title: Studies on analogues of classical antifolates bearing the naphthoyl group in place of benzoyl in the side chain.
abstract: Analogues of classical antifolates with the 4-aminobenzoyl group replaced by 4-amino-1-naphthoyl were synthesized for study after molecular modeling indicated ample spatial accommodation for the naphthalene ring and even larger groups in models based on reported X-ray crystallographic data describing the binding of methotrexate to human dihydrofolate reductase (DHFR). The side-chain precursors, N-(4-amino- and 4-(methylamino)-1-naphthoyl)-L-glutamic acid diethyl esters, were synthesized, and the 2,4-diamino-substituted heterocyclic groups were attached using several methods. Target compounds included naphthoyl analogues of aminopterin (AMT), methotrexate (MTX), 5-deazaAMT, 5-deazaMTX, 5-methyl-5-deazaAMT, 5-methyl-5-deazaMTX, and 5,8-dideazaAMT. A 5,6,7,8-tetrahydronaphthoyl analogue of 5-deazaAMT was also prepared. None of the naphthoyl analogues showed loss in binding to DHFR compared with the corresponding antifolate bearing the benzoyl group, thus confirming the anticipated bulk tolerance. Only the 5,6,7,8-tetrahydronaphthoyl analogue displayed reduced antifolate effects. Substrate activity toward folylpolyglutamate synthetase was, however, severely compromised. The naphthoyl compounds were transported into L1210 cells 3-6 times more readily than MTX, and despite apparently low levels of intracellular polyglutamylation, each compound was found to be significantly more potent than MTX in inhibiting tumor cell growth in vitro in three lines (L1210, HL60, and S180). The MTX, 5-methyl-5-deazaAMT, and 5-methyl-5-deazaMTX analogues were evaluated in vivo alongside MTX against E0771 mammary adenocarcinoma in mice. All three proved more effective than MTX in retarding the tumor growth. The naphthoyl analogue of 5-deazaAMT strongly inhibited DHFR from Pneumocystis carinii, Toxoplasma gondii, and rat liver giving IC50 (pM) values of 0.53, 2.1, and 1.6 respectively, but this compound did not inhibit in vitro growth of T. gondii, thus indicating lack of transport.
authors.affiliation: Organic Chemistry Research Department, Southern Research Institute, Birmingham, Alabama 35255.
authors.forename: J R
authors.initials: JR
authors.lastname: Piper
authors.forename: C A
authors.initials: CA
authors.lastname: Johnson
authors.forename: J A
authors.initials: JA
authors.lastname: Maddry
authors.forename: N D
authors.initials: ND
authors.lastname: Malik
authors.forename: J J
authors.initials: JJ
authors.lastname: McGuire
authors.forename: G M
authors.initials: GM
authors.lastname: Otter
authors.forename: F M
authors.initials: FM
authors.lastname: Sirotnak
mesh_terms: D000630:Aminopterin / Q000031:analogs & derivatives / Q000737:chemistry; D000818:Animals; D001565:Benzoates / Q000737:chemistry*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003198:Computer Simulation; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007939:Leukemia L1210 / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D008727:Methotrexate / Q000031:analogs & derivatives / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry*; D011010:Pneumocystis / Q000201:enzymology; D051381:Rats; D013329:Structure-Activity Relationship; D014122:Toxoplasma / Q000201:enzymology; D014407:Tumor Cells, Cultured
chemical_list: D001565:Benzoates; D005493:Folic Acid Antagonists; D009281:Naphthalenes; D000630:Aminopterin; D008727:Methotrexate