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

Megan Lee, Olivia Brockway, Armaan Dandavati, Samuel Tzou, Robert Sjoholm, Alexis Nickols, Balaji Babu, Sameer Chavda, Vijay Satam, Rachel M. Hartley, Cara Westbrook, Susan L. Mooberry, Gregory Fraley, Moses Lee

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 IC50 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.

Original languageEnglish (US)
Pages (from-to)2087-2091
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number7
DOIs
StatePublished - Apr 1 2011
Externally publishedYes

Fingerprint

Water
Experimental Melanomas
Depolymerization
Molecular modeling
antineoplaston A10
Cytotoxicity
Discrete Fourier transforms
Microtubules
Solubility
Inhibitory Concentration 50
Conformations
Assays
Lymphoma
Cell Culture Techniques
Cells
Cell Line
Growth
fosbretabulin
ethylene

Keywords

  • Combretastatins
  • Cytotoxicity
  • Lymphoma
  • Melanoma
  • Microtubules
  • Solubility
  • Tubulin

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Design and synthesis of novel enhanced water soluble hydroxyethyl analogs of combretastatin A-4. / Lee, Megan; Brockway, Olivia; Dandavati, Armaan; Tzou, Samuel; Sjoholm, Robert; Nickols, Alexis; Babu, Balaji; Chavda, Sameer; Satam, Vijay; Hartley, Rachel M.; Westbrook, Cara; Mooberry, Susan L.; Fraley, Gregory; Lee, Moses.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 21, No. 7, 01.04.2011, p. 2087-2091.

Research output: Contribution to journalArticle

Lee, M, Brockway, O, Dandavati, A, Tzou, S, Sjoholm, R, Nickols, A, Babu, B, Chavda, S, Satam, V, Hartley, RM, Westbrook, C, Mooberry, SL, Fraley, G & Lee, M 2011, 'Design and synthesis of novel enhanced water soluble hydroxyethyl analogs of combretastatin A-4', Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 7, pp. 2087-2091. https://doi.org/10.1016/j.bmcl.2011.01.136
Lee, Megan ; Brockway, Olivia ; Dandavati, Armaan ; Tzou, Samuel ; Sjoholm, Robert ; Nickols, Alexis ; Babu, Balaji ; Chavda, Sameer ; Satam, Vijay ; Hartley, Rachel M. ; Westbrook, Cara ; Mooberry, Susan L. ; Fraley, Gregory ; Lee, Moses. / Design and synthesis of novel enhanced water soluble hydroxyethyl analogs of combretastatin A-4. In: Bioorganic and Medicinal Chemistry Letters. 2011 ; Vol. 21, No. 7. pp. 2087-2091.
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