| Chapter I provides a brief introduction to the various causes of DNA damage, as well as the numerous cellular processes responsible for the repair of this damage, including nucleotide excision and base excision repair (BER). BER, in particular has been shown to significantly reduce the efficacy of antitumor DNA damaging agents, such as cisplatin and bleomycin. Thus, retarding DNA repair through the inhibition of DNA polymerase beta (DNA pol beta), a critical enzyme in base excision repair, offers the prospect of adjuvant chemotherapy. Moreover, a new class of agents are discussed which are capable of affecting both Cu2+-dependent DNA damage and maintaining the subsequent lesion through the inhibition of DNA pol beta.; Chapter II describes the stereoselective synthesis of the atropisomeric flavans, myristinin A and myristinin B/C. The convergent synthetic approach relies on a Lewis acid-promoted condensation reaction to stereo selectively install the C-4 phenolic functionality. Additionally, simple modification of this route provided access to the (2,4-cis) myristinin B/C isomer in a rapid manner. These compounds exhibit dual biochemical activity as potent DNA damaging agents and DNA pol beta inhibitors. The myristinins have also been shown to greatly potentiate the cytotoxicity of bleomycin.; Chapter III details the stereoselective synthesis of another DNA polymerase beta inhibitor, delta-trans-tocotrienoloic acid. The synthesis demonstrated an incorrect structural assignment and provided access to the actual natural product in quantities sufficient for detailed biochemical testing. Key steps in the synthesis include an sp3-sp2 Suzuki-Miyaura coupling, and an acid-catalyzed cyclodehydration reaction for the formation of the fused pyran.; Chapter IV describes the synthesis of the naturally occurring kaemperol glycoside SL0101, and a number of structural homologs. SL0101 is a potent and selective inhibitor of p90 Rsk, a member of the 90 kDa ribosomal S6 kinase family. SL0101 displayed remarkable selectivity in antiproliferation assays of MCF-7 (human breast cancer cells) vs. MCF-10A (normal breast cells), making it a promising compound for cancer chemotherapy. Accordingly, in collaboration with Professor Lannigan's laboratory (UVa Center for Cell Signaling), we have been involved in ongoing studies probing the SAR of these kaempferol glycosides. |
