New Indole Tubulin Assembly Inhibitors Cause Stable Arrest of Mitotic Progression, Enhanced Stimulation of Natural Killer Cell Cytotoxic Activity, and Repression of Hedgehog-Dependent Cancer

被引：57

作者：

La Regina, Giuseppe ^{[1
]}

Bai, Ruoli ^{[2
]}

Coluccia, Antonio ^{[1
]}

Farniglini, Valeria ^{[1
]}

Pelliccia, Sveva ^{[3
]}

Passacantilli, Sara ^{[1
]}

Mazzoccoli, Carmela ^{[4
]}

Ruggieri, Vitalba ^{[4
]}

Verrico, Annalisa ^{[5
]}

Miele, Andrea ^{[5
]}

Monti, Ludovica ^{[1
]}

Nalli, Marianna ^{[1
]}

Alfonsi, Romina ^{[6
]}

Di Marcotullio, Lucia ^{[6
,7
]}

Gulino, Alberto ^{[6
]}

Ricci, Biancamaria ^{[6
]}

Soriani, Alessandra ^{[6
]}

Santoni, Angela ^{[5
,6
]}

Caraglia, Michele ^{[8
]}

Porto, Stefania ^{[8
]}

Da Pozzo, Eleonora ^{[9
]}

Martini, Claudia ^{[9
]}

Brancale, Andrea ^{[10
]}

Marinelli, Luciana ^{[3
]}

Novellino, Ettore ^{[3
]}

Vultaggio, Stefania ^{[11
]}

Varasi, Mario ^{[11
]}

Mercurio, Ciro ^{[12
]}

Bigogno, Chiara ^{[13
]}

Dondio, Giulio ^{[13
]}

Hamel, Ernest ^{[2
]}

Lavia, Patrizia ^{[5
]}

Silvestri, Romano ^{[1
]}

机构：

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

[2] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Ft Detrick, 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] Univ Roma La Sapienza, CNR, Inst Mol Biol & Pathol, I-00185 Rome, Italy

[6] Univ Roma La Sapienza, Fdn Cenci Bolognetti, Ist Pasteur, Dept Mol Med, I-00161 Rome, Italy

[7] Ist Italian Tecnol, Ctr Life NanoSci Sapienza, I-00161 Rome, Italy

[8] Univ Naples 2, Dept Biochem Biophys & Gen Pathol, I-80138 Naples, Italy

[9] Univ Pisa, Dept Pharm, I-56126 Pisa, Italy

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

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

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

[13] APHAD Srl, I-20090 Buccinasco, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 15期

关键词：

POTENT INHIBITORS; ANTICANCER AGENTS; COLCHICINE SITE; POLYMERIZATION; ANALOGS; ARYLTHIOINDOLES; DERIVATIVES; CYCLIZATION; GROWTH; BINDS;

D O I：

10.1021/acs.jmedchem.5b00310

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We designed 39 new 2-phenylindole derivatives as potential anticancer agents bearing the 3,4,5-trimethoxyphenyl moiety with a sulfur, ketone, or methylene bridging group at position 3 of the indole and with halogen or methoxy substituent(s) at positions 4-7. Compounds 33 and 44 strongly inhibited the growth of the P-glycoprotein-overexpressing multi-drug-resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, 33 and 44 stimulated the cytotoxic activity of NK cells. At 20-50 nM, 33 and 44 arrested >80% of HeLa cells in the G2/M phase of the cell cycle, with stable arrest of mitotic progression. Cell cycle arrest was followed by cell death. Indoles 33, 44, and 81 showed strong inhibition of the SAG-induced Hedgehog signaling activation in NIH3T3 Shh-Light II cells with IC50 values of 19, 72, and 38 nM, respectively. Compounds of this class potently inhibited tubulin polymerization and cancer cell growth, including stimulation of natural killer cell cytotoxic activity and repression of Hedgehog-dependent cancer.

引用

页码：5789 / 5807

页数：19

共 69 条

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