Novel Synthesis and Biological Evaluation of Enigmols as Therapeutic Agents for Treating Prostate Cancer

被引：28

作者：

Garnier-Amblard, Ethel C. ^{[1
]}

Mays, Suzanne G. ^{[3
]}

Arrendale, Richard F. ^{[2
]}

Baillie, Mark T. ^{[1
]}

Bushnev, Anatoliy S. ^{[1
]}

Culver, Deborah G. ^{[2
]}

Evers, Taylor J. ^{[2
]}

Holt, Jason J. ^{[1
]}

Howard, Randy B. ^{[2
]}

Liebeskind, Lanny S. ^{[1
]}

Menaldino, David S. ^{[2
]}

Natchus, Michael G. ^{[2
]}

Petros, John A. ^{[3
,4
]}

Ramaraju, Harsha ^{[3
]}

Reddy, G. Prabhakar ^{[2
]}

Liotta, Dennis C. ^{[1
,2
]}

机构：

[1] Emory Univ, Dept Chem, Atlanta, GA 30322 USA

[2] EIDD, Atlanta, GA 30322 USA

[3] Emory Univ, Dept Urol, Sch Med, Atlanta, GA 30322 USA

[4] Atlanta Vet Affairs Med Ctr, Atlanta, GA 30033 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2011年 / 2卷 / 06期

关键词：

Enigmol; palladium cross-coupling; 1-deoxysphingoid bases; Liebeskind-Srogl reaction; prostate cancer therapy; PC-3; LNCaP; STEREOSELECTIVE SYNTHESES; SPHINGOSINE-1-PHOSPHATE; METABOLISM; CHEMISTRY; SURVIVAL; DISEASE;

D O I：

10.1021/ml2000164

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Enigmol is a synthetic, orally active 1-deoxysphingoid base analogue that has demonstrated promising activity against prostate cancer. In these studies, the pharmacologic roles of stereochemistry and N-methylation in the structure of enigmols were examined. A novel enantioselective synthesis of all four possible 2S-diastereoisomers of enigmol (2-aminooctadecane-3,5-diols) from L-alanine is reported, which features a Liebeskind-Srogl cross-coupling reaction between L-alanine thiol ester and (E)-pentadec-1-enylboronic acid as the key step. In vitro biological evaluation of the four enigmol diastereoisomers and 2S,3S,5S-N-methylenigmol against two prostate cancer cell lines (PC-3 and LNCaP) indicates that all but one diastereomer demonstrate potent oncolytic activity. In nude mouse xenograft models of human prostate cancer, enigmol was equally effective as standard prostate cancer therapies (androgen deprivation or docetaxel), and two of the enigmol diastereomers, 2S,3S,5R-enigmol and 2S,3R,5S-enigmol, also caused statistically significant inhibition of tumor growth. A pharmacokinetic profile of enigmol and N-methylenigmol is also presented.

引用

页码：438 / 443

页数：6

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