Synthesis of 3-deazathiamine

Hawksley, Daniel; Griffin, David A.; Leeper, Finian J.

doi:10.1039/b006962k

Cited by 40 publications

(32 citation statements)

References 17 publications

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“…Precursor 3-deazathiamin was made by the route described originally by Hawksley et al 35 , except that a modification of the reaction described by Thomas et al 36 to make the thiophene ring was used. The 3-deazathiamin was acetylated on C-2 and on O using a FriedelCrafts acetylation and the amino group was then acetylated using acetic anhydride.…”

Section: Methodsmentioning

confidence: 99%

Sub-ångström-resolution crystallography reveals physical distortions that enhance reactivity of a covalent enzymatic intermediate

et al. 2013

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It is recognized widely that enzymes promote reactions by providing a pathway that proceeds through a transition state of lower energy. In principle, further rate enhancements could be achieved if intermediates are prevented from relaxing to their lowest energy state, and thereby reduce the barrier to the subsequent transition state. Here, we report sub-ångström-resolution crystal structures of genuine covalent reaction intermediates of transketolase. These structures reveal a pronounced out-of-plane distortion of over 20° for the covalent bond that links cofactor and substrate, and a specific elongation of the scissile substrate carbon-carbon bond (d > 1.6 Å). To achieve these distortions, the protein's conformation appears to prevent relaxation of a substrate-cofactor intermediate. The results implicate a reduced barrier to the subsequent step that is consistent with an intermediate of raised energy and leads to a more efficient overall process.

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Section: Methodsmentioning

confidence: 99%

Sub-ångström-resolution crystallography reveals physical distortions that enhance reactivity of a covalent enzymatic intermediate

et al. 2013

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“…The free amino group allowed the chain elongation and the growth of π-conjugated system to achieve structure with three thiophene units 86 ( Figure 9) upon its modification via deamination reaction 38,39,82,135 …”

Section: Synthesis Of π-Conjugated Thiophenes Via Gewald Reactionmentioning

confidence: 99%

“…The synthesis of 3-deazathiamine 61 was effected in ten chemical steps, though it was necessary to prepare and isolate substituted 2-aminothiophene. 135 As is outlined on Scheme 20, the synthesis starts from 3-acetyldihydrofuran-2(3H)-one 54 from which in four-step reaction sequence including the Gewald´s stepwise technique 35-37 appropriate 2-aminothiophene 56 is achieved. Deamination of aminothiophene 56 via the bromide 57 and following cleavage with zinc(0) in acidic media to afford derivative 58 was very efficient, displaying none of side reactions.…”

Section: Synthesis Of Pharmaceuticals and Drugsmentioning

confidence: 99%

Gewald reaction: synthesis, properties and applications of substituted 2-aminothiophenes

Puterová¹,

Krutošíková²,

Végh³

2010

Arkivoc

179

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Chemistry of 2-aminothiophenes is arguably one of the most extensive and dynamic field of present-day thiophene research. Since 1961 when first report on the Gewald reaction was reported it became a universal method for synthesis of substituted 2-aminothiophenes and has gained prominence in recent times. The availability of reagents and the mild reaction conditions all contribute to the versatility of this reaction. This review summarizes the synthetic strategies for substituted 2-aminothiophenes. Consequently, details about the proposed mechanism of Gewald-like reactions and the wide scope of substituted 2-aminothiophenes for real life applications.

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“…S1 and Fig. 3C) (32,33). Therefore, the configuration and conformation of this compound are expected to be similar to those of the substrate.…”

Section: Resultsmentioning

confidence: 99%

“…Here, we describe the X-ray crystal structures of a thiaminase I from N. gruberi in its unliganded state and bound to a substrate analog, 3-deazathiamin (3-dzThi) (Fig. S1), which is isoelectronic with and essentially identical in shape and size to thiamin (32,33). The N. gruberi thiaminase I has been shown to use thiamin, but not thiamin diphosphate, as a substrate and is active with both amines and sulfhydryl compounds as cosubstrates.…”

mentioning

confidence: 99%

Structure of a eukaryotic thiaminase I

Kreinbring¹,

Remillard

Hubbard³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Thiaminases, enzymes that cleave vitamin B1, are sporadically distributed among prokaryotes and eukaryotes. Thiaminase I enzymes catalyze the elimination of the thiazole ring moiety from thiamin through substitution of the methylene group with a nitrogenous base or sulfhydryl compound. In eukaryotic organisms, these enzymes are reported to have much higher molecular weights than their bacterial counterparts. A thiaminase I of the singlecelled amoeboflagellate Naegleria gruberi is the only eukaryotic thiaminase I to have been cloned, sequenced, and expressed. Here, we present the crystal structure of N. gruberi thiaminase I to a resolution of 2.8 Å, solved by isomorphous replacement and pseudotwo-wavelength multiwavelength anomalous diffraction and refined to an R factor of 0.231 (R free , 0.265). This structure was used to solve the structure of the enzyme in complex with 3-deazathiamin, a noncleavable thiamin analog and enzyme inhibitor (2.7 Å; R, 0.233; R free , 0.267). These structures define the mode of thiamin binding to this class of thiaminases and indicate the involvement of Asp272 as the catalytic base. This enzyme is able to use thiamin as a substrate and is active with amines such as aniline and veratrylamine as well as sulfhydryl compounds such as L-cysteine and β-mercaptoethanol as cosubstrates. Despite significant differences in polypeptide sequence and length, we have shown that the N. gruberi thiaminase I is homologous in structure and activity to a previously characterized bacterial thiaminase I.X-ray crystallography | thiamin degradation

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Synthesis of 3-deazathiamine

Cited by 40 publications

References 17 publications

Sub-ångström-resolution crystallography reveals physical distortions that enhance reactivity of a covalent enzymatic intermediate

Sub-ångström-resolution crystallography reveals physical distortions that enhance reactivity of a covalent enzymatic intermediate

Gewald reaction: synthesis, properties and applications of substituted 2-aminothiophenes

Structure of a eukaryotic thiaminase I

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