Arylthioindole Inhibitors of Tubulin Polymerization. 3. Biological Evaluation, Structure−Activity Relationships and Molecular Modeling Studies

• Published in: Journal of medicinal chemistry Vol. 50; no. 12; pp. 2865 - 2874
• Main Authors: La Regina, Giuseppe, Edler, Michael C, Brancale, Andrea, Kandil, Sahar, Coluccia, Antonio, Piscitelli, Francesco, Hamel, Ernest, De Martino, Gabriella, Matesanz, Ruth, Díaz, José Fernando, Scovassi, Anna Ivana, Prosperi, Ennio, Lavecchia, Antonio, Novellino, Ettore, Artico, Marino, Silvestri, Romano
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.06.2007; Amer Chemical Soc
• Subjects: Antineoplastic agents; Apoptosis; Biological and medical sciences; Biopolymers - chemistry; Cell Cycle - drug effects; Cell Line, Tumor; Chemistry, Medicinal; Drug Screening Assays, Antitumor; General aspects; Humans; Hydrogen Bonding; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Binding; Radioligand Assay; Science & Technology; Structure-Activity Relationship; Tubulin - chemistry; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; RING-C; SITE; STATES; COLCHICINE; ANALOGS; AGENTS; THIOPHENES; POTENT INHIBITORS; BINDING; DERIVATIVES; Antineoplastic agent; Nitrogen heterocycle; Contractile protein; Cytotoxicity; Uterine cervix; Modeling; Organic sulfide; Tubulin; Structure activity relation; Molecular model; Bicyclic compound; Binding mode; Aromatic compound; Mammary gland; Chemical synthesis; Antimitotic; Tumor cell; Human; Benzene derivatives; Antitubulin; Stability constant; In vitro; Hela cell line; Cell line; Indole derivatives
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061479u

The new arylthioindole (ATI) derivatives 10, 14−18, and 21−24, which bear a halogen atom or a small size ether group at position 5 of the indole moiety, were compared with the reference compounds colchicine and combretastatin A-4 for biological activity. Derivatives 10, 11, 16, and 21−24 inhibited MCF-7 cell growth with IC50 values <50 nM. A halogen atom (14−17) at position 5 caused a significant reduction in the free energy of binding of compound to tubulin, with a concomitant reduction in cytotoxicity. In contrast, methyl (21) and methoxy (22) substituents at position 5 caused an increase in cytotoxicity. Compound 16, the most potent antitubulin agent, led to a large increase (56%) in HeLa cells in the G2/M phase at 24 h, and at 48 h, 26% of the cells were hyperploid. Molecular modeling studies showed that, despite the absence of the ester moiety present in the previously examined analogues, most of the compounds bind in the colchicine site in the same orientation as the previously studied ATIs. Binding to β-tubulin involved formation of a hydrogen bond between the indole and Thr179 and positioning of the trimethoxy phenyl group in a hydrophobic pocket near Cys241.