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

J Med Chem. 2015 Aug 13;58(15):5789-807. doi: 10.1021/acs.jmedchem.5b00310.

Giuseppe La Regina ¹, Ruoli Bai ², Antonio Coluccia ¹, Valeria Famiglini ¹, Sveva Pelliccia ³, Sara Passacantilli ¹, Carmela Mazzoccoli ⁴, Vitalba Ruggieri ⁴, Annalisa Verrico ⁵, Andrea Miele ⁵, Ludovica Monti ¹, Marianna Nalli ¹, Romina Alfonsi ⁶, Lucia Di Marcotullio ⁶ ⁷, Alberto Gulino ⁶, Biancamaria Ricci ⁶, Alessandra Soriani ⁶, Angela Santoni ⁵ ⁶, Michele Caraglia ⁸, Stefania Porto ⁸, Eleonora Da Pozzo ⁹, Claudia Martini ⁹, Andrea Brancale ¹⁰, Luciana Marinelli ³, Ettore Novellino ³, Stefania Vultaggio ¹¹, Mario Varasi ¹¹, Ciro Mercurio ¹², Chiara Bigogno ¹³, Giulio Dondio ¹³, Ernest Hamel ², Patrizia Lavia ⁵, Romano Silvestri ¹

Affiliations

1 †Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
2 ‡Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
3 §Dipartimento di Farmacia, Università di Napoli Federico II, Via Domenico Montesano 49, I-80131 Napoli, Italy.
4 ∥Laboratorio di Ricerca Pre-Clinica e Traslazionale, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Centro di Riferimento Oncologico della Basilicata, Via Padre Pio 1, I-85028 Rionero in Vulture, Italy.
5 ⊥Institute of Molecular Biology and Pathology, Sapienza Università di Roma, Consiglio Nazionale delle Ricerche (CNR), Via degli Apuli 4, I-00185 Roma, Italy.
6 #Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma, Viale Regina Elena 291, I-00161 Roma, Italy.
7 ∇Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, I-00161 Roma, Italy.
8 ○Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Via S.M. Costantinopoli 16, I-80138 Naples, Italy.
9 ◆Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, I-56126 Pisa, Italy.
10 ¶Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom.
11 △European Institute of Oncology, Via Adamello 16, I-20139 Milano, Italy.
12 ☆DAC SRL, Genextra Group, Via Adamello 16, I-20139 Milano, Italy.
13 ▲APHAD Srl, Via della Resistanza 65, I-20090 Buccinasco, Italy.

PMID: 26132075 DOI: 10.1021/acs.jmedchem.5b00310

Abstract

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.

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