Structure-activity relationships of indole compounds derived from combretastatin A4: synthesis and biological screening of 5-phenylpyrrolo[3,4-a]carbazole-1,3-diones as potential antivascular agents.
A series of 5-(3',4',5'-trimethoxyphenyl)pyrrolo[3,4-a]carbazole-1,3(2H,10H)-diones was designed as cis-restricted analogues of 3-aroylindoles, arylthioindoles and 3-benzylidoneindolin-2-ones derived from combretastatin A4 (CA-4). Starting from various indoles, compounds were synthesized by means of a convenient two-step procedure involving a one-pot multicomponent reaction as key step. Intermediate tetrahydro[3,4-a]carbazoles and their corresponding carbazoles were submitted to biological screening tests involved in antivascular action, including the cytotoxicity against murine B16 melanoma cells, the rounding up of endothelial cells (EA.hy 926) and the inhibition of tubulin polymerization. Of the 31 compounds screened, those bearing a methoxy group at the 8-position endowed significant biological activities. A carbazole compound 30 was identified as a promising candidate for further development of novel vascular targeting agents.
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Nancy
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Laboratoire de Pharmacognosie, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, UMR 8638 CNRS, 4 avenue de l'Observatoire, 75006 Paris, France.
Dupeyre
Grégory
G
Chabot
Guy G
GG
Seguin
Johanne
J
Quentin
Lionel
L
Chiaroni
Angèle
A
Tillequin
François
F
Scherman
Daniel
D
Michel
Sylvie
S
Cachet
Xavier
X
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001808:Blood Vessels / Q000187:drug effects*; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D013267:Stilbenes / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D002227:Carbazoles; D013267:Stilbenes; D014404:Tubulin; C041514:carbazole; C058728:fosbretabulin