ANALOGS OF 10-DEAZAAMINOPTERIN AND 5-ALKYL-5,10-DIDEAZAAMINOPTERIN WITH THE 4-SUBSTITUTED 1-NAPHTHOYL GROUP IN THE PLACE OF 4-SUBSTITUTED BENZOYL

10-Deaza modifications of classical antifolate analogues bearing the 1 ,4-disubstituted naphthalene ring in place of the 1,4-disubstituted be nzene ring were prepared and tested for antitumor activity. Naphthalen e analogues (9a-c, respectively) of 10-deazaaminopterin, 5-methyl-5,10 -dideazaaminopterin, and 5-ethyl-5,10-dideazaaminopterin were prepared by a route consisting of C-alkylations of the anion derived from 4-ca rboxy-1-naphthaleneacetic acid dimethyl ester (2) by 6-(bromomethyl)-2 ,4-diaminopteridine (la) and 6-(bromomethyl)-2,4-diamino-5-methyl- and -5-ethyl-5-deazapteridines (Ib and Ic, respectively) followed by este r hydrolysis and subsequent decarboxylation to give naphthalene analog ues (7a-c, respectively) of 4-amino-4-deoxy-10-deazapteroic acid and 4 -amino-4-deoxy-5-methyl- and -5-ethyl-5,10-dideazapteroic acids. Pepti de coupling of 7a-c with L-glutamic acid dialkyl ester followed by mil d ester hydrolysis gave target compounds 9a-c. The key advantage of th is route is circumvention of a hydrogenation step requiring selectivit y as in earlier approaches involving 9,10-olefinic precursors. Steric limitations thwarted plans to prepare the naphthalene analogue of 10-e thyl-10-deazaaminopterin; attempted alkylations of 2-(4-carboxy-1-naph thyl)butyric acid dimethyl ester with la failed as did attempted furth er alkylation (by EtBr) of the product derived from la and 2. Growth i nhibition tests against three tumor cell lines (L1210, S180, and HL60) showed 9a to be 4-6-fold more inhibitory than methotrexate but not as inhibitory as 10-ethyl-10-deazaaminopterin; 9b and 9c were no more in hibitory than MTX. In tests against the E0771 mammary adenocarcinoma i n mice, 9a was less active than MTX.