Arylthioindole inhibitors of tubulin polymerization. 3. Biological evaluation, structure-activity relationships and molecular modeling studies.
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.
La Regina
Giuseppe
G
Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
Edler
Michael C
MC
Brancale
Andrea
A
Kandil
Sahar
S
Coluccia
Antonio
A
Piscitelli
Francesco
F
Hamel
Ernest
E
De Martino
Gabriella
G
Matesanz
Ruth
R
Díaz
José Fernando
JF
Scovassi
Anna Ivana
AI
Prosperi
Ennio
E
Lavecchia
Antonio
A
Novellino
Ettore
E
Artico
Marino
M
Silvestri
Romano
R
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
D001704:Biopolymers; D007211:Indoles; D014404:Tubulin; D050257:Tubulin Modulators