Toward Highly Potent Cancer Agents by Modulating the C-2 Group of the Arylthioindole Class of Tubulin Polymerization Inhibitors

被引：122

作者：

La Regina, Giuseppe ^{[1
]}

Bai, Ruoli ^{[2
]}

Rensen, Whilelmina Maria ^{[3
]}

Di Cesare, Erica ^{[3
]}

Coluccia, Antonio ^{[1
]}

Piscitelli, Francesco ^{[1
]}

Famiglini, Valeria ^{[1
]}

Reggio, Alessia ^{[1
]}

Nalli, Marianna ^{[1
]}

Pelliccia, Sveva ^{[8
]}

Da Pozzo, Eleonora ^{[4
]}

Costa, Barbara ^{[4
]}

Granata, Ilaria ^{[5
]}

Porta, Amalia ^{[5
]}

Maresca, Bruno ^{[5
]}

Soriani, Alessandra ^{[9
]}

Iannitto, Maria Luisa ^{[9
]}

Santoni, Angela ^{[3
,9
]}

Li, Junjie ^{[6
]}

Cona, Marlein Miranda ^{[6
]}

Chen, Feng ^{[6
]}

Ni, Yicheng ^{[6
]}

Brancale, Andrea ^{[7
]}

Dondio, Giulio ^{[10
]}

Vultaggio, Stefania ^{[11
]}

Varasi, Mario ^{[11
]}

Mercurio, Ciro ^{[12
]}

Martini, Claudia ^{[4
]}

Hamel, Ernest ^{[2
]}

Lavia, Patrizia ^{[3
]}

Novellino, Ettore ^{[8
]}

Silvestri, Romano ^{[1
]}

机构：

[1] Univ Roma La Sapienza, Fdn Cenci Bolognetti, Ist Pasteur, Dipartimento Chim & Tecnol Farmaco, 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 Roma La Sapienza, CNR Natl Res Council Italy, Inst Mol Biol & Pathol IBPM, I-00185 Rome, Italy

[4] Univ Pisa, Dept Psychiat Neurobiol Pharmacol & Biotechnol, I-56126 Pisa, Italy

[5] Univ Salerno, Dipartimento Sci Farmaceut, Sez Biomed, I-84084 Salerno, Italy

[6] Katholieke Univ Leuven, Fac Med, Biomed Sci Grp, Theragnost Lab,Dept Imaging & Pathol, B-3000 Louvain, Belgium

[7] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3NB, S Glam, Wales

[8] Univ Naples Federico II, Dipartimento Chim Farmaceut & Tossicol, I-80131 Naples, Italy

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

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

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

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 01期

关键词：

INDOLES; ARYL; COLCHICINE; APOPTOSIS; ANALOGS; INDUCTION; MECHANISM; LIGANDS; COMPLEX; GROWTH;

D O I：

10.1021/jm3013097

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized S. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC50 = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCl/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes.

引用

页码：123 / 149

页数：27

共 67 条

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