Design & Synthesis of MCR derived Novel Nuclear Receptor Modulators as Therapeutic Agents

Abstract

Multi-component reactions (MCRs) are convergent reactions, in which three or more starting materials react to form a product, where basically all or most of the atoms contribute to the newly formed product. By nature, MCRs are by no means restricted to a particular application, but rather they can be used advantageously in any area of modern chemistry-based technology. The application of MCRs in the synthesis of heterocycles is known since prebiotic era. Adenine, one of the major constituents of DNA and RNA, was prebiotically formed by the condensation of five molecules of HCN, a plentiful component of prebiotic atmosphere, in a multi-component reaction catalyzed by NH3. A growing number of products, including many heterocycles, can be prepared by MCRs just by mixing three or more educts, and in many cases practically quantitative yields of pure products can be obtained. A three-component reaction (α-aminoalkylations of nucleophiles) began in the middle of the 19th century and Hantzsch introduced the syntheses of heterocycles (1,4-dihydropyridines and pyrroles) by MCRs in the 1880s. Another significant contribution made by Biginelli (1891) who synthesized 3,4-dihydropyrimidinones via a three-component coupling of an aldehyde, urea and β-keto esters. Robinson (1917) was first to synthesize the naturally occurring alkaloid tropinone (an N-heterocycle) using Mannich reaction. Today, a large number of MCRs are known and many of them have been successfully applied in the synthesis of diverse heterocyclic scaffolds. The work embodied in this thesis is an attempt to synthesize novel nuclear receptor modulators targeting anti-hyperglycemic and anti-cancer activity using MCRs. The thesis entitled “Design & Synthesis of MCR Derived Novel Nuclear Receptor Modulators as Therapeutic Agents” describes our endeavors leading to the accomplishment of newer anti-hyperglycemic and anti-cancer agents. The thesis has been organized under five main chapters as summarized below: The first chapter is a concise review on multi-component reaction derived synthesis of diverse heterocyclic scaffolds. A large number MCRs are known and they have been utilized in synthesis of almost all classes of heterocycles. The review has been organized according to the number and type of heteroatoms in the ring systems.The second chapter describes design, synthesis and anti-hyperglycemic as well as lipid lowering activity of novel spiroindole derivatives. Spiroindole carboxylic acid as well as nitro derivatives have shown significant antidiabetic activity in SLM, STZ and db/db mice models. The third chapter describes design and synthesis of novel xanthene derivatives as selective estrogen receptor modulators. The synthesized compounds have shown promising anticancer activity in various cell lines. The fourth chapter describes design and synthesis of 3,4-dihydropyrimidinones as novel PPAR-α/γ dual agonist. The synthesized compounds have shown significant anti-hyperglycemic activity. The fifth chapter describes the design and synthesis of 1,4-dihydropyridine and polyhydroquinoline derivartives as novel anti-hyperglycemic agents. Polyhydroquinoline derivatives have shown promising anti-hyperglycemic activity in SLM and STZ models.