Garnier-Amblard Ethel C, Mays Suzanne G, Arrendale Richard F, Baillie Mark T, Bushnev Anatoliy S, Culver Deborah G, Evers Taylor J, Holt Jason J, Howard Randy B, Liebeskind Lanny S, Menaldino David S, Natchus Michael G, Petros John A, Ramaraju Harsha, Reddy G Prabhakar, Liotta Dennis C
Department of Chemistry, Emory University , 1521 Dickey Drive, Atlanta, Georgia 30322, United States.
School of Medicine, Department of Urology, Emory University , 1365 Clifton Road, NE, Atlanta, Georgia 30322, United States.
ACS Med Chem Lett. 2011 Mar 25;2(6):438-43. doi: 10.1021/ml2000164. eCollection 2011 Jun 9.
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.
Enigmol是一种合成的、口服活性的1-脱氧鞘氨醇碱基类似物，已显示出对前列腺癌有良好的活性。在这些研究中，研究了Enigmol结构中立体化学和N-甲基化的药理作用。报道了一种从L-丙氨酸出发对Enigmol（2-氨基十八烷-3,5-二醇）的所有四种可能的2S-非对映异构体进行的新型对映选择性合成方法，其关键步骤是L-丙氨酸硫醇酯与（E）-十五碳-1-烯基硼酸之间的Liebeskind-Srogl交叉偶联反应。对四种Enigmol非对映异构体和2S,3S,5S-N-甲基Enigmol针对两种前列腺癌细胞系（PC-3和LNCaP）的体外生物学评估表明，除一种非对映异构体外，其他所有异构体均显示出强大的溶瘤活性。在人前列腺癌的裸鼠异种移植模型中，Enigmol与标准前列腺癌疗法（雄激素剥夺或多西他赛）同样有效，并且Enigmol的两种非对映异构体，2S,3S,5R-Enigmol和2S,3R,5S-Enigmol，也对肿瘤生长产生了统计学上显著的抑制作用。还给出了Enigmol和N-甲基Enigmol的药代动力学概况。
