Chemical model for thymidylate synthetase catalysis

Wilson, Raymond S.; Mertes, Mathias P.

doi:10.1021/bi00739a017

Cited by 14 publications

(13 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The proton NMR of 18 was identical with that of 17 with the exception of the ring N-H peak which was absent; the elemental analysis agrees with the structure (18) proposed.…”

supporting

confidence: 78%

“…N-Bromo-l-(3-di-0-toluoyl-2-deoxy-|8-D-ribofuranosyl)-5-allyluracil (18) and l-(3,5-Di-0-toluoyl-2-deoxy-/3-D-ribofuranosyl)-5-(3-bromo-2-hydroxypropyl)uracil (19). To a solution of compound 17 (1.01 g, 2 mmol) in a mixture of tetrahydrofuran (20 ml) and water (10 ml), cooled in an ice bath, was added N-bromosuccinimide (370 mg, 2.08 mmol).…”

Section: Methodsmentioning

confidence: 99%

“…Compound 19 was isolated from the mother liquor of compound 18 by preparative TLC using dichloromethane-methanol (30:1) on silica. The mixture was separated into two bands, the high Rf being 18.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Synthesis of 5-substituted 2'-deoxyuridines

Kampf¹,

Pillar²,

Woodford³

et al. 1976

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

A series of thymidylate synthetase inhibitors was synthesized, some of which were potential irreversible inhibitors. 5-Formyl-2'-deoxyuridine (9) and its dithiolane derivative 11 were prepared by condensation of the bis(trimethylsilyl) derivative of 5-formyluracil dimethyl acetal and the protected chloro sugar followed by saponification of the protective groups. 5-Acetyl-2'-deoxyuridine (15) was prepared in the same way from 5-acetyluracil. Treatment of the diester of 5-allyl-2'-deoxyuridine (17 or 22) with m-chloroperbenzoic acid gave the corresponding epoxide. Dimethylamine removed the ester groups and opened the epoxide to give the amino alcohol 24. The diester of 5-chloromethyl-2'-deoxyuridine (27) treated with methanol or sodium azide gave 5-methoxymethyl- (29) and 5-azidomethyl- (31) 2'-deoxyuridines. Compound 27 also was converted to 5-iodoacetamidomethyl-2'-deoxyuridine by treatment with ammonia, chloroacetyl chloride, base saponification, and finally sodium iodide.

show abstract

“…The proton NMR of 18 was identical with that of 17 with the exception of the ring N-H peak which was absent; the elemental analysis agrees with the structure (18) proposed.…”

supporting

confidence: 78%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis of 5-substituted 2'-deoxyuridines

Kampf¹,

Pillar²,

Woodford³

et al. 1976

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Experiments with the deuterium-labeled analog demonstrated that a significant portion of the hydrogen transfer occurred intramolecularly. In this case, an exocyclic methylene intermediate was excluded because of the lack of exchange at the C-6 position, and the transfer was proposed to occur by a 1,3-shift directly to the methylene bridge (129). However, 5-thyminyltetrahydrofolate, a much closer analog of the natural cofactor, is not known to undergo rearrangement to thymine even when heated to 100°C (130).…”

Section: Reduction Of the Methylene Groupmentioning

confidence: 99%

Fluorinated Pyrimidines and Their Nucleosides

Heidelberger¹,

Danenberg²,

Moran³

1983

Advances in Enzymology - And Related Areas of Molecular Biology

View full text Add to dashboard Cite

“…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.…”

mentioning

confidence: 99%

Noncovalent Intermediate of Thymidylate Synthase: Fact or Fiction?

Kholodar

Kohen

2016

J. Am. Chem. Soc.

View full text Add to dashboard Cite

Thymidylate synthase is an attractive target for antibiotic and anticancer drugs due to its essential role in the de novo biosynthesis of the DNA nucleotide thymine. The enzymatic reaction is initiated by a nucleophilic activation of the substrate via formation of a covalent bond to an active site cysteine. The traditionally accepted mechanism is then followed by a series of covalently-bound intermediates, where that bond is only cleaved upon product release. Recent computational and experimental studies suggest that the covalent bond between the protein and substrate is actually quite labile. Importantly, these findings predict the existence of a non-covalently bound bi-substrate intermediate, not previously anticipated, which could be the target of a novel class of drugs inhibiting DNA biosynthesis. Here we report the synthesis of the proposed intermediate and findings supporting its chemical and kinetic competence. These findings substantiate the predicted non-traditional mechanism and the potential of this intermediate as a new drug lead.

show abstract

Chemical model for thymidylate synthetase catalysis

Cited by 14 publications

References 24 publications

Synthesis of 5-substituted 2'-deoxyuridines

Synthesis of 5-substituted 2'-deoxyuridines

Fluorinated Pyrimidines and Their Nucleosides

Noncovalent Intermediate of Thymidylate Synthase: Fact or Fiction?

Contact Info

Product

Resources

About