combretastatin-a-4-disodium-phosphate and Disease-Models--Animal

Here, we formulated and investigated the structure-activity relationships of novel N-substituted carbazole sulfonamide derivatives with improved physicochemical properties. Most of these new compounds displayed good aqueous solubility. Certain molecules presented strong in vitro antiproliferative and in vivo antitumor activity. Relative to the control, 50 mg/kg compound 3v substantially reduced human HepG2 xenograft mouse tumor growth by 54.5% and its efficacy was comparable to that of CA-4P. Compound 3h demonstrated anticancer efficacy in both subcutaneous and orthotopic HepG2 xenograft mouse models. We also developed a novel synthetic method for 7-hydroxy-substituted carbazole sulfonamides. Compared with the control, 25 mg/kg compound 4c inhibited human HepG2 xenograft mouse tumor growth by 71.7% and was more potent than 50 mg/kg CA-4P with only 50% tumor shrinkage efficacy. Among the three water-soluble carbazole sulfonamide derivatives formulated in the present study, compound 4c displayed the most effective tumor growth inhibition in vivo and merit further investigation as potential antitumor agents for cancer therapy.

Topics: Animals; Antineoplastic Agents; Carbazoles; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Neoplasms, Experimental; Rats; Solubility; Structure-Activity Relationship; Sulfonamides; Tumor Cells, Cultured; Water

Several stilbenoid compounds having structural similarity to the combretastatin group of natural products and characterized by the incorporation of two nitrogen-bearing groups (amine, nitro, serinamide) have been prepared by chemical synthesis and evaluated in terms of biochemical and biological activity. The 2',3'-diamino B-ring analogue 17 demonstrated remarkable cytotoxicity against selected human cancer cell lines in vitro (average GI 50 = 13.9 nM) and also showed good activity in regard to inhibition of tubulin assembly (IC 50 = 2.8 microM). In addition, a single dose (10 mg/kg) of compound 17 caused a 40% tumor-selective blood flow shutdown in tumor-bearing SCID mice at 24 h, thus suggesting the potential value of this compound and its corresponding salt formulations as new vascular-disrupting agents.

Topics: Animals; Antineoplastic Agents; Bibenzyls; Disease Models, Animal; Drug Design; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Leukemia P388; Mice; Molecular Structure; Neoplasms; Regional Blood Flow; Stilbenes; Tubulin