPPH- and NO- radicals’ scavenging propensities - as their molecular action mechanism- in comparison to ascorbic acid and indomethacin, respectively. Using Griess assay in lipopolysaccharide (LPS) prompted RAW264.7 macrophages inflammation, IC50 values (μM) in the ascending order of new FQs’ NO scavenging/antiinflammation capacity were 4a < 3a < 4c < indomethacin (23.8 < 33.4 < 36 vs. indomethacin’s 124, respectively). Exceptionally unlike the rest, reduced FQ, 4b exhibited remarkably superior DPPH radical scavenging capacity to ascorbic acid (IC50 values (μM) 19.9 vs. 123.9, p < 0.001). In comparison to cisplatin; nitroFQs (3a, 3b and 3c), the reduced FQs (4a, 4b, and 4c) and the TFQs (5a, 5b and 5c) exerted substantial micromolar antiproliferation IC50 values < 50 μM in cervical Hela cancer cells but lacked comparable bioactivity in leukaemia K562. In both breast MCF7 and T47D cancer cell lines, FQs/TFQs 4a < 3a < 5b (respective IC50 values (μM) 0.52 < 22.7 < 24 vs. cisplatin’s 41.8 and 0.03 < 4.8 < 27 vs. cisplatin’s 509), and in both GI system colorectal HT29 and pancreatic PANC1 cancer cells FQs/TFQs 4a < 3a < 5b and 4a< 3a (respective IC50 values (μM) 0.12 < 3.5 < 15.9 vs. cisplatin’s 148 and 1.5 < 10.4 vs. cisplatin’s 25.5), exerted nanomolar-micromolar affinities of antiproliferation potencies < 50μM. Besides in lung A375 cancer cells FQs/TFQs 4c < 4a < 3a and in skin A549 cancer cells 5c < 3c < 4a < 3a < 4c (respective IC50 values (μM) 0.07 < 3.2 < 10.3 vs. cisplatin’s 390 and 0.5 < 2.3 < 3.8 < 8.8 < 17.3 vs. cisplatin’s 107) exhibited nanomolar-micromolar antineoplastic capacities < 50 μM. Their spectrum of selectivity indices for safety in fibroblasts PDL-based 72h incubations was reported. Unequivocally 4b reduction of viability effectiveness linked with its DPPH radical scavenging effects (without a matching antiinflammation effect). Explicitly 4a, 3a and 4c exerted exquisite antiinflammation-selective cytotoxicity duality in vitro. Conclusion: Such a new potential chelation mechanism can explain the pronounced difference in antineoplastic activity of new FQs/TFQs.