Analogues of 10-deazaaminopterin and 5-alkyl-5,10-dideazaaminopterin with the 4-substituted 1-naphthoyl group in the place of 4-substituted benzoyl Journal Article
| Authors: | Piper, J. R.; Ramamurthy, B.; Johnson, C. A.; Otter, G. M.; Sirotnak, F. M. |
| Article Title: | Analogues of 10-deazaaminopterin and 5-alkyl-5,10-dideazaaminopterin with the 4-substituted 1-naphthoyl group in the place of 4-substituted benzoyl |
| Abstract: | 10-Deaza modifications of classical antifolate analogues bearing the 1,4- disubstituted naphthalene ring in place of the 1,4-disubstituted benzene ring were prepared and tested for antitumor activity. Naphthalene 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-carboxy-1-naphthaleneacetic acid dimethyl ester (2) by 6-(bromomethyl)-2,4-diaminopteridine (1a) and 6- (bromomethyl)-2,4-diamino-5-methyl- and -5-ethyl-5-deazapteridines (1b and 1c, respectively) followed by ester hydrolysis and subsequent decarboxylation to give naphthalene analogues (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. Peptide coupling of 7a-c with L-glutamic acid dialkyl ester followed by mild ester hydrolysis gave target compounds 9a-c. The key advantage of this route is circumvention of a hydrogenation step requiring selectivity as in earlier approaches involving 9,10-olefinic precursors. Steric limitations thwarted plans to prepare the naphthalene analogue of 10- ethyl-10-deazaaminopterin; attempted alkylations of 2-(4-carboxy-1- naphthyl)butyric acid dimethyl ester with 1a failed as did attempted further alkylation (by EtBr) of the product derived from 1a and 2. Growth inhibition 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 inhibitory than MTX. In tests against the E0771 mammary adenocarcinoma in mice, 9a was less active than MTX. |
| Keywords: | controlled study; unclassified drug; nonhuman; antineoplastic agents; methotrexate; adenocarcinoma; animal cell; mouse; animals; mice; cell division; animal experiment; animal model; antineoplastic activity; drug structure; tumor cells, cultured; drug synthesis; cancer inhibition; tumor cell line; drug clearance; alkylation; breast adenocarcinoma; aminopterin; benzene derivative; mammary neoplasms, experimental; hydrogenation; 10 deazaaminopterin; naphthalene derivative; edatrexate; aminopterin derivative; article; 5,10 dideazaaminopterin; n [4 [2 (2,4 diamino 6 pteridinyl)ethyl] 1 naphthoyl]glutamic acid |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 39 |
| Issue: | 2 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 1996-01-19 |
| Start Page: | 614 |
| End Page: | 618 |
| Language: | English |
| DOI: | 10.1021/jm9506940 |
| PUBMED: | 8558535 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 22 November 2017 -- Source: Scopus |
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