Synthesis and cytotoxicity of epoxide and pyrazole analogs of the combretastatins

• Published in: Bioorganic & medicinal chemistry 2005-11, Vol.13 (21), p.6025-6034
• Main Authors: LeBlanc, Regan, Dickson, John, Brown, Toni, Stewart, Michelle, Pati, Hari N., VanDerveer, Don, Arman, Hadi, Harris, Jeff, Pennington, William, Holt, Herman L., Lee, Moses
• Format: Article
• Language: English
• Subjects: Animals; Anticancer; Antineoplastic agents; Bibenzyls - chemical synthesis; Bibenzyls - chemistry; Bibenzyls - toxicity; Biological and medical sciences; Cell Line; Chalcones; Combretastatins; Crystallography, X-Ray; Cytotoxicity; Epoxides; Epoxy Compounds - chemistry; General aspects; Medical sciences; Mice; Molecular Structure; Pharmacology. Drug treatments; Pyrazoles; Pyrazoles - chemistry; Stilbenes - chemical synthesis; Stilbenes - chemistry; Stilbenes - toxicity; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.06.028

Twenty-six epoxide and corresponding pyrazole derivatives, of the structurally related chalcones and combretastatin A-4 ( CA- 4), were synthesized and tested for in vitro cytotoxicity. These molecules were synthesized by epoxidation of the relevant chalcones, followed by reaction with hydrazine. The structures of epoxides 3 and 7, and pyrazole 17, were confirmed by X-ray diffraction studies. The relatively coplanar conformation of a 3′,3″,4′,4″,5′,5″-hexamethoxypyrazole 17 was in good agreement with the shape for 3′,3″,4′,4″,5′-pentamethoxypyrazole 16, which was determined from molecular mechanics optimization. In vitro cytotoxicity of each class of compounds was obtained using a 72 h continuous exposure MTT assay against two murine cancer cell lines; B16 melanoma and L1210 leukemia. The effect of substitution in the A-ring is addressed: three methoxy groups versus two, generally increased cytotoxicity across both cell lines. In the majority of cases, the pyrazoles are generally more active than the epoxides, with the most active, 5-(3″-amino-4″-methoxyphenyl)-3-(3′,4′,5′-trimethoxyphenyl)pyrazole 21, possessing an IC 50 value of 5 and 2.4 μM (B16 and L1210, respectively). Due to their planar conformations, the pyrazoles are typically less active than the corresponding chalcones, which adopt angular conformations similar to CA- 4. B-ring modifications confirmed that in general the amino compounds are more active than the corresponding nitro compounds. Varying the number and orientation of methoxy groups on the A-ring did not produce any significant differences in toxicity in the cell lines studied.