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).

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The alkylating antitumor agents mitomycin A (MMA), mitomycin C (MMC), and seven N7 analogs were compared in terms of their cardiotoxic and antitumor activity in vitro. Neonatal rat-heart myocytes were sensitive to five of the compounds studied, including MMA, 7-dimethylamidinomitosane (BMY-25282), 7-(N-methyl-piperazinyl)-mitosane (RR-194), N7-(4-iodophenyl)-MMC (RR-208), and N7-(4-hydroxyphenyl)-MMC (M-83) in order of descending molar potency. MMA and RR-208 possessed the greatest cytotoxic potency against 8226 human myeloma tumor cells in vitro. Two of the nine mitomycins studied, BMY-25282 and M-83, showed greater cytotoxic potency for heart cells. For these two agents, the ratio of the 50% inhibitory concentration in heart cells to that in 8226 myeloma cells was 50 and 32, respectively. For the other analogs, the tumor-cell cytotoxic potency was much higher (ranging from 200 to 7,000). For the nine mitomycin compounds, a correlation was found between heart-cell toxicity and low reduction potentials (E1/2 values) ranging from -0.16 to -0.37 V. Thus, as the reduction potential decreased (easier reducibility), the cardiotoxic potency in vitro increased (r = 0.81). In contrast, mitomycins with reduction potentials of higher than -0.37 V were much less potent cardiotoxins. Thus, mitomycin C (E1/2 = -0.45 V) was noncardiotoxic even when tested at concentrations 100-fold above those pharmacologically achievable in humans. Mitomycin C also failed to enhance doxorubicin (Adriamycin) cardiotoxicity in vitro. Importantly, no correlation was found between the reduction potential and the antitumor activity of the nine analogs (n = 0.51), in this small series.

Mitomycin analogues were tested against metacestode stages of Hymenolepis microstoma and H. nana developing in Tribolium confusum. The effects of the mitomycins varied according to both the drug and the species of the parasite. In general, the most effective compound was mitomycin C, followed by mitomycin A and then by mitomycin F. The efficacy of drugs improved further when sodium bicarbonate was added to the diet.

. Can. J. Chem. 65, 1316Chem. 65, (1987. Carbon-13 nuclear magnetic resonance chemical shifts are reported for a series of 4-substituted phenols and 2-nitrophenols in dimethyl sulfoxide solution. For chemical shift correlations, it was found by factor analysis and iterative multiple linear regression that the para chemical shifts require two substituent factors whereas the ipso, ortho, and meta chemical shifts require three factors. Regression analyses were performed using the field and resonance parameters (uF, uRO) and the appropriate ipso, ortho, and meta parameters (I, 0, M) determined by Reynolds. Good correlations were obtained except for the three meta carbon analyses, where the correlation coefficients range from 0.877 to 0.963. On a dttermint les dCplacements chimiques, en rmn I3c, d'une strie de phtnols substituts en position 4 ainsi que de nitro-2 phtnols en solution dans le dimCthylsulfoxyde. Pour les corrtlations des dtplacements chimiques, on a trouvt par des analyses factorielles et par des rtgressions IinCaires multiples itCratives que les diplacements chimiques des positions para requikrent deux facteurs de substituants alors que les diplacements chimiques des positions ipso, ortho et me'trr requikrent trois facteurs. On a effectuk des analyses de regression en utilisant les paramktres de champ et de risonance (uF, uR0) ainsi que les paramktres ipso, ortho et me'ta appropriis (I, 0 et M) diterminCs par Reynolds. On a obtenu de bonnes corrilations, excepti pour trois analyses de carbones tnita pour lesquelles on a obtenu des coefficients de corrClation allant de 0,877 i 0,963.[Traduit par la revue]

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