Synthesis and antitumor activity of benzils related to combretastatin A-4

• Published in: Bioorganic & medicinal chemistry letters Vol. 18; no. 11; pp. 3266 - 3271
• Main Authors: Mousset, Céline, Giraud, Anne, Provot, Olivier, Hamze, Abdallah, Bignon, Jérôme, Liu, Jian-Miao, Thoret, Sylviane, Dubois, Joëlle, Brion, Jean-Daniel, Alami, Mouâd
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.06.2008; Elsevier
• Subjects: Alkynes; Antiangiogenic; Antimitotic; Antineoplastic agents; Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Antiproliferative; Antitumor; Benzils; Biological and medical sciences; Catalysis; Cell Cycle; Cellular Biology; Chemical Sciences; Combinatorial Chemistry Techniques; Combretastatin; Drug Screening Assays, Antitumor; General aspects; Humans; Inhibition of tubulin assembly; Inhibitory Concentration 50; Life Sciences; Medical sciences; Medicinal Chemistry; Organic chemistry; Oxidation; Pharmacology. Drug treatments; Phenylglyoxal - analogs & derivatives; Phenylglyoxal - chemical synthesis; Phenylglyoxal - chemistry; Phenylglyoxal - pharmacology; Stilbenes - chemical synthesis; Stilbenes - chemistry; Stilbenes - pharmacology; Structure-Activity Relationship; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Antiproliferative; Antitumor; Combretastatin; Benzils; Oxidation; Inhibition of tubulin assembly; Antimitotic; Antiangiogenic; Alkynes; Antineoplastic agent; Flow cytometry; Solid tumor; Acetylenic compound; Leukemia; Lung; Colon; Mammary gland; Antiangiogenic agent; Chemical synthesis; Tumor cell; Human; Antitubulin; Diketone; In vitro; Biological activity; Stilbene derivatives; Cell line; Alkyne; Combretastatin derivative
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.04.053

Benzil derivatives related to combretastatin A-4 exhibit excellent antiproliferative and antimitotic activities by arresting the cell cycle in G2/M phase. A series of benzil derivatives related to combretastatin A-4 (CA-4) have been synthesized by oxidation of diarylalkynes promoted by PdI 2 in DMSO. Using this new protocol, 14 benzils were prepared in good to excellent yields and their biological activity has been delineated. Several benzils exhibited excellent antiproliferative activity: for example, 4j and 4k bearing the greatest resemblance to CA-4 and AVE-8062, respectively, were found to inhibit cell growth at the nanomolar level (20–50 nM) on four human tumor cell lines. Flow cytometric analysis indicates that these compounds act as antimitotics and arrest the cell cycle in G 2/M phase. A cell-based assay indicated that compounds 4j and 4k displayed a similar inhibition of tubulin assembly with an IC 50 value similar to CA-4. These results clearly demonstrated that the Z-double bond of CA-4 can be replaced by a 1,2-diketone unit without significant loss of cytotoxicity and inhibition of tubulin assembly potency.