Strategies towards the Synthesis of 6‐<i>N</i>,<i>N</i>‐Diethylcarbamyloxy‐1,4‐dimethoxy‐ 7‐naphthylboronic Acid

Ameer, Farouk; Green, Ivan R.; Krohn, Karsten; Sitoza, M.

doi:10.1080/00397910701542962

Cited by 12 publications

(9 citation statements)

References 12 publications

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“…Compounds 1-3 , 7 , 9 , 12 , 13 , 15 , 17 , 23-25 were obtained from commercial sources while compounds 4-6 , 11 , 20 , 21 , 26 were obtained from the Baran lab. [34] Compounds 10 ,[25] 14 ,[35] 16 , 18 ,[36] 19, [37] 40 / 41 ,[38] were synthesized as reported previously.…”

Section: Methodsmentioning

confidence: 99%

Benzoquinones as inhibitors of botulinum neurotoxin serotype A

Bremer

Hixon

Janda

2014

Bioorganic & Medicinal Chemistry

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Although botulinum neurotoxin serotype A (BoNT/A) is known for its use in cosmetics, it causes a potentially fatal illness, botulism, and can be used as a bioterror weapon. Many compounds have been developed that inhibit the BoNTA zinc-metalloprotease light chain (LC), however, none of these inhibitors have advanced to clinical trials. In this study, a fragment-based approach was implemented to develop novel covalent inhibitors of BoNT/A LC. First, electrophilic fragments were screened against BoNT/A LC, and benzoquinone (BQ) derivatives were found to be active. In kinetic studies, BQ compounds acted as irreversible inhibitors that presumably covalently modify cysteine 165 of BoNT/A LC. Although most BQ derivatives were highly reactive toward glutathione in vitro, a few compounds such as natural product naphthazarin displayed low thiol reactivity and good BoNT/A inhibition. In order to increase the potency of the BQ fragment, computational docking studies were employed to elucidate a scaffold that could bind to sites adjacent to Cys165 while positioning a BQ fragment at Cys165 for covalent modification; 2-amino-N-arylacetamides met these criteria and when linked to BQ displayed at least a 20-fold increase in activity to low μM IC50 values. Unlike BQ alone, the linked-BQ compounds demonstrated only weak irreversible inhibition and therefore acted mainly as non-covalent inhibitors. Further kinetic studies revealed a mutual exclusivity of BQ covalent inactivation and competitive inhibitor binding to sites adjacent to Cys165, refuting the viability of the current strategy for developing more potent irreversible BoNT/A inhibitors. The highlights of this study include the discovery of BQ compounds as irreversible BoNT/A inhibitors and the rational design of low μM IC50 competitive inhibitors that depend on the BQ moiety for activity.

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Section: Methodsmentioning

confidence: 99%

Benzoquinones as inhibitors of botulinum neurotoxin serotype A

Bremer

Hixon

Janda

2014

Bioorganic & Medicinal Chemistry

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“…1 H NMR (300.33 MHz, CDCl 3 ): δ = 1.04–1.13 (m, 6H) 3.22–3.32 (m, 4H) 7.02 (d, J = 8.05, 1H) 7.18–7.23 (m, 1H) 7.33–7.39 (m, 1H) 7.85–7.88 (m, 1H), 13 C NMR (62.90 MHz, CDCl 3 ): δ = 11.45, 12.03, 40.09, 40.52, 74.84, 75.34, 75.86, 117.54, 123.20, 128.44, 133.60, 153.62 (Lit. [23]). …”

Section: Methodsmentioning

confidence: 99%

General Approach to the Synthesis of Prochiral Atropisomeric Biaryls

Kielar

Demchuk

Pietrusiewicz

2011

ISRN Organic Chemistry

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General approach to the synthesis of prochiral precursors of chiral atropisomeric biaryls based on several complementary methods has been developed. Biaryls were obtained in good to excellent yields depending on their structure and selected method of synthesis. Furthermore, we demonstrate a possibility of utilisation of the obtained compounds possessing 2 or 3 ortho substituents around the aryl-aryl bond in direct and directed arylation reaction leading through transition metal-mediated C–H bond activation to atropisomeric compounds.

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“…3 (B) After acetylation, condensation between Danishefsky's diene and benzoquinone afforded a stable methoxytriacetoxydihydronaphthalene intermediate 2, which was subsequently transformed into the regiospecific 7-naphthylboronic acid 3 by the Snieckus DOM protocol. 4 (C) Mandai and co-workers delineated the reaction of Danishefsky's diene with aryl-/alkyl-substituted aldimine catalyzed by silver in the presence of a ligand leading to the formation of pyridinone 4. (D) Alaimo and co-workers have designed domino reactions where the nitroarene reduction by indium(0) generates an amine to which addition of an aldehyde followed by Danishefsky's diene provides access to dihydropyridin-4-ones 5.…”

Section: Methodsmentioning

confidence: 99%