SYNTHESIS AND POTENTIAL ANTINEOPLASTIC ACTIVITY OF SOME CONFORMATIONALLY DEFINED MUSTARDS OF THE 2-AZAADAMANTANE TYPE

Date of Completion

January 1982

Keywords

Chemistry, Pharmaceutical

Degree

Ph.D.

Abstract

The cytotoxicity of the nitrogen mustards and the nitrosoureas is due to the formation of reactive intermediates possessing the ability to alkylate cellular macromolecules. For the nitrosoureas, the reactive species appears to be related to a 2-haloethyl carbenium ion, which produces a 2-carbon DNA cross-link. For the nitrogen mustards, in which the alkylating species is the aziridinium ion, a 5-atom cross-link is ultimately produced. This difference could explain, in part, the contrasting therapeutic profiles of these compounds.^ One approach to the investigation of this hypothesis is by way of 4,9-dichloro-2-azaadamantane (1) and 4,8-dichloro-2-azadamantane (2). These isomers differ only in the distance between their alkylating centers, which is defined by the rigid stereochemistry of the adamantane framework. In compound 1 the distance between alkylating centers is approximately 2.5 A, therefore 1 may produce cross-links over a distance similar to the nitrosoureas. In compound 2, the greater interatomic distance of 3.6 A between alkylating centers suggests that cross-linking behavior similar to the nitrogen mustards may occur. Compounds 1 and 2 are rigid probes of the alkylating and cross-linking process leading to cytotoxicity.^ For 1 and 2 to be effective cytotoxic agents, an aziridine or aziridinium-like intermediate (dependent upon the nature of the N-substituent) will likely be present. To establish that such strained intermediates are accessible within this system, anti-4-chloro-2-n-propyl-2-azadamantane (3) was synthesized and its rate of cyclization was studied. When 3 was subjected to solvolysis in aqueous methanolic NaOH, a rate enhancement of approximately 2 x 10('6) at 25(DEGREES)C was observed, compared to 2-chloroadamantane. To our knowledge, this rate acceleration represents one of the largest observed to date for the (beta)-haloamines, clearly establishing substantial anchimeric assistance to ionization.^ The synthesis of a series of congeners of both 1 and 2 has been accomplished. Compound 2 was synthesized in six steps starting from Meerwein's ester, while 1 was synthesized in six steps starting from 4-vinylcyclohexene. All of the compounds tested in both series have significant cytotoxic activity. Indeed, certain of the congeners possess biological activity in the submicromolar range. The derivatives of 1 are approximately three times more active than those of 2. In view of their similar chemical and physicochemical properties, the observed differences in cytotoxicities between these series may reflect differences in cross-linking behavior at the molecular level. ^

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