| Summary: | 碩士 === 高雄醫學大學 === 天然藥物研究所 === 90 === Pyrrolo[2,1-c][1,4]benzodiazepines(PBDs) are a group of potent, naturally occurring antitumor antibiotics produced by Streptomyces species. The cytotoxic and antitumor effects of these compounds are believed to arise from modification of DNA, which leads to inhibition of nucleic acid synthesis and production of excision-dependent single- and double-strand breaks in cellular DNA. These antibiotics have been proposed to covalently bond to N2 to guanine to form a neutral minor groove adduct. tomaymycin, anthromycin and CD-81 are the best known examplees of th PBDs .
We have designed and synthesized hybrid agents based on the DC-81 coupled with indole carboxylate (IC) moiety. Preliminary in vivo tests showed that these compounds have highly potent broad-spectrum antitumor activity against several cancer cell lines. These encourage us to design more diversity of antitumor agents on DC-81 analogues. In this thesis, we propose two routes for the synthesis of a new class of anticancer alkylating agent containing amino group in C ring of PBD. First, the synthesis starts from the methylation of trans-4- hydroxy-L-proline 120, followed by protection with benzyl carbomate to give compound 122. Transformation of the hydroxy group 122 with toluenesulfonyl chloride, followed by azidolation gives compound 124. Reduction of compound 124 with lithium borohydride affords the corresponding alcohol 125. Swern oxidation of the alcohol 125, followed by reaction with ethanethiol forms thioacetal 127. Deprotection of benzyl carbamate 127, followed by reaction with O-nitrobenzoic acid generates [4-azido-2-(bis-ethylsulfanylmethyl)pyrrolidin-1-yl]-(2-nitrophenyl)-methanone 130. Reduction of the azido group 130 with triphenylphosphine to give the compound 131. The overall yield is 21% in ten steps. The remaining two steps, reduction the nitro group to give compound 132, followed by cyclization would give the compound 133. They are well precedented, and should present no insurmountable problems.
The second route is similar to our previous reported. This synthesis starts from combining the isotonic anhydride and trans-4-hydroxy-L- proline, followed by protection with MOMCl to give compound 146. Transformation of the hydroxy group with toluenesulfonyl chloride, followed by azidolation generates compound 148. Reduction of the azido group with triphenylphosphine to give compound 149. The overall yield is 45% in five steps. There are remaining one step, reduction with LiBH4 to form an imine PBD 133.
|
|---|
