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Thieno[3,2-d]- and pyrrolo[3,2-d]pyrimidines and their C-nucleosides: Synthesis and biological evaluation
Ort / Verlag
ProQuest Dissertations & Theses
Erscheinungsjahr
2012
Quelle
ProQuest Dissertations & Theses A&I
Beschreibungen/Notizen
The evolution of medicine from alchemy to rationale-based drug design has been instrumental in alleviating human ailments and improving the quality of life. Nucleosides occupy an important place in drug design and discovery as they are inherent in many cellular functions. As a result, structural modifications to the nucleoside scaffold can have far reaching biological consequences. Hence, nucleoside analogues have been central to the discovery of potent anticancer and antiviral drugs. Thieno[3,2-d]- and pyrrolo[3,2-d]pyrimidines hold an important place in drug design particularly anticancer drugs due to their ability to mimic nucleoside bases and recognition by enzymes. Our lab has been involved in synthesis and biological evaluation of modified nucleobases and nucleosides to explore their anticancer and antiviral properties. In that context, synthesis of thieno[3,2-d]- and pyrrolo[3,2- d]pyrimidines and their C-nucleosides was accomplished. Their subsequent biological evaluation resulted in identification of a series of halogenated compounds that possess excellent antiproliferative activity, notably against cancer cell lines. In due course of structure activity relationship (SAR) the importance of the C-4 halogen and sulfur towards imparting biological activity to the heterocyclic scaffold was established. Furthermore, the 7-halogenated thieno[3,2-d]- and pyrrolo[3,2-d]pyrimidines impart themselves to functional group conversions and preparation of C-nucleosides via Palladium catalyzed cross-coupling reactions. The synthesis of C-nucleosides of thieno[3,2-d]- and pyrrolo[3,2-d]pyrimidines was accomplished using Heck coupling methodology. The importance of pyrrole protection was established followed by identification of a suitable pyrrole protecting group in order to synthesize the corresponding C-nucleosides of the pyrrolo[3,2- d]pyrimidines that was facile and high yielding. The synthesis of thieno[3,2-d]- and pyrrolo[3,2-d]pyrimidines and their corresponding C-nucleosides is reported herein along with their biological activity that resulted in the identification of biologically active lead compounds.