New Pyrrole Derivatives with Potent Tubulin Polymerization Inhibiting Activity As Anticancer Agents Including Hedgehog-Dependent Cancer

被引：82

作者：

La Regina, Giuseppe ^{[1
]}

Bai, Ruoli ^{[2
]}

Coluccia, Antonio ^{[1
]}

Famiglini, Valeria ^{[1
]}

Pelliccia, Sveva ^{[3
]}

Passacantilli, Sara ^{[1
]}

Mazzoccoli, Carmela ^{[4
]}

Ruggieri, Vitalba ^{[4
]}

Sisinni, Lorenza ^{[4
]}

Bolognesi, Alessio ^{[5
]}

Rensen, Whilelmina Maria ^{[5
]}

Miele, Andrea ^{[5
]}

Nalli, Marianna ^{[1
]}

Alfonsi, Romina ^{[6
]}

Di Marcotullio, Lucia ^{[6
]}

Gulino, Alberto ^{[6
]}

Brancale, Andrea ^{[7
]}

Novellino, Ettore ^{[3
]}

Dondio, Giulio ^{[8
]}

Vultaggio, Stefania ^{[9
]}

Varasi, Mario ^{[9
]}

Mercurio, Ciro ^{[10
]}

Hamel, Ernest ^{[2
]}

Lavia, Patrizia ^{[5
]}

Silvestri, Romano ^{[1
]}

机构：

[1] Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur Fdn Cenci Bolognetti, I-00185 Rome, Italy

[2] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA

[3] Univ Naples Federico II, Dipartimento Farm, I-80131 Naples, Italy

[4] IRCCS, Ctr Riferimento Oncol Basilicata, Lab Ric Preclin & Traslaz, I-85028 Rionero In Vulture, Italy

[5] Sapienza Univ Roma, CNR Natl Res Council Italy, Inst Mol Biol & Pathol IBPM, I-00185 Rome, Italy

[6] Sapienza Univ Roma, Dipartimento Med Sperimentale & Patol, I-00161 Rome, Italy

[7] Cardiff Univ, Cardiff Sch Pharm & Pharmaceut Sci, Cardiff CF10 3NB, S Glam, Wales

[8] NiKem Res Srl, I-20021 Milan, Italy

[9] European Inst Oncol, I-20139 Milan, Italy

[10] DAC SRL, Genextra Grp, I-20139 Milan, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 15期

关键词：

MICROTUBULE INHIBITORS; COLCHICINE; BINDING; CELLS; DOMAIN; DRUGS; ACYLTHIOUREA; DISCOVERY; APOPTOSIS; STATHMIN;

D O I：

10.1021/jm500561a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We synthesized 3-aroy1-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 343,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light 11 cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway.

引用

页码：6531 / 6552

页数：22

共 40 条

[1]

[Anonymous], 2010, MOL OP ENV MOE 2010

[2]

[Anonymous], 2009, GLID VERS 5 5

[3] Stathmin and Interfacial Microtubule Inhibitors Recognize a Naturally Curved Conformation of Tubulin Dimers [J].