Aryne-Mediated Synthetic Methodologies Development For Heterocycles And Design, Synthesis And Anticancer Activity Studies Of Pyrimidine Derivatives

The aim of this thesis is to provide a contribution to the study and synthesis of hetrocycles,discussing observations and issues encountered during my graduate studies.The work will be divided into two parts:?i?Aryne-mediated synthetic methodology development for heterocycles;and?ii?Design,synthesis and anticancer activity studies of pyrimidine derivatives.The studies on synthesis of hetrocycles was due to their importance in pharmaceutical research,agriculture and drug discovery.Described herein are several novel synthetic and biological studies on some of the important category of drug substances particularly indole,xanthone and pyrimidine containing hetero cyclic rings.The first chapter of the thesis reviews the aryne chemistries.The last decade has seen an outgrowth in the development of synthetic methodologies to expose the rich and fascinating chemistries of arynes,especially for the transition-metal free carbon-carbon and carbon-heteroatom bond-forming reactions.Arynes have found multitude of applications in pericyclic reactions,insertion reactions and multicomponent reactions.Some of these reactions result in the formation of valuable heterocycles with interesting biological activities.The second chapter describes a synthetic methodology which could be utilized to the constructbiologicallyactivecyclohepta[b]indolesandpolycyclic oxacyclohepta[b]indoles.An efficient[8+2]/aryl-ene tandem reaction between azaheptafulvenes and arynes has been developed,leading to the formation of cyclohepta[b]indoles in a single step with good yield excellent regioselectivity.In addition,employment of excess arynes provides a[8+2]/aryl-ene/[6+2]tandem reaction,giving rise to polycyclic oxacyclohepta[b]indoles.The heteroazulenes provides a novel strategy for the synthesis of the unique nitrogen-containing tricyclic fused ring system.The efficient[8+2]/aryl-ene reaction madulated to access indole and indoline derivatives in a 1:1 ratio with good yields.The third chapter describes a novel methodology involving efficient protocols to rapidly access either dihydrobenzo[c]xanthone or benzo[c]xanthone derivatives selectively by simply changing the atmosphere of the reaction.Thus an efficient Diels–Alder reaction of 2-styrylchromones with arynes for the synthesis of dihydrobenzo[c]xanthone under very mild conditions was developed.Interestingly,under the oxygen atmosphere,the reaction underwent a tandem Diels–Alder/oxidation-aromatization reaction to provide benzo[c]xanthones in a single step,demonstrating the flexibility of method in the synthesis of benzo[c]xanthone derivatives.The foruth chapter summarizes the synthesis and biological anticancer avaluations novel macrocyclic pyrimidins.Pyrimidine is an important class of heterocyclic compounds with wide applications in pharmaceutical research due to their broad range of biological acticities.Among the existing large number of structurally diverse pyrimidine derivatives,2,4-diaminopyrimidines have attracted significant attention due to their potent activities against cancers and favorable pharmaceutical properties.The prevalence of biologically active macrocycles in medicinal chemistry literature has been increasing.Among the synthetic macromolecules,calixarenes and their derivatives are of great significance.As part of our efforts in searching for novel anticancer agents as well as special interest in macrocyclic compounds,we designed and synthesized a series of novel azacalix[2]arene[2]pyrimidines,and evaluated their antiproliferative activities against human cancer cell lines.A number of compounds showed low micromolar antiproliferative activities against MCF7 cell line.Among these,the derivatives bearing a pyrrolidine group,exhibited the strongest inhibitory activity with an IC₅₀ value of 0.58?M.Furthermore,breast cancer cells were used to explore the inhibition mechanism of these azacalix[2]arene[2]pyrimidines.The results suggested these compounds were involved in inducing cell apoptosis via up-regulation of caspase-3 and caspase-9 protein expression,and the cell cycle was arrested at the S phase.