Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
gamma-tert-Butylaminopterin (gamma-tBAMT), the first example of an aminopterin (AMT) gamma-monoester, was synthesized, and new routes to the known N10-methyl analogue gamma-tert-butyl methotrexate (gamma-tBMTX) were developed. The inhibitory effects of gamma-tBAMT on the activity of purified dihydrofolate reductase (DHFR) from L1210 murine leukemia cells, the growth of L1210 cells and CEM human leukemic lymphoblasts in suspension culture, and the growth of several lines of human squamous cell carcinoma of the head and neck in monolayer culture were compared with the effects of gamma-tBMTX and the parent acids AMT and methotrexate (MTX). Patterns of cross-resistance to gamma-tBAMT, gamma-tBMTX, and AMT among several MTX-resistant cell lines were examined. In vivo antitumor activities of gamma-tBAMT and gamma-tBMTX were compared in mice with L1210 leukemia. While the activity of gamma-tBAMT was very close to that of gamma-tBMTX in the DHFR inhibition assay, the AMT ester was more potent than the MTX ester against cells in culture and against L1210 leukemia in vivo. Only partial cross-resistance was shown against gamma-tBMTX and gamma-tBAMT in cultured cells that were resistant to MTX by virtue of a transport defect or a combination of defective transport and elevated DHFR activity.
D000630:Aminopterin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D002460:Cell Line; D004351:Drug Resistance; D004951:Esterification; D005493:Folic Acid Antagonists; D006801:Humans; D066298:In Vitro Techniques; D007938:Leukemia / Q000188:drug therapy; D007939:Leukemia L1210 / Q000188:drug therapy / Q000201:enzymology; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051379:Mice; D013601:T-Lymphocytes / Q000187:drug effects
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; C045204:gamma-tert-butyl methotrexate; C045203:gamma-tert-butyl aminopterin; D000630:Aminopterin; D008727:Methotrexate