Alkylation reactions of mitomycin C at acid pH

Nucleophilic Activation of a Tetra-Substituted Mitomycin Cyclic Bis-Disulfide

“…Since 8 retained the key structural components found in 1, we envisioned that this multimeric mitomycin would also be activated under reductive [2][3][4] and acidic conditions. [25][26][27] Several structural features distinguished 8 from most previous mitomycin analogs. First, the linker is composed of cyclic 16-membered bisdisulfide, permitting the attachment of four mitomycins.…”

“…When 20 eq of L-DTT were employed per 8, the t 1/2 value determined by UV-vis spectroscopy (374 nm) was 1.8 d, and when 40 eq of L-DTT were utilized, the t 1/2 decreased to 0.67 d. Significantly, when we followed the reactions at 313 nm we saw a concomitant increase in the 313 nm signal with time; a finding consistent with mitosene production. 26) Thus, adding L-DTT led to modest increases in 8 consumption rates, which depended upon L-DTT concentration. The HPLC chromatograms for the L-DTT activation experiments showed a complex pattern between ca.…”

Solvolysis Study of Cycliciminomitomycins

“…We found that for the cis-isomers the C(1)H-C(2)H and the C(2)H-C(3)H b vicinal coupling constants were moderate (ca. [4][5][6][7] and the C(2)H-C(3)H a coupling interaction was large (ca. 9 Hz), whereas in the trans-isomers the C(1)H-C(2)H vicinal coupling was nearly zero, the C(2)H-C(3)H b vicinal coupling was small (ca.…”

“…[1][2][3][4] Mitomycin C (1) is the prototype of a major class of bio-reductive alkylating agents and can be activated by reductive conditions 5,6) and mild acidic conditions. [7][8][9] The toxicity of 1 and the resistance of tumor cells to 1 have compromised the clinical utility of mitomycin C. An intensive effort to identify more effective mitomycin derivatives has led to the discovery of KW-2149 (3) and BMS-181174 (4). Both compounds exhibited improved in vivo and in vitro pharmacological profiles compared to 1 and had been advanced to clinical trial.…”

Electronic studies of the pyrrolidine molecule with aziridine ring

“…The same conclusion was reached by the experiments of Tomasz and co-workers found a 4:l ratio of the cis isomer to the trans isomer in the case of N-methylmitomycin hydrolysis. The predominance of the cis isomer surprised experimentalists since it is known that the aziridine ring by itself opens to trans amino alcohols [8]. In this work the pyrrolidine + aziridine ring solvolysis is used as a model in order to compare the theoretically calculated energies of the cis amino alcohols to the trans isomers, and establish which isomer features the lowest energy and consequently will be more favorable thermodynamically.…”