Gabaculine: γ-aminobutyrate aminotransferase inhibitor of microbial origin

Tetrahedron Letters
1976.0

Abstract

In the course of the studies on enzyme inhibitors produced by microorganisms, gabaculine was discovered in a culture filtrate of Streptomyces toyocaensis subsp. 1039 and it showed inhibition (10⁻⁸ - 10⁻⁹ mole/ml for IC50) of γ-aminobutyrate aminotransferase. Herein we report the structural elucidation and synthesis of gabaculine. Gabaculine, isolated as an amorphous powder with [α] = -454° (c=1, H₂O), has the formula C₇H₉NO₂ (M⁺ 139.0642). Spectroscopic data (IR: conjugated carbonyl absorption at 1650 cm⁻¹; UV: maximum at 275 nm (ε 8680) indicating a carbonyl chromophore conjugated with a dienyl group; NMR: ABX system, vicinal cis olefinic protons (J=9.5 Hz), allylic geminal methylene, proton on amino/hydroxyl-attached carbon; MS: peaks similar to benzoic acid except molecular ion and base peak m/e 94 (M⁺-COOH)) and functional group analysis (carboxyl group esterified with diazomethane, amino group with positive ninhydrin test) led to its structure determination as 1. The synthetic approach avoided thermal reaction conditions and extensive work-up: electrophilic addition of iodo-isocyanate to methyl 2,5-dihydrobenzoate, followed by treatment with p-methoxybenzylalcohol, dehydroiodonation with DABCU, and protective group manipulations (tert-butyloxycarbonyl protection, hydrolysis, deprotection) yielded dl-gabaculine. Identity of dl-gabaculine with natural gabaculine was confirmed by spectroscopic data (IR, UV, NMR, MS), TLC, and amino acid analysis. dl-Gabaculine exhibited half the γ-aminobutyrate aminotransferase inhibitory activity of the natural form.

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