title: A novel class of trans-methylpyrazoline analogs of combretastatins: synthesis and in-vitro biological testing.
abstract: Thirteen methylpyrazoline analogs (1a-m) of combretastatin A-4 (CA-4, 2) were synthesized. The trans-geometry of the two substituted phenyl moieties was ascertained by a single crystal X-ray diffraction study of compound 1d. The cytotoxicities of the analogs against the growth of murine B16 melanoma and L1210 lymphoma cells in culture were measured using the MTT assay. One of the derivatives, 1j, which has the same substituents as CA-4 was the most active in the series with IC(50) values of 3.3 μM and 6.8 μM against the growth of L1210 and B16 cells, respectively. The activity of this analog against human cancer cell lines was confirmed in the NCI 60 panel. The other active analogs against L1210 were 1b and 1f, which gave IC(50) values in the 6-8 μM range. Compound 1j caused microtubule depolymerization with an EC(50) value of 4.1 μM. This compound has good water solubility of 372 μM. Molecular modeling studies using DFT showed that compound 1j adopts a "twisted" conformation mimicking CA-4 that is optimal for binding to the colchicine site of tubulin.
authors.affiliation: Department of Chemistry, Division of Natural and Applied Sciences, Hope College, Holland, MI 49423, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Lee
authors.forename: Olivia
authors.initials: O
authors.lastname: Brockway
authors.forename: Armaan
authors.initials: A
authors.lastname: Dandavati
authors.forename: Samuel
authors.initials: S
authors.lastname: Tzou
authors.forename: Robert
authors.initials: R
authors.lastname: Sjoholm
authors.forename: Vijay
authors.initials: V
authors.lastname: Satam
authors.forename: Cara
authors.initials: C
authors.lastname: Westbrook
authors.forename: Susan L
authors.initials: SL
authors.lastname: Mooberry
authors.forename: Matthias
authors.initials: M
authors.lastname: Zeller
authors.forename: Balaji
authors.initials: B
authors.lastname: Babu
authors.forename: Moses
authors.initials: M
authors.lastname: Lee
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology; D001632:Bibenzyls / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008870:Microtubules / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D062105:Molecular Docking Simulation; D011720:Pyrazoles / Q000737:chemistry*; D013267:Stilbenes / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001632:Bibenzyls; D011720:Pyrazoles; D013267:Stilbenes; D050257:Tubulin Modulators; C040105:combretastatin; C058728:fosbretabulin