Synthesis of Two Potential Inhibitors of <i>p</i><i>ara</i>-Aminobenzoic Acid Synthase

Stigers, Kimberly D.; Mar-Tang, Roger; Bartlett, Paul A.

doi:10.1021/jo9908750

Cited by 18 publications

(7 citation statements)

References 16 publications

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“…Thus, it was considered that ADCS might employ a concerted Mg + -bound transition state involving S N 2‘ addition of an exogenous nucleophile (e.g., H 2 O) to C6 instead of C2 in a first step, followed by a second S N 2‘ step in which NH 3 adds to C4. The compounds 12-O and 12-N (Figure ) were synthesized to probe this possibility . The data presented in Figure and summarized in Table show that both of these compounds are very poor inhibitors of ADCS.…”

Section: Discussionmentioning

confidence: 99%

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Conservation of Mechanism in Three Chorismate-Utilizing Enzymes

et al. 2004

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Chorismate is the end-product of the shikimate pathway for biosynthesis of carbocyclic aromatic compounds in plants, bacteria, fungi, and some parasites. Anthranilate synthase (AS), 4-amino-4-deoxychorismate synthase (ADCS), and isochorismate synthase (IS) are homologous enzymes that carry out the initial transformations on chorismate in the biosynthesis of tryptophan, p-aminobenzoate, and enterobactin, respectively, and are expected to share a common mechanism. Poor binding to ADCS of two potential transition state analogues for addition of a nucleophile to C6 of chorismate implies that it, like AS and IS, initiates reaction by addition of a nucleophile to C2. Molecular modeling based on the X-ray structures of AS and ADCS suggests that the active site residue K274 is the nucleophile employed by ADCS to initiate the reaction, forming a covalent intermediate. The K274A and K274R mutants were shown to have 265- and 640-fold reduced k(cat) values when PabA (the cognate amidotransferase) + glutamine are used as the nitrogen source. Under conditions of saturating chorismate and NH(4)(+), ADCS and the K274A mutant have identical k(cat) values, suggesting the participation of NH(4)(+) as a rescue agent. Such participation was confirmed by the buildup of 2-amino-2-deoxyisochorismate in the reactions of the K274A mutant but not ADCS, when either NH(4)(+) or PabA + glutamine is used as the nitrogen source. Additionally, the inclusion of ethylamine in the reactions of K274A yields the N-ethyl derivative of 2-amino-2-deoxyisochorismate. A unifying mechanism for AS, ADCS, and IS entailing nucleophile addition to C2 of chorismate in an S(N)2' ' process is proposed.

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Section: Discussionmentioning

confidence: 99%

“…Primers were synthesized by Invitrogen. Synthetic routes to the inhibitors 3 , 12-O , and 12-N have been described. , …”

Section: Methodsmentioning

confidence: 99%

Conservation of Mechanism in Three Chorismate-Utilizing Enzymes

et al. 2004

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“…The tasks remaining at this stage were: (1) conversion of C‐5 OH into an amino functionality, and (2) introduction of the C‐3 3‐pentyloxy group. The conversion of C‐5 OH into an amino functionality was achieved by Mitsunobu inversion of the C‐5 β‐hydroxy group with DPPA, diisopropyl azodicarboxylate (DIAD), and Ph 3 P 39. After hydrolysis of the acetal under acidic conditions, the C‐3 hydroxy group was inverted by triflate formation followed by S N 2 attack of KNO 2 .…”

Section: Fang's Synthesismentioning

confidence: 99%

Synthetic Strategies for Oseltamivir Phosphate

2008

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We review here the synthetic strategies for oseltamivir phosphate, an important orally active anti‐influenza drug. The Roche synthesis utilized naturally occurring shikimic acid as a starting material. Introduction of the 1‐ethylpropyloxy (“3‐pentyloxy”) functionality by regioselective reduction of the acetal and iterative ring‐opening reactions with azide to introduce nitrogen functionalities were the key steps. Corey and Fukuyama's syntheses utilized catalytic asymmetricDiels–Alder reactions as the starting points, whereas Shibasaki and Kanai's synthesis began with an asymmetric aziridine‐opening reaction with TMSN3 catalyzed by a polymetallic gadolinium complex. These three syntheses demonstrate the power of asymmetric catalysis in pharmaceutical synthesis. Although Kann's synthesis required resolution to provide an enantiomerically pure intermediate, the properties of chiral iron–diene complexes were elegantly utilized. Yao and Fang's syntheses started from abundant natural chiral sources: L‐serine and D‐xylose, respectively. Specifically, Fang's study identified new analogues of oseltamivir with higher potency against several neuraminidases, including oseltamivir‐resistant mutants. Despite the relatively small molecular size, oseltamivir synthesis highlights an important frontier in organic synthesis.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

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“…These versatile reagents are also used as building blocks in many asymmetric transformations, including Diels‐Alder cycloadditions,7–9 Michael addition,10 1,3‐dipolar cycloaddition reactions11, 12 and bioreductions 13–18. Owing to this wide range of applications, many efforts have been made trying to find optimal synthetic routes of α‐methylene carbonyl compounds6, 19–36 for their use as synthetic intermediates,37–40 to mimic biologically active natural products41–46 and as potential antitumor drugs 47–51. Recently, we reported several methods to directly prepare α‐methylene carbonyl compounds 29.…”

Section: Introductionmentioning

confidence: 99%

Probing the mechanism of direct Mannich‐type α‐methylenation of ketoesters via electrospray ionization mass spectrometry

Milagre

Santos

et al. 2007

J. Mass Spectrom.

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Reactions promoting direct Mannich-type alpha-methylenation of alpha, beta and gamma-ketoesters have been monitored via electrospray ionization mass and tandem mass spectrometric experiments. Key intermediates of the catalytical cycle of this synthetically useful reaction have been intercepted and characterized. The mechanistic information provided by electrospray ionization mass spectrometry/mass spectrometry (ESI-MS/MS) guided the optimization of reaction conditions, allowing alpha-methyleneketoesters to be prepared in high yields (80-95%) and in high-enough purity for immediate further manipulation.

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Synthesis of Two Potential Inhibitors of para-Aminobenzoic Acid Synthase

Cited by 18 publications

References 16 publications

Conservation of Mechanism in Three Chorismate-Utilizing Enzymes

Conservation of Mechanism in Three Chorismate-Utilizing Enzymes

Synthetic Strategies for Oseltamivir Phosphate

Probing the mechanism of direct Mannich‐type α‐methylenation of ketoesters via electrospray ionization mass spectrometry

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