MOLECULAR-STRUCTURES OF CHEMICAL CARCINOGENS 7-CHLOROMETHYLBENZ[A]ANTHRACENE AND 7-CHLOROMETHYL-12-METHYLBENZ[A]ANTHRACENE

Abstract

The 3-dimensional structures of 2 carcinogens, 7-chloromethyl-12-methylbenz[a]anthracene and 7-chloromethylbenz[a]anthracene, were determined by X-ray crystallographic techniques. Both compounds are carcinogenic and are believed to act by alkylating DNA. The 1st has a nonplanar ring system, wherease the 2nd has a planar ring system. The nonplanarity of 7-chloromethyl-12-methylbenz[a]anthracene results from steric hindrance between a H atom of the 12-methyl group and a H atom on the [a] ring. This molecule cannot be made planar unless the 12-methyl group or the [a] ring is removed. The carcinogenic activity of these compounds does not correlate with planarity of the ring system. This implies that, if DNA is the critical target of attack by these carcinogens, complete intercalation of the aromatic ring system of the carcinogen between the bases of DNA is not a likely mechanism of carcinogenic action in this system of compounds. The results presented here and those of others are more consistent with a model for a common interaction of the carcinogens 7-chloromethyl-12-methylbenz[a]anthracene and 7-chloromethylbenz[a]anthracene with DNA, in which they alkylate the bases of DNA and then lie with their long axes approximately parallel to the helix axis, probably in the major groove.