Core Modification of Cytisine: A Modular Synthesis

被引：28

作者：

Hirschhaeuser, Christoph ^{[1
]}

Haseler, Claire A. ^{[1
]}

Gallagher, Timothy ^{[1
]}

机构：

[1] Univ Bristol, Sch Chem, Bristol BS8 1TS, Avon, England

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2011年 / 50卷 / 22期

基金：

英国工程与自然科学研究理事会;

关键词：

acetylcholine receptor; cytisine; heterocycles; pyridone; varenicline; NICOTINIC ACETYLCHOLINE-RECEPTORS; SMOKING-CESSATION; CRYSTAL-STRUCTURE; DIASTEREOSELECTIVE FUNCTIONALIZATION; BINDING PROTEIN; PARTIAL AGONIST; (-)-CYTISINE; DERIVATIVES; SELECTIVITY; VARENICLINE;

D O I：

10.1002/anie.201100441

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Getting down to the core: A novel, modular, and more robust synthesis of cytisine, a partial agonist selective for the α4β2 nicotinic acetylcholine receptor, also allows modification of the core structure, as exemplified by the first azacytisine and a cytisine-varenicline hybrid. Key steps include Stille coupling of heteroarylstannanes with a bromolactam motif and an in situ epimerization/alkylative cyclization to complete the tricyclic core (see scheme). Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

引用

页码：5162 / 5165

页数：4

共 31 条

[1] In silico characterization of cytisinoids docked into an acetylcholine binding protein [J].

Andres Abin-Carriquiry, Juan ;

Paulino Zunini, Margot ;

Cassels, Bruce K. ;

Wonnacott, Susan ;

Dajas, Federico .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (12) :3683-3687

[2]

Boido Caterina Canu, 2003, Farmaco (Lausanne), V58, P265, DOI 10.1016/S0014-827X(03)00017-X

[3] Crystal structure of a Cbtx-AChBP complex reveals essential interactions between snake α-neurotoxins and nicotinic receptors [J].

Bourne, Y ;

Talley, TT ;

Hansen, SB ;

Taylor, P ;

Marchot, P .

EMBO JOURNAL, 2005, 24 (08) :1512-1522

[4] Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors [J].

Brejc, K ;

van Dijk, WJ ;

Klaassen, RV ;

Schuurmans, M ;

van der Oost, J ;

Smit, AB ;

Sixma, TK .

NATURE, 2001, 411 (6835) :269-276

[5] Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures [J].

Celie, PHN ;

van Rossum-Fikkert, SE ;

van Dijk, WJ ;

Brejc, K ;

Smit, AB ;

Sixma, TK .

NEURON, 2004, 41 (06) :907-914

[6] Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity [J].

Chellappan, SK ;

Xiao, YX ;

Tueckmantel, W ;

Kellar, KJ ;

Kozikowski, AP .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (09) :2673-2676

[7] Case History: Chantix™/Champix™ (Varenicline Tartrate), a Nicotinic Acetylcholine Receptor Partial Agonist as a Smoking Cessation Aid [J].

Coe, Jotham W. ;

Rollema, Hans ;

O'Neill, Brian T. .

ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 44, 2009, 44 :71-+

[8] Varenicline:: An α4β2 nicotinic receptor partial agonist for smoking cessation [J].

Coe, JW ;

Brooks, PR ;

Vetelino, MG ;

Wirtz, MC ;

Arnold, EP ;

Huang, JH ;

Sands, SB ;

Davis, TI ;

Lebel, LA ;

Fox, CB ;

Shrikhande, A ;

Heym, JH ;

Schaeffer, E ;

Rollema, H ;

Lu, Y ;

Mansbach, RS ;

Chambers, LK ;

Rovetti, CC ;

Schulz, DW ;

Tingley, FD ;

O'Neill, BT .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (10) :3474-3477

[9] Crystal structure of the extracellular domain of nAChR α1 bound to α-bungarotoxin at 1.94 A resolution [J].

Dellisanti, Cosma D. ;

Yao, Yun ;

Stroud, James C. ;

Wang, Zuo-Zhong ;

Chen, Lin .

NATURE NEUROSCIENCE, 2007, 10 (08) :953-962

[10] Lactam Enolate-Pyridone Addition: Synthesis of 4-Halocytisines [J].

Durkin, Patrick ;

Magrone, Pietro ;

Matthews, Stella ;

Dallanoce, Clelia ;

Gallagher, Timothy .

SYNLETT, 2010, (18) :2789-2791

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