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

被引：11

作者：

Lee, Megan ^{[1
]}

Brockway, Olivia ^{[1
]}

Dandavati, Armaan ^{[1
]}

Tzou, Samuel ^{[1
]}

Sjoholm, Robert ^{[1
]}

Nickols, Alexis ^{[2
]}

Babu, Balaji ^{[1
]}

Chavda, Sameer ^{[1
]}

Satam, Vijay ^{[1
]}

Hartley, Rachel M. ^{[3
]}

Westbrook, Cara ^{[3
]}

Mooberry, Susan L. ^{[3
,4
]}

Fraley, Gregory ^{[2
]}

Lee, Moses ^{[1
]}

机构：

[1] Hope Coll, Div Nat & Appl Sci, Dept Chem, Holland, MI 49422 USA

[2] Hope Coll, Div Nat & Appl Sci, Dept Biol, Holland, MI 49422 USA

[3] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA

[4] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 07期

关键词：

Combretastatins; Cytotoxicity; Lymphoma; Melanoma; Solubility; Tubulin; Microtubules; SPINDLE PROTEIN KSP; ANTINEOPLASTIC AGENTS; CELL-GROWTH; INHIBITORS; POTENT; TUBULIN; CYTOTOXICITY; DUOCARMYCINS; DERIVATIVES; PHOSPHATE;

D O I：

10.1016/j.bmcl.2011.01.136

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Thirteen hydroxyethyl-analogs of combretastatin A-4 (CA-4) that contain the 1-(10-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 mu M 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 EC50 of 21.2 mu M. Analog 3j, which has excellent water solubility of 479 mu M, had antitumor activity in a syngeneic L1210 murine model. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：2087 / 2091

页数：5

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