title: Arylthioindole inhibitors of tubulin polymerization. 3. Biological evaluation, structure-activity relationships and molecular modeling studies.
abstract: 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 beta-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.
authors.affiliation: Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: La Regina
authors.forename: Michael C
authors.initials: MC
authors.lastname: Edler
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Sahar
authors.initials: S
authors.lastname: Kandil
authors.forename: Antonio
authors.initials: A
authors.lastname: Coluccia
authors.forename: Francesco
authors.initials: F
authors.lastname: Piscitelli
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Gabriella
authors.initials: G
authors.lastname: De Martino
authors.forename: Ruth
authors.initials: R
authors.lastname: Matesanz
authors.forename: José Fernando
authors.initials: JF
authors.lastname: Díaz
authors.forename: Anna Ivana
authors.initials: AI
authors.lastname: Scovassi
authors.forename: Ennio
authors.initials: E
authors.lastname: Prosperi
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Marino
authors.initials: M
authors.lastname: Artico
authors.forename: Romano
authors.initials: R
authors.lastname: Silvestri
mesh_terms: D017209:Apoptosis; D001704:Biopolymers / Q000737:chemistry; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001704:Biopolymers; D007211:Indoles; D014404:Tubulin; D050257:Tubulin Modulators