Design, synthesis, and evaluation of novel thienopyrrolizinones as antitubulin agents.
Herein, we describe the structure-activity relationship study of a new 3-aryl-8H-thieno[2,3-b]pyrrolizin-8-one series of antitubulin agents. The pharmacological results from the National Cancer Institute in vitro human disease oriented tumor cell line screening allowed us to identify compound 1d (NSC 676693) as a very efficient antitumoral drug in all cancer cell lines tested. This prompted us to define the structural requirements essential for this antiproliferative activity. Among all analogues synthesized in this study, compound 1o was the most promising, being 10-fold more potent than compound 1d. Its activity over a panel of nine tumoral cell lines was in the nanomolar range for all of the histological types tested, and surprisingly, the resistant KB-A1 cell line was also sensitive to this compound. Moreover, a flow cytometric study showed that L1210 cells treated by the most potent compounds were arrested in the G(2)/M phases of the cell cycle with a significant percentage of cells having reinitiated a cycle of DNA synthesis without cell division. This interesting pharmacological profile, resulting from inhibition of tubulin polymerization, encouraged us to perform preliminary in vivo studies that led to a new prodrug chemical approach.
Centre d'Etudes et de Recherche sur le Médicament de Normandie, UFR des Sciences Pharmaceutiques, Université de Caen, 1 Rue Vaubénard, 14032 Caen Cedex, France.
Vincent
V
Lisowski
Stéphane
S
Léonce
Laurence
L
Kraus-Berthier
Jana
J
Sopková-de Oliveira Santos
Alain
A
Pierré
Ghanem
G
Atassi
Daniel-Henri
DH
Caignard
Pierre
P
Renard
Sylvain
S
Rault
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011763:Pyrrolizidine Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D050257:Tubulin Modulators
C483894:3-(3,4-dihydroxyphenyl)-8H-thieno(2,3-b)pyrrolizin-8-one; C483893:3-(3-hydroxy-4-methoxyphenyl)-8H-thieno(2,3-b)pyrrolizin-8-one; D000970:Antineoplastic Agents; D011758:Pyrroles; D011763:Pyrrolizidine Alkaloids; D050257:Tubulin Modulators