One-pot synthesis and biological evaluation of 2-pyrrolidinyl-4-amino-5-(3',4',5'-trimethoxybenzoyl)thiazole: a unique, highly active antimicrotubule agent.
A wide variety of small molecules with diverse molecular scaffolds inhibit microtubule formation. In this article we report a one-pot procedure for the preparation of a novel 2-(N-pyrrolidinyl)-4-amino-5-(3',4',5'-trimethoxybenzoyl)thiazole in which the size of the substituent at the C-2 position of the thiazole ring plays an essential role in compound activity. The most active agent (3f) inhibited at submicromolar concentrations the growth of tumor cell lines. It also inhibited tubulin polymerization with an activity quantitatively similar to that of CA-4, and treatment of HeLa cells resulted in their arrest at the G2-M phase of the cell cycle. Furthermore, 3f was effective against multidrug resistant cancer cells and inhibited the growth of the HT-29 xenograft in a nude mouse model. This indicated that 3f is a promising new antimitotic agent with encouraging preclinical potential.
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy. rmr@unife.it
Romeo
R
Romagnoli
Pier Giovanni
PG
Baraldi
Carlota
C
Lopez Cara
Maria
M
Kimatrai Salvador
Roberta
R
Bortolozzi
Giuseppe
G
Basso
Giampietro
G
Viola
Jan
J
Balzarini
Andrea
A
Brancale
Xian-Hua
XH
Fu
Jun
J
Li
Su-Zhan
SZ
Zhang
Ernest
E
Hamel
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D013844:Thiazoles; D014404:Tubulin; D050257:Tubulin Modulators; D053148:Caspase 3