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

• Published in: European journal of medicinal chemistry Vol. 45; no. 9; pp. 3726 - 3739
• Main Authors: Ty, Nancy, Dupeyre, Grégory, Chabot, Guy G., Seguin, Johanne, Quentin, Lionel, Chiaroni, Angèle, Tillequin, François, Scherman, Daniel, Michel, Sylvie, Cachet, Xavier
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 01.09.2010; Elsevier
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor agents; Biological and medical sciences; Blood Vessels - drug effects; Carbazoles - chemical synthesis; Carbazoles - chemistry; Carbazoles - pharmacology; Cell Line, Tumor; Chemical Sciences; Chemistry, Medicinal; Drug Evaluation, Preclinical; Endothelial cells; General aspects; Humans; Life Sciences & Biomedicine; Medical sciences; Mice; Multicomponent reactions; Organic chemistry; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Multimerization - drug effects; Protein Structure, Quaternary; Science & Technology; Stilbenes - chemistry; Structure-Activity Relationship; Tubulin; Tubulin - chemistry; Tubulin - metabolism; Vascular-disrupting agents; Antitumor agents; Multicomponent reactions; Tubulin; Vascular-disrupting agents; Endothelial cells; VASCULAR DISRUPTING AGENTS; A-4 ANALOGS; TUBULIN POLYMERIZATION; ANTINEOPLASTIC AGENTS; CELL-GROWTH; SU5416; THERAPY; 3-AROYLINDOLES; CONFORMATIONALLY RESTRICTED ANALOGS; INHIBITORS; Antineoplastic agent; Endothelial cell; Spontaneous; Cytotoxicity; Antivascular agent; Vascularization; Structure activity relation; B16-Melanoma; Chemical synthesis; Antimitotic; Tumor cell; Multicomponent reaction; Rodentia; Antitubulin; Malignant tumor; In vitro; Stilbene derivatives; Screening; Vertebrata; Mammalia; Mouse; Animal; Cancer
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2010.05.022

A series of 5-(3′,4′,5′-trimethoxyphenyl)pyrrolo[3,4- a]carbazole-1,3(2 H,10 H)-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. [Display omitted]