Design and synthesis of novel enhanced water soluble hydroxyethyl analogs of combretastatin A-4.
Bioorg Med Chem Lett
; 21(7): 2087-91, 2011 Apr 01.
Article
in En
| MEDLINE
| ID: mdl-21345671
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Stilbenes
Limits:
Animals
/
Humans
Language:
En
Journal:
Bioorg Med Chem Lett
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2011
Document type:
Article
Affiliation country:
United States