Design, synthesis and structure-activity relationship of 2-(3',4',5'-trimethoxybenzoyl)-benzo[b]furan derivatives as a novel class of inhibitors of tubulin polymerization.
The biological importance of microtubules in mitosis and cell division makes them an interesting target for the development of anticancer agents. Small molecules such as benzo[b]furans are attractive as inhibitors of tubulin polymerization. Thus, a new class of inhibitors of tubulin polymerization based on the 2-(3',4',5'-trimethoxybenzoyl)-benzo[b]furan molecular skeleton, with electron-donating (Me, OMe or OH) or electron-withdrawing (F, Cl and Br) substituents on the benzene ring, was synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization and cell cycle effects. Adding a methyl group at the C-3 position resulted in increased activity. The most promising compound in this series was 2-(3',4',5'-trimethoxybenzoyl)-3-methyl-6-ethoxy-benzo[b]furan, which inhibits cancer cell growth at nanomolar concentrations and interacts strongly with tubulin by binding to the colchicine site.
Romagnoli
Romeo
R
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy. rmr@unife.it
Baraldi
Pier Giovanni
PG
Carrion
Maria Dora
MD
Cara
Carlota Lopez
CL
Cruz-Lopez
Olga
O
Tolomeo
Manlio
M
Grimaudo
Stefania
S
Di Cristina
Antonietta
A
Pipitone
Maria Rosaria
MR
Balzarini
Jan
J
Zonta
Nicola
N
Brancale
Andrea
A
Hamel
Ernest
E
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D055503:Protein Multimerization; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000494:pharmacology
D000970:Antineoplastic Agents; D001572:Benzofurans; D050257:Tubulin Modulators; D003078:Colchicine