Design, synthesis and pharmacological evaluation of new acyl sulfonamides as potent and selective Bcl-2 inhibitors

被引：15

作者：

Liu, Xiaohua ^{[1
,2
]}

Zhang, Yu ^{[3
]}

Huang, Wenjing ^{[3
]}

Tan, Wenfu ^{[3
]}

Zhang, Ao ^{[1
,2
,4
]}

机构：

[1] Univ Chinese Acad Sci, SIMM, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China

[2] Univ Chinese Acad Sci, State Key Lab Drug Res, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China

[3] Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China

[4] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2018年 / 26卷 / 02期

关键词：

Bcl-2; Bcl-xL; Sulfonamide; Navitoclax; Apoptosis; FAMILY; ANTAGONISTS; DISCOVERIES; PROTEINS; DOCKING;

D O I：

10.1016/j.bmc.2017.12.001

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：

The antiapoptotic protein Bcl-2, overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, we report a different structural modification approach on ABT-263 by merging the piperazinyl-phenyl fragment into a bicyclic framework leading to a series of novel analogues, among which tetrahydroisoquinoline 13 was nearly equally potent against Bcl-2 as ABT-263. Further SAR in the P4-interaction pocket affored the difluoroazetidine substituted analogue 55, which retained good Bcl-2 activity with improved Bcl-2/Bcl-xL selectivity. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：443 / 454

页数：12

共 25 条

[1] From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors [J].

Ashkenazi, Avi ;

Fairbrother, Wayne J. ;

Leverson, Joel D. ;

Souers, Andrew J. .

NATURE REVIEWS DRUG DISCOVERY, 2017, 16 (04) :273-284

[2] Studies leading to potent, dual inhibitors of bcl-2 and Bcl-xL [J].

Bruncko, Milan ;

Oost, Thorsten K. ;

Belli, Barbara A. ;

Ding, Hong ;

Joseph, Mary K. ;

Kunzer, Aaron ;

Martineau, Darlene ;

McClellan, William J. ;

Mitten, Michael ;

ng, Shi-Chu Ng ;

Nimmer, Paul M. ;

Oltersdorf, Tilman ;

Park, Cheol-Min ;

Petros, Andrew M. ;

Shoemaker, Alexander R. ;

Song, Xiaohong ;

Wang, Xilu ;

Wendt, Michael D. ;

Zhang, Haichao ;

Fesik, Stephen W. ;

Rosenberg, Saul H. ;

Elmore, Steven W. .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (04) :641-662

[3] 5-Aryl-1H-pyrazole-3-carboxylic acids as selective inhibitors of human carbonic anhydrases IX and XII [J].

Cvijetic, Ilija N. ;

Tanc, Muhammet ;

Juranic, Ivan O. ;

Verbic, Tatjana Z. ;

Supuran, Claudiu T. ;

Drakulic, Branko J. .

BIOORGANIC & MEDICINAL CHEMISTRY, 2015, 23 (15) :4649-4659

[4] Cell death: Critical control points [J].

Danial, NN ;

Korsmeyer, SJ .

CELL, 2004, 116 (02) :205-219

[5] Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies [J].

Delbridge, Alex R. D. ;

Grabow, Stephanie ;

Strasser, Andreas ;

Vaux, David L. .

NATURE REVIEWS CANCER, 2016, 16 (02) :99-109

[6] Synthesis and anti-inflammatory evaluation of new sulfamoylheterocarboxylic derivatives [J].

Diaz, JA ;

Morante, ME ;

Vega, S ;

Darias, V ;

Abdala, S ;

Delgado, L ;

Heras, BD ;

Villar, A ;

Vivas, JM .

ARCHIV DER PHARMAZIE, 1996, 329 (05) :229-238

[7]

Elmore SW, 2013, NAT MED, V19, P2020

[8] Imaging Cellular Distribution of Bcl Inhibitors Using Small Molecule Drug Conjugates [J].

Giedt, Randy J. ;

Sprachman, Melissa M. ;

Yang, Katherine S. ;

Weissleder, Ralph .

BIOCONJUGATE CHEMISTRY, 2014, 25 (11) :2081-2085

[9] Selective inhibitors of Bcl-2 and Bcl-xL: Balancing antitumor activity with on-target toxicity [J].

Hennessy, Edward J. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2016, 26 (09) :2105-2114

[10] Melanin-concentrating hormone receptor 1 antagonists: Synthesis, structure-activity relationship, docking studies, and biological evaluation of 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives [J].

Kasai, Shizuo ;

Kamaura, Masahiro ;

Kamata, Makoto ;

Aso, Kazuyoshi ;

Ogino, Hitomi ;

Nakano, Yoshihide ;

Watanabe, Kaoru ;

Kaisho, Tomoko ;

Tawada, Michiko ;

Nagisa, Yasutaka ;

Takekawa, Shiro ;

Kato, Koki ;

Suzuki, Nobuhiro ;

Ishihara, Yuji .

BIOORGANIC & MEDICINAL CHEMISTRY, 2011, 19 (21) :6261-6273

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