Structure-activity relationships for mitomycin C and mitomycin A analogues.
A set of 30 mitomycin C and mitomycin A analogues, including five new compounds, was screened against three different solid human tumor cell lines using the MTT tetrazolium dye assay. A statistically significant correlation among antitumor activity, quinone reduction potential (E1/2), and the logarithm of the partition coefficient (log P) was obtained, with the most easily reduced and the most lipophilic compounds being the most potent. When these analogues were separated into mitomycin C and mitomycin A subsets, the former gave a correlation only with E1/2, whereas the latter (which differ little in their E1/2 values) gave a correlation only with log P. These correlations are in contrast to those made in the P388 leukemia assay in mice wherein the most active mitomycin C and mitomycin A analogues were the most hydrophilic ones. When the same compounds were tested against P388 leukemia cells in the MTT assay, the results were the same as those of the solid tumor assays. Thus, the substantial differences in relative potencies of mitomycins are related not to the kind of tumor cell, but to the type of assay performed, cell culture versus whole animal. No correlation was found between antitumor potency in the cell culture systems and calculated relative DNA binding strengths, probably because the limiting factors in antitumor potency of mitomycins appear to be tumor cell uptake (log P) and/or bioreductive activation (E1/2).
Kunz
K R
KR
Department of Pharmaceutical Sciences, University of Arizona, Tucson 85721.
Iyengar
B S
BS
Dorr
R T
RT
Alberts
D S
DS
Remers
W A
WA
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy; D055598:Chemical Phenomena; D002621:Chemistry; D003110:Colonic Neoplasms / Q000188:drug therapy; D005260:Female; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D016685:Mitomycin; D008937:Mitomycins / Q000138:chemical synthesis* / Q000627:therapeutic use; D008958:Models, Molecular; D010051:Ovarian Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D008937:Mitomycins; D016685:Mitomycin; C046000:mitomycin A