Synthesis and biological evaluation of 2-amino-3-(3',4',5'-trimethoxybenzoyl)-6-substituted-4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivatives as antimitotic agents and inhibitors of tubulin polymerization.
Microtubules are among the most successful targets of compounds potentially useful for cancer therapy. A new series of inhibitors of tubulin polymerization based on the 2-amino-3-(3,4,5-trimethoxybenzoyl)-4,5,6,7-tetrahydrothieno[b]pyridine molecular skeleton was synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell cycle effects. The most promising compound in this series was 2-amino-3-(3,4,5-trimethoxybenzoyl)-6-methoxycarbonyl-4,5,6,7-tetrahydrothieno[b]pyridine, which inhibits cancer cell growth with IC(50)-values ranging from 25 to 90 nM against a panel of four cancer cell lines, and interacts strongly with tubulin by binding to the colchicine site. In this series of N(6)-carbamate derivatives, any further increase in the length and in the size of the alkyl chain resulted in reduced activity.
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
Cruz-Lopez
Olga
O
Cara
Carlota Lopez
CL
Tolomeo
Manlio
M
Grimaudo
Stefania
S
Di Cristina
Antonietta
A
Pipitone
Maria Rosa
MR
Balzarini
Jan
J
Kandil
Sahar
S
Brancale
Andrea
A
Sarkar
Taradas
T
Hamel
Ernest
E
D000818:Animals; D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism*
D050256:Antimitotic Agents; D011725:Pyridines; D014404:Tubulin