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

doi:10.1016/j.bmcl.2011.01.136

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 journal › Article › peer-review

13 Scopus citations

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 language	English (US)
Pages (from-to)	2087-2091
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	7
DOIs	https://doi.org/10.1016/j.bmcl.2011.01.136
State	Published - Apr 1 2011
Externally published	Yes

Keywords

Combretastatins
Cytotoxicity
Lymphoma
Melanoma
Microtubules
Solubility
Tubulin

ASJC Scopus subject areas

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

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10.1016/j.bmcl.2011.01.136

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Lee, M., Brockway, O., Dandavati, A., Tzou, S., Sjoholm, R., Nickols, A., Babu, B., Chavda, S., Satam, V., Hartley, R. M., Westbrook, C., Mooberry, S. L., Fraley, G., & Lee, M. (2011). Design and synthesis of novel enhanced water soluble hydroxyethyl analogs of combretastatin A-4. Bioorganic and Medicinal Chemistry Letters, 21(7), 2087-2091. https://doi.org/10.1016/j.bmcl.2011.01.136

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

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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.",

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AU - Brockway, Olivia

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AU - Sjoholm, Robert

AU - Nickols, Alexis

AU - Babu, Balaji

AU - Chavda, Sameer

AU - Satam, Vijay

AU - Hartley, Rachel M.

AU - Westbrook, Cara

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AU - Fraley, Gregory

AU - Lee, Moses

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AB - 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.

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KW - Cytotoxicity

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KW - Solubility

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

Abstract

Keywords

ASJC Scopus subject areas

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