Synthesis and biological activities of tetrahydroquinazoline analogs of aminopterin and methotrexate

A. Gangjee, N. Zaveri, Sherry Queener, R. L. Kisliuk

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 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 x 10-8 M.

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

Fingerprint

Aminopterin
Bioactivity
Aldehydes
Methotrexate
Folic Acid Antagonists
Amination
Methylation
Cyclization
Cell culture
Antineoplastic Agents
Tumors
Glutamic Acid
Screening
Cells
Derivatives
Oxidation

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis and biological activities of tetrahydroquinazoline analogs of aminopterin and methotrexate. / Gangjee, A.; Zaveri, N.; Queener, Sherry; Kisliuk, R. L.

In: Journal of Heterocyclic Chemistry, Vol. 32, No. 1, 1995, p. 243-247.

Research output: Contribution to journalArticle

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