| The bleomycins are a class of glycopeptides showing antitumor properties and used extensively in the clinic for the treatment of several type of cancers. Removal of glycosides from BLM gives deglycobleomycin, which have properties similar to BLMs, albeit approximately 2--5 fold lesser potency. Deglycobleomycins are good models for potential new BLM derivatives. In the first part of this study, two bleomycin analogs, with R- and S-proline replacing the methylvalerate moiety, were synthesized on a solid support and their biochemical properties evaluated. It was found that the conformationally constrained deglycoBLMs were able to transfer oxygen to small molecules albeit with reduced efficiencies compared to the respective BLMs. They also induced relaxation of supercoiled DNA, although also with greatly reduced potency. However, while BLM cleaves DNA sequence selectively, this selectivity was absent for these constrained analogs. Nine new non-constrained methylvalerate analogs were also synthesized.; In the second part of this study, luotonin A and related analogs were synthesized and evaluated for binding to the topoisomerase I-DNA covalent binary complex. Luotonin A, a naturally occurring pyrroloquinazolinoquinoline alkaloid, is structurally similar to camptothecin, a well known topoisomerase I poison. In this context a number of luotonin A analogs have been prepared through the condensation of appropriate anthranilic acid derivatives with 1,2-dihydropyrrolo[3,4-b]quinoline-3-one in the presence of phosphorus oxychloride. When dichloromethane was used as a solvent the reaction proceeded to afford a single product. On the other hand when reaction was carried out in tetrahydrofuran or in neat phosphorus oxychloride, a rearranged product, structurally similar to luotonin A, was also isolated. The cytotoxic activity of these derivatives was examined in a yeast cell line that lacks the homologous topoisomerase I but expresses human topoisomerase I. They were also tested for their ability to promote topo I-mediated cleavage of a 3'-32 P labeled 222 base pair DNA fragment. The biochemical and biological analysis of these derivatives revealed key differences relative to those required for camptothecin. |
