STRUCTURE-ACTIVITY-RELATIONSHIPS OF ISOTHIOCYANATES AS MECHANISM-BASED INHIBITORS OF ETHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE-INDUCED LUNG TUMORIGENESIS IN A J MICE/

A structure-activity relationship study was carried out to identify st ructural features in arylalkyl and alkyl isothiocyanates that are asso ciated with the inhibitory potency of these compounds against lung tum origenesis induced in A/J mice by the tobacco-specific nitrosamine 4-( methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These features incl ude the alkyl chain length, phenyl substitution, and secondary isothio cyanates. The naturally occurring allyl isothiocyanate, phenethyl isot hiocyanate, and the synthetic analogues such as 6-phenylhexyl isothioc yanate, 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. T he isothiocyanates were given in corn oil by gavage at doses of either 0.04, 0.1, and 0.2 mu mol or 1 and 5 mu mol 2 h prior to a single i.p . injection of 10 mu mol NNK. Mice were sacrificed 16 weeks later and lung adenomas were counted. At 0.2 mu mol, 8-phenyloctyl isothiocyanat e and 10-phenyldecyl isothiocyanate were stronger inhibitors than the previously tested 6-phenylhexyl isothiocyanate, but the difference in potency was not obvious at the lower doses. At both 1 and 5 mu mol, al lyl isothiocyanate was inactive, while the other five synthetic isothi ocyanates were considerably more potent than phenethyl isothiocyanate. In the alkyl isothiocyanate series, 2-hexyl isothiocyanate was more p otent than 1-hexyl isothiocyanate, while 1-dodecyl isothiocyanate was the most potent at 1 mu mol, reducing tumor multiplicity in the group treated with NNK alone from 11.1 to the background level. Also, 1,2-di phenylethyl isothiocyanate appeared to be a stronger inhibitor than 2, 2-diphenylethyl isothiocyanate. In this study we have shown that the p henyl moiety is not essential for the inhibitory activity since alkyl isothiocyanates exhibit strong inhibitory effects against lung tumorig enesis. We have also shown that secondary isothiocyanates possess a hi gher potency than their structural isomers bearing a primary isothiocy anate. From results of this study and of seven previously studied isot hiocyanates, we conclude that the observed inhibitory potency of isoth iocyanates in the A/J mouse lung tumor model is correlated with their partition coefficients (log P) and the pseudo first order rate constan ts for the reaction of isothiocyanates toward glutathione (k(obs). The se results reveal that both high lipophilicity and low reactivity of i sothiocyanates are important for inhibitory activity toward NNK-induce d lung tumorigenesis. These observations provide a structural basis fo r the discovery of more effective chemopreventive agents.