Journal of the American Chemical Society, Vol.116, No.13, 5631-5646, 1994
Total Synthesis of Bleomycin-A(2) and Related Agents .3. Synthesis and Comparative-Evaluation of Deglycobleomycin-A(2), Epideglycobleomycin-A(2), Deglycobleomycin-A(1), and Desacetamidodeglycobleomycin, Descarboxamidodeglycobleomycin, Desmethyldeglycobleomycin, and Desimidazolyldeglycobleomycin-A(2)
Full details of the completion of the total synthesis of deglycobleomyein A(2) (2) and deglycobleomycin A(1) (3), the algycones of two naturally occurring bleomycins, are provided. Extensions of the studies to the preparation of epideglycobleomycin A(2) (4), desacetamidodeglycobleomycin A(2) (5), descarboxamidodeglycobleomycin A(2) (6), desmethyldeglycobleomycin A(2) (7), and desimidazolyldeglycobleomycin A(2) (8) are described. The agents 4-8, which are not accessible through structural modification of the natural products themselves, constitute key substructure analogs incorporating deep-seated and mechanistically relevant structural modifications in the metal chelation subunit. Extensions of the studies to the preparation of GABA,Gly-deglycobleomycin A(2) (43) and GABA,Gly-desacetamidodeglycobleomycin A(2) (45) are detailed in efforts that confirm a subtle and significant role for the C2 acetamido side chain detected in the initial comparisons of 2 with 4 and 5 and additionally provide an initial assessment of the role of the tetrapeptide S backbone substituents (43 versus 2, 45 versus 5). The comparative examination of the DNA cleavage properties of the Fe(II) or Fe(III) complexes of 1-8 and 43, 45 has been conducted, and four properties have been assessed including the relative DNA cleavage efficiency and ratio of double- to single-strand DNA breaks with supercoiled Phi X174 DNA as well as the relative DNA cleavage efficiency and the DNA cleavage selectivity with 5’-end-labeled w794/w836 duplex DNA. The results of the relative DNA cleavage studies and the assessment of double- to single-strand DNA cleavage events demonstrate important, productive roles for the terminal sulfonium salt, and the pyrimidoblamic acid C2 acetamido side chain, a more subtle but perceptible role for the C2 side chain beta-amino-L-alanine carboxamide, no role for the pyrimidine C5 methyl group, and an expected essential role for the histidine imidazole. Similarly, the tetrapeptide S backbone substituents absent in 43 and 45 were determined to substantially but not dramatically diminish DNA cleavage efficiency without altering DNA binding affinity or the characteristic DNA cleavage selectivity. In contrast to the relative impact that the structural changes within the bleomycin A(2) metal binding domain had on the relative DNA cleavage efficiencies and with the important exception of 8, they had no perceptible impact on the observed selectivity of DNA cleavage, 5’-GC, 5/-GT > 5’-GA. Similarly, deglycobleomycin A(1), lacking the C-terminal sulfonium salt, or 43 and 45, lacking all the tetrapeptide S backbone substituents, exhibited the identical and characteristic 5’-GC, 5’-GT > 5’-GA DNA cleavage selectivity of 1 and 2, indicating that they affect DNA cleavage efficiency but not cleavage selectivity. Only 8, lacking the essential imidazole, was found to exhibit an altered and nonselective DNA cleavage pattern presumably derived from oxidative cleavage of duplex DNA via generation of a diffusable oxidant.