N-METHYL THREONINE ANALOGS OF DEGLYCOBLEOMYCIN A(2) - SYNTHESIS AND EVALUATION

The synthesis of 5 and its D-allo-threonine epimer 6 and the compariso n of their DNA cleavage efficiency and selectivity with that of deglyc obleomycin A(2) (3) are detailed. The studies illustrate that N-methyl ation of the L-threonine subunit within deglycobleomycin A(2) dramatic ally reduces the DNA cleavage efficiency (10-15-fold), weakens and nea rly abolishes the inherent DNA cleavage selectivity, but has little ef fect on the inherent oxidation capabilities of the activated Fe(III) c omplexes. The results are consistent with a previously unrecognized pr ominent role for the threonine NH and the potential importance of a hy drogen bond to the Fe(III) hydroperoxide complex of bleomycin or a sub sequent activated complex implicated in recent structural models. (C) 1997 Elsevier Science Ltd.