Rational design, synthesis and characterization of potent, non-peptidic Smac mimics/XIAP inhibitors as proapoptotic agents for cancer therapy

被引：36

作者：

Seneci, Pierfausto ^{[1
,2
]}

Bianchi, Aldo ^{[2
]}

Battaglia, Cristina ^{[2
,3
]}

Belvisi, Laura ^{[1
,2
]}

Bolognesi, Martino ^{[4
,5
]}

Caprini, Andrea ^{[2
]}

Cossu, Federica ^{[4
,5
]}

de Franco, Elena ^{[2
]}

de Matteo, Marilenia ^{[2
]}

Delia, Domenico ^{[6
]}

Drago, Carmelo ^{[2
]}

Khaled, Amira ^{[2
]}

Lecis, Daniele ^{[6
]}

Manzoni, Leonardo ^{[2
,7
]}

Marizzoni, Moira ^{[2
]}

Mastrangelo, Eloise ^{[4
,5
]}

Milani, Mario ^{[4
,5
]}

Motto, Ilaria ^{[2
]}

Moroni, Elisabetta ^{[2
]}

Potenza, Donatella ^{[1
,2
]}

Rizzo, Vincenzo ^{[2
]}

Servida, Federica ^{[8
]}

Turlizzi, Elisa ^{[9
]}

Varrone, Maurizio ^{[9
]}

Vasile, Francesca ^{[2
]}

Scolastico, Carlo ^{[1
,2
]}

机构：

[1] Univ Milan, Dipartimento Chim Organ & Ind, I-20133 Milan, Italy

[2] Univ Milan, Ctr Interdisciplinare Studi Biomol & Applicaz Ind, I-20138 Milan, Italy

[3] Univ Milan, Dipartimento Sci & Tecnol Biomed, I-20090 Segrate, MI, Italy

[4] Univ Milan, Dipartimento Sci Biomol & Biotecnol, I-20133 Milan, Italy

[5] Univ Milan, CNR, INFM, I-20133 Milan, Italy

[6] Ist Nazl Tumori, Dipartimento Oncol Sperimentale, I-20133 Milan, Italy

[7] CNR, ISTM, I-20138 Milan, Italy

[8] Univ Milan, Dipartimento Farmacol Chemioterapia & Tossicol Me, Fdn Mat, I-20129 Milan, Italy

[9] SienaBiotech SpA, I-53100 Siena, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 16期

关键词：

XIAP; Smac; Apoptosis; Oncology; Rational drug design; Crystallography; NMR; Medicinal chemistry; X-LINKED INHIBITOR; XIAP BIR3 DOMAIN; CELL-DEATH; APOPTOSIS PROTEIN; STRUCTURAL BASIS; FLUORESCENCE POLARIZATION; ANTICANCER THERAPY; CASPASE ACTIVATION; CYTOCHROME-C; BINDING;

D O I：

10.1016/j.bmc.2009.07.009

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：

Novel proapoptotic Smac mimics/IAPs inhibitors have been designed, synthesized and characterized. Computational models and structural studies (crystallography, NMR) have elucidated the SAR of this class of inhibitors, and have permitted further optimization of their properties. In vitro characterization (XIAP BIR3 and linker-BIR2-BIR3 binding, cytotox assays, early ADMET profiling) of the compounds has been performed, identifying one lead for further in vitro and in vivo evaluation. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：5834 / 5856

页数：23

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