The Effect of Vicinal Difluorination on the Conformation and Potency of Histone Deacetylase Inhibitors

被引：5

作者：

Ariawan, A. Daryl ^{[1
]}

Mansour, Flora ^{[1
]}

Richardson, Nicole ^{[1
]}

Bhadbhade, Mohan ^{[2
]}

Ho, Junming ^{[1
]}

Hunter, Luke ^{[1
]}

机构：

[1] UNSW Sydney, Sch Chem, Sydney, NSW 2052, Australia

[2] UNSW Sydney, Mark Wainwright Analyt Ctr, Sydney, NSW 2052, Australia

来源：

MOLECULES | 2021年 / 26卷 / 13期

关键词：

SAHA; Scriptaid; stereoselective fluorination; HDAC; FLUORINATION; CYCLIZATION;

D O I：

10.3390/molecules26133974

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Histone deacetylase enzymes (HDACs) are potential targets for the treatment of cancer and other diseases, but it is challenging to design isoform-selective agents. In this work, we created new analogs of two established but non-selective HDAC inhibitors. We decorated the central linker chains of the molecules with specifically positioned fluorine atoms in order to control the molecular conformations. The fluorinated analogs were screened against a panel of 11 HDAC isoforms, and minor differences in isoform selectivity patterns were observed.

引用

页数：17

共 30 条

[1] Epigenetic protein families: a new frontier for drug discovery [J].

Arrowsmith, Cheryl H. ;

Bountra, Chas ;

Fish, Paul V. ;

Lee, Kevin ;

Schapira, Matthieu .

NATURE REVIEWS DRUG DISCOVERY, 2012, 11 (05) :384-400

[2] Tuning the properties of a cyclic RGD-containing tetrapeptide through backbone fluorination [J].

Au, Catherine ;

Gonzalez, Christina ;

Leung, Yun Cheuk ;

Mansour, Flora ;

Trinh, Johny ;

Wang, Zhiyong ;

Hu, Xiang-Guo ;

Griffith, Renate ;

Pasquier, Eddy ;

Hunter, Luke .

ORGANIC & BIOMOLECULAR CHEMISTRY, 2019, 17 (03) :664-674

[3] Catalytic, Diastereoselective 1,2-Difluorination of Alkenes [J].

Banik, Steven M. ;

Medley, Jonathan William ;

Jacobsen, Eric N. .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2016, 138 (15) :5000-5003

[4] The preferred conformation of α-fluoroamides [J].

Banks, JW ;

Batsanov, AS ;

Howard, JAK ;

O'Hagan, D ;

Rzepa, HS ;

Martin-Santamaria, S .

JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 2, 1999, (11) :2409-2411

[5]

BARCO A, 1974, ORG PREP PROCEDURES, V6, P217

[6] Interplay of Cascade Oxidative Cyclization and Hydride Shifts in the Synthesis of the ABC Spiroketal Ring System of Pectenotoxin-4 [J].

Donohoe, Timothy J. ;

Lipinski, Radoslaw M. .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2013, 52 (09) :2491-2494

[7] Synthesis and Biological Evaluation of Bromo- and Fluorodanicalipin A [J].

Fischer, Stefan ;

Huwyler, Nikolas ;

Wolfrum, Susanne ;

Carreira, Erick M. .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2016, 55 (07) :2555-2558

[8] A Computational Study of Vicinal Fluorination in 2,3-Difluorobutane: Implications for Conformational Control in Alkane Chains [J].

Fox, Stephen J. ;

Gourdain, Stephanie ;

Coulthurst, Anton ;

Fox, Clare ;

Kuprov, Ilya ;

Essex, Jonathan W. ;

Skylaris, Chris-Kriton ;

Linclau, Bruno .

CHEMISTRY-A EUROPEAN JOURNAL, 2015, 21 (04) :1682-1691

[9]

Gore V.G., 2015, U.S. Patent, Patent No. [9162974B2, 9162974]

[10] Minimising conformational bias in fluoroprolines through vicinal difluorination [J].

Hofman, Gert-Jan ;

Ottoy, Emile ;

Light, Mark E. ;

Kieffer, Bruno ;

Kuprov, Ilya ;

Martins, Jose C. ;

Sinnaeve, Davy ;

Linclau, Bruno .

CHEMICAL COMMUNICATIONS, 2018, 54 (40) :5118-5121

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