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New mitomycin C and porfiromycin analogues were prepared by treating mitomycin A and N-methylmitomycin A with a variety of amines, including aziridines, allylamines, propargylamines, chloroalkylamines, hydroxyalkylamines, glycine derivatives, aralkylamines, and heterocyclic amines. All analogues were evaluated against P-388 murine leukemia and selected ones were examined for their leukopenic properties. Certain analogues were found to be superior to mitomycin C in potency, efficacy, and therapeutic ratio in the P-388 assay. The most active substituents at the mitosane 7 position included aziridine, 2-methylaziridine, propargylamine, furfurylamine, methyl glycinate, and 3-aminopyridine. Mitomycin A and the 7-aziridino, 7-(2-methylaziridino), and 3-aminopyridine analogues were less leukopenic than mitomycin C. Certain other analogues, including propargylamino and methyl glycinate, were highly leukopenic. The three compounds tested against B-16 melanoma in mice were significantly more effective than mitomycin C in this assay. Previously established structure--activity relationships were found inadequate to account for all of the new data.

Fade substitution reactions at the tertiary carbon of p-nitrocumyl chloride and a,p-dinitrocumene are described. These reactions occur with a wide range of organic and inorganic nucleophiles and are noteworthy for providing novel and powerful means of synthesis; they occur readily under mild conditions, give excellent yields of pure products, and, in contrast to SN2 displacements, are rather insensitive to steric hindrance. They are, therefore, especially valuable for the preparation of highly branched compounds. The view that these are electron-transfer chain processes derives from inhibition studies and, also, from the fact that these reactions are induced by one-electron-transfer agents. (1) Substitution Reactions Which Proceed via Radical Anion Intermediates. 29. Part 2 8 Kornblum, N.; Kelly, W. J.; Kestner, M. M. J. Org. Chem. 1985,50, 4720. This paper is based on the doctoral dissertations of the 12 junior authors. Reference to these theses is made by employing the initials of the author and the date of the thesis. Preliminary communications have appeared in:

A useful method was found for the conversion of mitomycin C into N-methylmitomycin A. The latter compound gave only two products on acid hydrolysis, the cis- and trans-1-hydroxy-7-methoxy-2-methylaminomitosenes. This selectivity allowed the cis--trans ratio to be quantitatively determined as 4:1. Such a predominance of the cis isomer is unexpected in view of the trans stereochemistry obtained in the opening of simple aziridines. In order to determine if the 9a-methoxy group of mitomycins controlled the direction of aziridine ring opening 7-methoxy-1,2-(N-methylaziridino)mitosene, which lacks this substituent, was prepared and hydrolyzed in acid. It gave the same two products in a 3:1 cis-trans ratio. In the induction of lambda-bacteriophage in Escherichia coli cis-1-hydroxy-7-methoxy-2-methylaminomitosene was more active than the corresponding trans isomer, but both of these compounds were less active than the aziridinomitosene or the mitomycins. Mitomycin A, mitomycin C, and N-methylmitomycin A were active against P388 leukemia in mice.