Synthesis and antitumor activity of 10-propargyl-10-deazaaminopterin

Abstract

Successive alkylation of dimethyl homoterephthalate with propargyl bromide and 2,4-diamino-6-(bromomethyl)pteridine followed by ester saponification at room temperature afforded 2,4-diamino-4-deoxy-10-carboxy-10-propargyl-10-deazapteroic acid. The 10-COOH was readily decarboxylated by heating in DMSO at a temperature of only 120 degrees C to yield the diamino-10-propargyl-10-deazapteroic acid intermediate. Coupling with diethyl L-glutamate and ester hydrolysis gave the title compound. The 10-propargyl analogue was about 5 times more potent than MTX as an inhibitor of growth in L1210 cells, but was only one-third as potent as an inhibitor of DHFR from L1210. The analogue was transported inward very effectively in L1210 cells showing a 10-fold advantage over MTX. At a dose of 36 mg/kg the 10-propargyl compound caused shrinkage of the E0771 solid murine mammary tumor to only 1% of untreated controls.

Pralatrexate Pharmacology and Clinical Development

“…1). Pralatrexate was rationally designed to have high affinity for the RFC and folylpolyglutamate synthase (FPGS), leading to enhanced and selective intracellular internalization and retention in tumor cells (5). RFC is an oncofetal protein known to be highly expressed in embryonic and malignant tissues (6,7).…”

From methotrexate to pemetrexed and beyond. A review of the pharmacodynamic and clinical properties of antifolates

“…It is approximately 5 fold more potent than MTX as an inhibitor of L1210 cells [184]. A phase I study defined a dose of 150 mg/m 2 given every 2 weeks as the recommended phase II dose [185].…”

Pralatrexate-induced tumor cell apoptosis in the epidermis of a patient with HTLV-1 adult T-cell lymphoma/leukemia causing skin erosions

“…In preclinical studies, pralatrexate has shown greater antitumor activity compared with methotrexate. 1 Human tumor xenograft studies in mice (including human breast cancer and human lung cancer xenografts) demonstrated improved regression of tumors with pralatrexate treatment, whereas methotrexate treatment resulted only in delayed tumor growth without a sustained regression at comparable doses. 2,3 Comparison of the efficacy of pralatrexate and methotrexate against several lymphoma cell lines (including diffuse large B-cell lymphoma, Burkitt lymphoma, transformed follicular lymphoma, T-cell lymphoma, and Hodgkin disease) showed a more than 10-fold increased in vitro cytotoxicity in pralatrexate-treated cells and improved regression of xenografts in nonobese diabetic/severe combined immunodeficiency mice.…”