A novel class of trans-methylpyrazoline analogs of combretastatins: Synthesis and in-vitro biological testing

Megan Lee, Olivia Brockway, Armaan Dandavati, Samuel Tzou, Robert Sjoholm, Vijay Satam, Cara Westbrook, Susan L Mooberry, Matthias Zeller, Balaji Babu, Moses Lee

Research output: Contribution to journalArticle

35 Citations (Scopus)

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 IC50 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 IC50 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.

Original languageEnglish (US)
Pages (from-to)3099-3104
Number of pages6
JournalEuropean Journal of Medicinal Chemistry
Volume46
Issue number7
DOIs
StatePublished - Jul 2011

Fingerprint

Inhibitory Concentration 50
Experimental Melanomas
Depolymerization
Molecular modeling
Colchicine
Testing
Tubulin
Cytotoxicity
Growth
Discrete Fourier transforms
Microtubules
X-Ray Diffraction
Solubility
Conformations
Assays
Lymphoma
Cell Culture Techniques
Cells
Single crystals
Derivatives

Keywords

  • Combretastatins
  • Cytotoxicity
  • Lymphoma
  • Melanoma
  • Microtubules
  • Pyrazolines
  • Tubulins

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

A novel class of trans-methylpyrazoline analogs of combretastatins : Synthesis and in-vitro biological testing. / Lee, Megan; Brockway, Olivia; Dandavati, Armaan; Tzou, Samuel; Sjoholm, Robert; Satam, Vijay; Westbrook, Cara; Mooberry, Susan L; Zeller, Matthias; Babu, Balaji; Lee, Moses.

In: European Journal of Medicinal Chemistry, Vol. 46, No. 7, 07.2011, p. 3099-3104.

Research output: Contribution to journalArticle

Lee, M, Brockway, O, Dandavati, A, Tzou, S, Sjoholm, R, Satam, V, Westbrook, C, Mooberry, SL, Zeller, M, Babu, B & Lee, M 2011, 'A novel class of trans-methylpyrazoline analogs of combretastatins: Synthesis and in-vitro biological testing', European Journal of Medicinal Chemistry, vol. 46, no. 7, pp. 3099-3104. https://doi.org/10.1016/j.ejmech.2011.03.064
Lee, Megan ; Brockway, Olivia ; Dandavati, Armaan ; Tzou, Samuel ; Sjoholm, Robert ; Satam, Vijay ; Westbrook, Cara ; Mooberry, Susan L ; Zeller, Matthias ; Babu, Balaji ; Lee, Moses. / A novel class of trans-methylpyrazoline analogs of combretastatins : Synthesis and in-vitro biological testing. In: European Journal of Medicinal Chemistry. 2011 ; Vol. 46, No. 7. pp. 3099-3104.
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