Structure-Activity Relationships of Isothiocyanates as Mechanism-based Inhibitors of 4-(Methy Initrosamino) -1-(3-py ridy 1)-1-butanone-induced Lung Tumorigenesis in A/J Mice1

A structure-activity relationship study was carried out to identify struc tural features in arylalkyl and alkyl isothiocyanates that are associated with the inhibitory potency of these compounds against lung tumorigenesis induced in A/J mice by the tobacco-specific nitrosamine 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK). These features include the alkyl chain length, phenyl substitution, and secondary isothiocyanates. The naturally occurring ally! isothiocyanate, phenethyl ¡sothiocyanate, and the synthetic analogues such as 6-phenylhexyl isothiocyanate, 8-phenyloctyl isothiocyanate, 10-phenyldecyl isothiocyanate, 1,2-diphenylethyl isothiocyanate, 2,2-diphenylethyl isothiocyanate, and alkyl isothiocyanates (with 1-hexyl, 2-hexyl, and 1-dodecyl as alkyl moieties) were assayed in mice for their tumor inhibitory potential. The isothiocyanates were given in corn oil by gavage at doses of either 0.04, 0.1, and 0.2 juniol or 1 and 5 /imol 2 h prior to a single i.p. injection of 10 jumol NNK. Mice were sacrificed 16 weeks later and lung adenomas were counted. At 0.2 /¿mol, 8-phenyloctyl isothiocyanate and 10-phenyldecyl isothiocyanate were stronger inhibitors than the previously tested 6-phenylhexyl isothiocya nate, but the difference in potency was not obvious at the lower doses. At both 1 and 5 /xmol, ally! isothiocyanate was inactive, while the other five synthetic isothiocyanates were considerably more potent than phenethyl isothiocyanate. In the alkyl isothiocyanate series, 2-hexyl isothiocyanate was more potent than 1-hexyl isothiocyanate, while 1-dodecyl isothiocya nate was the most potent at 1 itmol, reducing tumor multiplicity in the group treated with NNK alone from 11.1 to the background level. Also, 1,2-diphenylethyl isothiocyanate appeared to be a stronger inhibitor than 2,2-diphenylethyl isothiocyanate. In this study we have shown that the phenyl moiety is not essential for the inhibitory activity since alkyl iso thiocyanates exhibit strong inhibitory effects against lung tumorigenesis. We have also shown that secondary isothiocyanates possess a higher potency than their structural isomers bearing a primary isothiocyanate. From results of this study and of seven previously studied isothiocyanates, we conclude that the observed inhibitory potency of isothiocyanates in the A/J mouse lung tumor model is correlated with their partition coefficients (log /') and the pseudo first order rate constants for the reaction of isothiocyanates toward glutathione (A,,,,J. These results reveal that both high lipophilicity and low reactivity of isothiocyanates are important for inhibitory activity toward NNK-induced lung tumorigenesis. These obser vations provide a structural basis for the discovery of more effective chemopreventive agents.