New arylthioindoles and related bioisosteres at the sulfur bridging group. 4. Synthesis, tubulin polymerization, cell growth inhibition, and molecular modeling studies.
New arylthioindoles along with the corresponding ketone and methylene compounds were potent tubulin assembly inhibitors. As growth inhibitors of MCF-7 cells, sulfur derivatives were superior or sometimes equivalent to the ketones, while methylene derivatives were substantially less effective. Esters 24, 27-29, 36, 39, and 41 showed approximately 50% of inhibition on human HeLa and HCT116/chr3 cells at 0.5 microM, and these compounds inhibited the growth of HEK, M14, and U937 cells with IC(50)'s in the 78-220 nM range. While murine macrophage J744.1 cell growth was significantly less affected (20% at higher concentrations), four other nontransformed cell lines remained sensitive to these esters. The effect of drug treatment on cell morphology was examined by time-lapse microscopy. In a protocol set up to evaluate toxicity on the Saccharomyces cerevisiae BY4741 wild type strain, compounds 24 and 54 strongly reduced cell growth, and 29, 36, and 39 also showed significant inhibition.
La Regina
Giuseppe
G
Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
Sarkar
Taradas
T
Bai
Ruoli
R
Edler
Michael C
MC
Saletti
Roberto
R
Coluccia
Antonio
A
Piscitelli
Francesco
F
Minelli
Lara
L
Gatti
Valerio
V
Mazzoccoli
Carmela
C
Palermo
Vanessa
V
Mazzoni
Cristina
C
Falcone
Claudio
C
Scovassi
Anna Ivana
AI
Giansanti
Vincenzo
V
Campiglia
Pietro
P
Porta
Amalia
A
Maresca
Bruno
B
Hamel
Ernest
E
Brancale
Andrea
A
Novellino
Ettore
E
Silvestri
Romano
R
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship; D013455:Sulfur / Q000737:chemistry*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*
D007211:Indoles; D014404:Tubulin; D013455:Sulfur; D003078:Colchicine