First use of the Taylor pteridine synthesis as a route to polyglutamate derivatives of antifolates. 46. Side chain modified 5-deazafolate and 5-deazatetrahydrofolate analogs as mammalian folylpolyglutamate synthetase and glycinamide ribonucleotide formyl transferase inhibitors: synthesis and in vitro biological evaluation
| Autor: | Richard G. Moran, Andre Rosowsky, James H. Freisheim, Ronald A. Forsch, Valerie E. Reich |
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| Rok vydání: | 1992 |
| Předmět: | |
| Zdroj: | Journal of Medicinal Chemistry. 35:1578-1588 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 5-Deazafolate and 6-deazatetrahydrofolate (DATHF) analogues with the glutamic acid side chain replaced by homocysteic aicd (HCysA), 2-amino-4-phosphonobutanoic acid (APBA), and ornithine (Om) were synthesized as part of a larger program directed toward inhibitors of folylpolyglutamate synthetase (FPGS) as probes of the FPGS active site and as potential therapeutic agents. The tetrahydro compounds were also of intereat as non-polyglutamatable inhibitors of the purine biosynthetic enzyme glycinamide ribonucleotide formyltransferase (GARFT). Reductive coupling of W-acetamido-6-formylpyrido[2,3-d]pyrimidin-4(3H)-one with 4-aminobenzoic acid, followed by NIOformyhtion, mixed anhydride condensation of the reaultant N2-acetyl-No-formyl-5deazapteroic acid with bhomocysteic acid, and removal of the W-acetyl and No-formyl groups with NaOH, afforded N-(5-deazapteroyl)-~-homocysteic acid (5-dPteHCysA). Mixed anhydride condensation of W-acetyl-No-formyl-5-deazapteroic acid with methyl ~~2-amino-4(dietho~hosp~yl)butanoic acid, followed by consecutive treatment with MeaiBr and NaOH, yielded D,L-2- [ (5-deazapteroyl)amino]-4-phoephonobutanoic acid (BdPteAPBA). Treatment with NaOH alone led to retention of one ethyl eater group on the phosphonate moiety. Catalytic hydrogenation of h"-acetyl-No-formyl-5-deazapteroic acid followed by mixed anhydride condensation with methyl L-homocystsate and deproktion with NaOH afforded N-(5,6,7,8tetrahy~~5-deazapteroyl)-~-hom~teic acid (5-dH4PteHCysA). Similar chemistry starting from methyl ~,~-2-amino-4-(diethoxyphosphinyl)butanoic acid and methyl A@-(benzyloxycarbonyl)-L-ornithinate yielded D,L2-[(5-deaza-5,6,7,8-tetrahydropteroyl)amino]-4-phosphonobu~oic acid (5-dH4Pte-APBA) and N"-(bdeaza5,6,7,&tetrahydropteroyl)-~-ornithine (B-dH,PteOrn), respectively. The 5-deazafolate analogues were inhibitors of mouse liver FPGS, and the DATHF analogues inhibited both mouse FPGS and mouse leukemic cell GARFT. Analogues with HCysA and monoethyl APBA side chains were less active as FPGS inhibitors than those containing an unesteritied -pPO(OH), group, and their interaction with the enzyme was noncompetitive against variable folyl substrate. In contrast, Orn and APBA analogues obeyed competitive inhibition kinetics and were more potent, with Ki values as low as 30 nM. Comparison of the DATHF analogues as GARFT inhibitors indicated that the Om side chain diminished activity relative to DAW, but that the compounds with ysulfonate or y-phosphonate substitution retained activity, with Ki values in the submicromolar range. The best GARFT inhibitor was the 5-dH4PteAPBA diaetereomer mixture, with a Ki of 47 nM versua 65 nM for DATHF. None of the compounds showed activity against cultured WI-L2 or CEM human leukemic lymphoblasts at concentrations of up to 100 pM. We conclude that linking the Meazapteroyl moiety to these amino acid side chains previously found inhibitory to FPGS enhances binding to FPGS, and that negatively charged groups at the yposition of the DATHF analogues allow maintenance of GARFT inhibition. However, inefficient cellular uptake is an obstacle to the use of these potential dual inhibitors of FPGS and GARFT as therapeutic agents. |
| Databáze: | OpenAIRE |
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