Total synthesis of deamido bleomycin a(2), the major catabolite of the antitumor agent bleomycin.
Metabolic inactivation of the antitumor antibiotic bleomycin is believed to be mediated exclusively via the action of bleomycin hydrolase, a cysteine proteinase that is widely distributed in nature. While the spectrum of antitumor activity exhibited by the bleomycins is believed to reflect the anatomical distribution of bleomycin hydrolase within the host, little has been done to characterize the product of the putative inactivation at a chemical or biochemical level. The present report describes the synthesis of deamidobleomycin demethyl A(2) (3) and deamido bleomycin A(2) (4), as well as the respective aglycones. These compounds were all accessible via the key intermediate N(alpha)-Boc-N(beta)-[1-amino-3(S)-(4-amino-6-carboxy-5-methylpyrimidin-2-yl)propion-3-yl]-(S)-beta-aminoalanine tert-butyl ester (16). Synthetic deamido bleomycin A(2) was shown to be identical to the product formed by treatment of bleomycin A(2) with human bleomycin hydrolase, as judged by reversed-phase HPLC analysis and (1)H NMR spectroscopy. Deamido bleomycin A(2) was found to retain significant DNA cleavage activity in DNA plasmid relaxation assays and had the same sequence selectivity of DNA cleavage as bleomycin A(2). The most significant alteration of function noted in this study was a reduction in the ability of deamido bleomycin A(2) to mediate double-strand DNA cleavage, relative to that produced by BLM A(2).
Zou
Ying
Y
Contribution from the Department of Chemistry, University of Virginia, Charlottesville 22901, USA.
Fahmi
Nour Eddine
NE
Vialas
Corine
C
Miller
Guy M
GM
Hecht
Sidney M
SM
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000378:metabolism; D001761:Bleomycin / Q000138:chemical synthesis* / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D006867:Hydrolases