C(7)-SUBSTITUTED DIAMINOMITOMYCINS - SYNTHESIS, STRUCTURE, AND CHEMICAL-REACTIVITY

Five mitomycins (23-27) were prepared to determine if an appended C(7) diamine substituent would promote C(1) nucleophilic substitution tran sformations by covalent modification of the C(8) quinone group. The ap pended C(7) diamine units varied in the basicity of the terminal amine and in the type and length of the carbon backbone. The mitomycins wer e prepared in high yield by treatment of mitomycin A (28) with selecte d diamines. Mitomycin 25, which contained a C(7) 3-amino-2,2-dimethylp ropylamine unit, underwent rapid conversion to the corresponding albom itomycin-type adduct 34 in which the C(8) quinone group was converted to the corresponding C(8) imine. Dissolution of each mitomycin (23, 24 , 26, 27, and 34) in methanol (''pH'' 5.5, 25 degrees C) led to the pr oduction of the cis- and trans-C(1) methoxymitosenes. The rates of sal volysis were monitored by HPLC and followed pseudo-first-order kinetic s. Modest rate enhancements (5.1-15.2-fold), compared with mitomycin C (1), were observed for 7-N-(2-aminobenzyl)mitomycin C (23) and 7-N(2-a nilinoethyl)mitomycin C(24), the two mitomycins containing terminal an iline groups. Solvolysis of 23 gave the C(1) methoxymitosenes 37 and 3 8, in which the C(8) site was converted to the cyclized C(8) imine; so lvolysis of 24 gave C(1) methoxy products 39 and 40, in which the C(8) quinone unit was not modified. No appreciable rate enhancements over 1 were observed for 26 and 27, the two mitomycins containing terminal- substituted aliphatic amine groups. Albomitomycin 34 solvolyzed 6.9 ti mes faster than 1. The observed rate data indicated that the aniline u nits in 23 and 24 promoted solvolysis by modifying the C(8) quinone gr oup to give either the C(8) hemiaminal or the C(8) imine adduct, Forma tion of these adducts disrupted the delocalization of the indoline N(4 ) electrons with the C(5a)-C(8a)-C(8)-O conjugated system, permitting the sequential activation of the C(1) site toward nucleophilic substit ution. The significance of these findings for the mode of action of KW -2149 and BMS-181174 is briefly discussed.