title: Design and synthesis of novel enhanced water soluble hydroxyethyl analogs of combretastatin A-4.
abstract: Thirteen hydroxyethyl- analogs of combretastatin A-4 (CA-4) that contain the 1-(1'-hydroxyethyl)-1-(3",4",5"-trimethoxyphenyl)-2-(substituted phenyl)ethene framework were synthesized. Molecular modeling studies at the DFT level showed that compound 3j adopts a 'twisted' conformation mimicking CA-4. The cytotoxicity of the novel compounds against the growth of murine B16 melanoma and L1210 lymphoma cells in culture was measured using an MTT assay. Three analogs 3f, 3h, and 3j were active. Of these, 3j, which has the same substituents as CA-4 and IC(50) values of 16.1 and 4.1 μM against B16 and L1210 cells, respectively, was selected for further biological evaluation. The activity of 3j was verified by the NCI 60 cell line screen. Compound 3j causes microtubule depolymerization in A-10 cells with an EC(50) of 21.2 μM. Analog 3j, which has excellent water solubility of 479 μM, had antitumor activity in a syngeneic L1210 murine model.
authors.affiliation: Department of Chemistry, Division of Natural and Applied Sciences, Hope College, Holland, MI 49422, 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: Alexis
authors.initials: A
authors.lastname: Nickols
authors.forename: Balaji
authors.initials: B
authors.lastname: Babu
authors.forename: Sameer
authors.initials: S
authors.lastname: Chavda
authors.forename: Vijay
authors.initials: V
authors.lastname: Satam
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Hartley
authors.forename: Cara
authors.initials: C
authors.lastname: Westbrook
authors.forename: Susan L
authors.initials: SL
authors.lastname: Mooberry
authors.forename: Gregory
authors.initials: G
authors.lastname: Fraley
authors.forename: Moses
authors.initials: M
authors.lastname: Lee
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D012995:Solubility; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D013267:Stilbenes; D014867:Water; C058728:fosbretabulin