5-[(4-Methyl-1,2,3,4-tetrahydroquinoxalyl)methyl]-2'-deoxyuridine 5'-phosphate: an analogue of a proposed intermediate in thymidylate synthetase catalysis

Abstract

In a study of the sequence steps involved in the mechanism of thymidylate synthetase catalysis, 5-[(N-methyl-piperazinyl)methyl]- (5) and 5-[(4-methyl-1,2,3,4-tetrahydroquinoxalyl)methyl]-2'-deoxyuridine 5'-phosphate (6) were synthesized. Compound 6 has high affinity for the Lactobacillus casei enzyme (Ki = 0.75 microM, KI/Km - 0.23), which is 50 times stronger than that of the piperazinyl derivative 5. Compound 6, a possible multisubstrate inhibitor, is an analogue of a proposed intermediate in the reaction mechanism wherein the enzyme is eliminated from the covalent complex (enzyme--substrate--cofactor) prior to the redox reaction leading to the products 2'-deoxythymidine 5'-phosphate and 7,8-dihydrofolic acid.

Multisubstrate adduct inhibitors: Drug design and biological tools

“…Mertes et al synthesized the first thymidylate synthase inhibitor with a K i of 0.75 M, which was a thymidylate substituted on the 5-methyl with a simple tetrahydroquinoxaline 61 . Subsequent to this, Broom et al described the synthesis and biological evaluation of other multisubstrate analog inhibitors (Table 3) 59 .…”

Synthesis and .beta.-adrenergic antagonism of 2-(aryloxy)-1-(2-piperidyl)ethanols

“…Aiming to determine the effect of cyclization upon /3-blocking potency, we have also synthesized and tested the open-chain analogues 4a-h, bearing an N-isopropyl group. Chemistry 2-(2-Oxiranyl)pyridine (6) was obtained in 64% yield from 2-vinylpyridine (5), through the method of Hanzlik (1) A preliminary account of this work was presented by Pujol, M. D.; Minguillón, C.; Rosell, G.; Mauleón; D., Miquel, J.; Barenys, B. at the XXII Rencontres Internationales de Chimie Thérapeutique, Clermont-Ferrand, France, September 1986; Communication C-19.…”

Noncovalent Intermediate of Thymidylate Synthase: Fact or Fiction?

“…In fact, Int-B had been originally considered to be TSase intermediate , until the discovery of nucleophilic covalent activation of dUMP with active site cysteine and detection of the covalently bound ternary complex in crystal structures . Inspired by that early prediction, several studies reported synthesis and biological activity of stable analogues of Int-B , including thyminyl derivatives of H 4 F , and thymidinyl derivatives of dihydro- and tetrahydroquinoline, tetrahydropyridopyrimidines, pyrimidines, tetrahydroquinoxalines, and 8-deaza-5,6,7,8-tetrahydrofolate. , Interestingly, the latter compound, differing from Int-B only at the position 8 of the folate, appeared to be a potent nanomolar competitive inhibitor of human TSase. This intriguing fact and the prediction of QM/MM calculations encouraged us to examine competence of Int-B as an intermediate in the TSase-catalyzed reaction.…”