Design and Synthesis of Novel Heterocycles as Therapeutic Agents

Abstract

Heterocycles constitute the largest diversity of organic molecules of chemical, biomedical, and industrial significance. They widely exist in numerous natural products, such as vitamins, hormones, antibiotics, alkaloids, herbicides, and dyes. They are also among the most frequently encountered scaffolds in numerous drugs and pharmaceutically relevant substances. In the past several decades, a significant number of efforts have been made on the discovery and development of more efficient pharmaceuticals, pesticides, insecticides, rodenticides and weed killers by following well studied natural models and biochemical pathways in living cells. In addition, a series of libraries consisting of heterocycles have been successfully established for the structure activity-relationship studies (SAR) for drug design and synthesis. The work embodied in this thesis is an attempt to synthesize novel heterocycles as therapeutic agents. The thesis entitled “Design and Synthesis of Novel Heterocycles as Therapeutic Agents” describes our endeavors leading to the accomplishment of newer anti-breast cancer and anti-hyperglycemic agents. The thesis has been organized under six main chapters as summarized below: The first chapter presents a concise review on “Modern strategies for the Synthesis of Diverse Heterocyclic Ring Scaffolds” via methodologies commonly used now days. A large number MCRs are known and they have been utilized in synthesis of almost all classes of heterocycles. As illustrated in this review, a wide variety of heterocycles of different sizes and ring systems can be readily synthesized through MCR strategies that often result in a broad scope of applications. Further Functional Ionic Liquid Mediated Synthesis (FILMS) of a number of heterocycles have been reported in which a functional group is covalently tethered to the cation or anion (or both) of the imidazolium salts, which behave not only as a reaction medium but also as a reagent or catalyst. These ionic liquids have been considered as eco-friendly alternatives to volatile organic media because of their negligible vapor pressure and nonflammable nature. Direct C-H transformation has attracted continuous interest since the early 1970s because it meets not only the efficient and sustainable requirement of organic transformations but also the understanding of the intrinsic features of the broadly existing C-H bonds in organic molecules, for example, their accessibility, activity, and selectivity. Thus in this review, we have also focused our attention on the synthesis of various type of heterocycles via highly efficient transformations through metal catalysed or metal free C-H activation. The second chapter describes the “Design, Synthesis and Biological Evaluation of Novel Spiropyrrolidine-Oxindole Derivatives as Potent Anti-Breast Cancer Agents”. We have designed and synthesized various spiropyrrolidine-oxindoles derivatives with and without basic amino alkyl chain as anti-breast cancer agents. Among all the compounds 11b was found to be most active in the series. Cell proliferation assay indicated that the compound inhibited the growth of both types of breast cancer cells MCF-7 and MDA-MB 231 and showed favorable toxicity profile in non-cancerous HEK-293 cells. The Apoptosis analysis by FACS confirms that the compound inhibits cancer cell growth by apoptosis and not by necrosis. The Bax:Bcl2 ratio was found to increase significantly by the compound confirming the apoptotic potential of the compound. The mitochondrial membrane potential was also found to decrease drastically in both MCF-7 and MDA-MB 231 cells confirming the involvement of mitochondrial pathway in apoptosis. Flow cytometry of the PI stained cells indicated that the compound arrests cell cycle progression at G1 phase in MDA-MB 231 and MCF-7 cells. Real time analysis of G1 cyclins indicated a down regulation of cyclin D1, cyclin E1 and cyclin A1 while there was no effect on the expression of G2 specific cyclin dependent kinase cdc2 reconfirming that the compound exhibits its antiproliferative properties by causing accumulation of cells in the G1 phase. The studies suggest that the compound 11b could serve as a lead molecule for further optimization and development to get novel compounds for the cure of aggressive breast cancer. The third chapter of the thesis illustrates the “Design, Synthesis and Biological Evaluation of Novel Spiropyrrolidine-Oxindole Derivatives Targeted to Breast Cancer Cells”. Encouraged by the results of previous chapter (Chapter 2), we synthesized another novel spiropyrrolidine-oxindole derivatives exhibiting promising anticancer activity against human breast cancer cells in vitro. Most of these compounds inhibited the cell growth of human breast cancer cell lines, MCF-7 and MDA-MB-231 cells with IC50 of less than 20.0 μM and minimum growth inhibitory effect in normal HEK-293 cells. Two of the relatively non toxic compounds in normal human HEK-293 cells (11b and 11i) appeared to be promising lead against aggressive breast cancer and the induction of cell death by these compounds in MCF-7 cells is probably through mitochondrial-mediated apoptosis. Inhibition of cell growth is due to G1/S arrest in MCF-7 cells. Their good relative binding affinity for ERα and from docking studies it was observed that the molecules 11i and 11b fit well in the active site of ERα. The active compounds could be speculated to employ some ER dependant pathway. These studies led to recognition of new prototypes for further optimization and development to get novel compounds for the cure of aggressive breast cancer. The fourth chapter involves “Synthesis of New Class of Alkyl Azarene Pyridinium Zwitterions as Anti-Proliferative Agents via Iodine Mediated sp3 C-H Bond Activation”. Herein we have described an interesting transition metal free sp3 C-H bond activation of alkyl azaarene to form first AAP zwitterions in a new multicomponent reaction. A series of unusual charge separated AAP zwitterionic salts were prepared in moderate to good yields in a very convenient manner. Prominent among the advantages of this new methodology are operational simplicity, novelty, and good yields. The target compounds 5a-5q, 6a, 6b, 7a, 7b were evaluated for their anti-proliferative activity in MCF-7 (ER+ve) cells using MTT assay. However, unfortunately most of the compounds were found to be inactive with IC50 > 15μM. The compounds 5c, 5k and 5m have shown IC50 of 14.2, 13.9 and 14.5 μM respectively in MCF-7 cells. Further extension of the reaction scope and synthetic applications of this methodology are in progress in our laboratory. The fifth chapter of the thesis depicts the “Functional Ionic Liquid Mediated Synthesis (FILMS) of Dihydrothiophenes and Hexahydrothieno Quinoline Carboxamides as Anti-Hyperglycemic Agents”. We have developed natural amino acid based functional ionic liquid mediated synthesis of diastereoselective dihydrothiophenes and hexahydrothieno quinoline carboxamides. The advantages of this procedure are good yield, short reaction time, reusable medium and environmentally friendly procedure. It is interesting to report a new approach of organic synthesis for functional ionic liquid promoted reactions named as Functional Ionic Liquid Mediated Synthesis (FILMS). The compounds 4a-4m, 5a-5g were screened in vivo for antihyperglycemic activity under sucrose loaded model (SLM) and sucrose-challenged streptozotocin-induced diabetic rat model (STZ-S). Compounds 4c and 4j were showing promising in vivo antihyperglycemic activity. In vitro screening of these compounds in various models of type-2 diabeties revealed that DPP-IV enzyme inhibition may be the possible mechanism of their in vivo antihyperglycemic action. The compounds 4g and 4i have also shown significant antidyslipidemic as well as antioxidant activities. The sixth chapter describes “Diversity Oriented Synthesis of Pyrrolidines as Anti-Diabetic Agents via Natural Carbohydrate Solid Acid Catalyst”. We have developed a novel, metal free, diastereoselective diversity-oriented synthesis of substituted pyrrolidines catalysed by cellulose sulfuric acid as natural carbohydrate solid acid catalyst. This process involves avoidance of harsh reaction condition, ecofriendly chemistry, reusable catalyst, high diastereoselectivity and yield. The results of anti-hyperglycemic activity evaluation in SLM and STZ models are awaited.