Synthesis and biological activities of tetrahydroquinazoline analogs of aminopterin and methotrexate

Aleem Gangjee, Nurulain Zaveri, Sherry F. Queener, Roy L. Kisliuk

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

(6R,6S)‐5,8‐Dideaza‐5,6,7,8‐tetrahydroaminopterin (1) and (6R,6S)‐5,8‐dideaza‐5,6,7,8‐tetrahydromethotrexate (2) were synthesized as potential inhibitors of dihydrofolate reductase (DHFR) and as antitumor agents. Cyclohexanone‐4‐carboxaldehyde dimethyl acetal, a key intermediate [10] was synthesized from cyclohexane‐1,4‐dione monoethylene ketal, which was converted via a Wittig reaction to its exocyclic 4‐methylene derivative which in turn, was converted to the 4‐aldehyde via a hydroboration‐oxidation sequence. Selective protection of the 4‐aldehyde as the dimethylacetal and cyclization with dicyandiamide afforded the 6‐dimethylacetal of 2,4‐diamino‐5,6,7,8‐tetrahydroquinazoline. Protection of the 2,4‐diamino moieties and selective deprotection of the 6‐aldehyde followed by reductive amination with p‐aminobenzoyl‐L‐glutamate afforded 2,4‐bisacetamido‐5,8‐dideaza‐5,6,7,8‐tetrahydroaminopterin (11). Deprotection of 11 afforded 1. Compound 2 was obtained from 11 via N10‐methylation and deprotection. The N10‐methyl analogue 2 was 2–10 fold more potent than 1 as an inhibitor of various DHFRs. In the in vitro preclinical screening program of the National Cancer Institute, compound 2 inhibited the growth of eighteen of the twenty nine tumor cell lines in culture at a GI50 > 1.0 × 10−8 M.

Original languageEnglish (US)
Pages (from-to)243-247
Number of pages5
JournalJournal of Heterocyclic Chemistry
Volume32
Issue number1
DOIs
StatePublished - Jan 1 1995

ASJC Scopus subject areas

  • Organic Chemistry

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