Design and synthesis of novel enhanced water soluble hydroxyethyl analogs of combretastatin A-4

Megan Lee, Hope College
Olivia Brockway, Hope College
Armaan Dandavati, Hope College
Samuel Tzou, Hope College
Robert Sjoholm, Hope College
Alexis Nickols, Hope College
Balaji Babu, Hope College
Sameer Chavda, Hope College
Vijay Satam, Hope College
Rachel Hartley, University of Texas Health Science - San Antonio
Cara Westbrook, University of Texas Health Science - San Antonio
Susan Mooberry, University of Texas Health Science - San Antonio
Gregory S. Fraley, Hope College
Moses Lee, Hope College


Thirteen hydroxyethyl-analogs of combretastatin A-4 (CA-4) that contain the 1-(10-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 IC50 values of 16.1 and 4.1 mu M 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 EC50 of 21.2 mu M. Analog 3j, which has excellent water solubility of 479 mu M, had antitumor activity in a syngeneic L1210 murine model.