Comparative stereochemistry in the aziridine ring openings of N-methylmitomycin A and 7-methoxy-1,2-(N-methylaziridino)mitosene

Abstract

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.

Alkylation reactions of mitomycin C at acid pH

“…This is in contrast to the exclusively trans opening of simple aziridines.4d The participation of the neighboring methoxy group as a directing influence during the ring-opening step is not a likely explanation since the mitosene-type aziridine (6) also hydrolyzes predominantly to the cis aminohydrin and thus the problem of mechanism remains open. 32 In the present work ring-opening by inorganic phosphate gives almost exclusively the cis product (less than 5% trans product was detected, see Results) and the other phosphate-opened products 8b and 8c have cis/trans ratios ca. 4/1 and 9/1, respectively.…”

Aspects of the Chemical Stability of Mitomycin and Porfiromycin in Acidic Solution

“…Although an overall scheme for the degradation of I1 (4) and mechanisms for the aziridine ring to open in deuteroacetic acid (2) and in water (12) have been published, no explanation for the very fast opening of the aziridine ring in I and I1 in comparison with other aziridines (13) has been given. The fmt degradation products of I and I1 isolated after degradation in an acidic solution appear to be compounds 111 and IV, respectively, where the 9-methoxyl group is cleaved, the m a double bond is formed, and the aziridine ring is opened to form a 2-amino-I-hydroxy compound.…”

“…12) in which A represents the frequency factor, AH the enthalpy of activation, R the gas constant, and T the temperature in 'Kelvin. The AH values for the initial degradation of I at various pH values in the acidic region, using buffers with [total phosphate] = lo-* M, are listed in Table IV.…”

Studies concerning the mechanism of electrophilic substitution reactions of mitomycin C

“…15) from the trans derivative (q:-H). 4,6,7,18 This analysis would require a reversal of the assignments previously made for the hydrogens at carbons 1 and 3 in 6a. 4 The results of this study provide evidence in favor of the previously proposed route for the formation of 6a.…”