Synthesis of 5,11-methenyltetrahydrohomofolate and its antifolate activity in vitro

Publisher Website
Google Scholar
Abstract
The synthesis of 5,11-methenyltetrahydrohomofolate was accomplished by treatment of tetrahydrohomofolate (H4 homofolate) with triethyl orthoformate in glacial acetic acid. This compound is a homofolate analog of 5,10-methenyltetrahydrofolate which serves as 1 precursor to the 10-formyl 1-carbon donor for the 1st transformylation in de novo purine biosynthesis, i.e., the conversion of glycinamide ribonucleotide (GAR) to N-formylglycinamide ribonucleotide (FGAR), catalyzed by the enzyme glycinamide ribonucleotide transformylase (EC 2.1.2.2). The analog proved to retard the rate of formation of formylglycinamide ribonucleotide apparently by inhibiting the rate of synthesis of 10-formyltetrahydrofolate, the actual cofactor for the transformylase enzyme, from 5,10-methenyltetrahydrofolate. Its inhibition of the enzyme, 5,10-methenyltetrahydrofolate cyclohydrolase (EC 3.5.4.9), was competitive against (+)-L-5,10-methenyltetrahydrofolate, with a Ki = 41 .mu.M. This derivative of homofolate may be responsible for its inhibition of purine biosynthesis in [mouse] Sarcoma 180 cells.