Acetyl analogs of combretastatin A-4: Synthesis and biological studies

Moses Lee; Balaji Babu; Megan Lee; Lauren Lee; Raymond Strobel; Olivia Brockway; Alexis Nickols; Robert Sjoholm; Samuel Tzou; Sameer Chavda; Dereje Desta; Gregory Fraley; Adam Siegfried; William Pennington; Rachel M. Hartley; Cara Westbrook; Susan L. Mooberry; Konstantinos Kiakos; John A. Hartley

doi:10.1016/j.bmc.2011.02.018

Acetyl analogs of combretastatin A-4: Synthesis and biological studies

Moses Lee, Balaji Babu, Megan Lee, Lauren Lee, Raymond Strobel, Olivia Brockway, Alexis Nickols, Robert Sjoholm, Samuel Tzou, Sameer Chavda, Dereje Desta, Gregory Fraley, Adam Siegfried, William Pennington, Rachel M. Hartley, Cara Westbrook, Susan L. Mooberry, Konstantinos Kiakos, John A. Hartley

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

The combretastatins have received significant attention because of their simple chemical structures, excellent antitumor efficacy and novel antivascular mechanisms of action. Herein, we report the synthesis of 20 novel acetyl analogs of CA-4 (1), synthesized from 3,4,5-trimethoxyphenylacetone that comprises the A ring of CA-4 with different aromatic aldehydes as the B ring. Molecular modeling studies indicate that these new compounds possess a 'twisted' conformation similar to CA-4. The new analogs effectively inhibit the growth of human and murine cancer cells. The most potent compounds 6k, 6s and 6t, have IC₅₀ values in the sub-μM range. Analog 6t has an IC₅₀ of 182 nM in MDA-MB-435 cells and has advantages over earlier analogs due to its enhanced water solubility (456 μM). This compound initiates microtubule depolymerization with an EC₅₀ value of 1.8 μM in A-10 cells. In a murine L1210 syngeneic tumor model 6t had antitumor activity and no apparent toxicity.

Original language	English (US)
Pages (from-to)	2359-2367
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry
Volume	19
Issue number	7
DOIs	https://doi.org/10.1016/j.bmc.2011.02.018
State	Published - Apr 1 2011
Externally published	Yes

Keywords

Cancer
Combretastatin A-4
Cytotoxicity
Microtubule
Trimethoxyphenylacetone
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.bmc.2011.02.018

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Lee, M., Babu, B., Lee, M., Lee, L., Strobel, R., Brockway, O., Nickols, A., Sjoholm, R., Tzou, S., Chavda, S., Desta, D., Fraley, G., Siegfried, A., Pennington, W., Hartley, R. M., Westbrook, C., Mooberry, S. L., Kiakos, K., & Hartley, J. A. (2011). Acetyl analogs of combretastatin A-4: Synthesis and biological studies. Bioorganic and Medicinal Chemistry, 19(7), 2359-2367. https://doi.org/10.1016/j.bmc.2011.02.018

Lee, M, Babu, B, Lee, M, Lee, L, Strobel, R, Brockway, O, Nickols, A, Sjoholm, R, Tzou, S, Chavda, S, Desta, D, Fraley, G, Siegfried, A, Pennington, W, Hartley, RM, Westbrook, C, Mooberry, SL, Kiakos, K & Hartley, JA 2011, 'Acetyl analogs of combretastatin A-4: Synthesis and biological studies', Bioorganic and Medicinal Chemistry, vol. 19, no. 7, pp. 2359-2367. https://doi.org/10.1016/j.bmc.2011.02.018

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abstract = "The combretastatins have received significant attention because of their simple chemical structures, excellent antitumor efficacy and novel antivascular mechanisms of action. Herein, we report the synthesis of 20 novel acetyl analogs of CA-4 (1), synthesized from 3,4,5-trimethoxyphenylacetone that comprises the A ring of CA-4 with different aromatic aldehydes as the B ring. Molecular modeling studies indicate that these new compounds possess a 'twisted' conformation similar to CA-4. The new analogs effectively inhibit the growth of human and murine cancer cells. The most potent compounds 6k, 6s and 6t, have IC50 values in the sub-μM range. Analog 6t has an IC50 of 182 nM in MDA-MB-435 cells and has advantages over earlier analogs due to its enhanced water solubility (456 μM). This compound initiates microtubule depolymerization with an EC50 value of 1.8 μM in A-10 cells. In a murine L1210 syngeneic tumor model 6t had antitumor activity and no apparent toxicity.",

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AU - Nickols, Alexis

AU - Sjoholm, Robert

AU - Tzou, Samuel

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AU - Desta, Dereje

AU - Fraley, Gregory

AU - Siegfried, Adam

AU - Pennington, William

AU - Hartley, Rachel M.

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AU - Kiakos, Konstantinos

AU - Hartley, John A.

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Acetyl analogs of combretastatin A-4: Synthesis and biological studies

Abstract

Keywords

ASJC Scopus subject areas

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