催化不对称合成法在手性药物合成中的应用

结合实例就催化不对称合成的两种方法应用于手性药物合成作简要概述。外消旋体拆分、化学计量不对称合成和催化不对称合成是利用化学手段获得手性药物的 3种方法 ,其中催化不对称合成法是最经济有效地合成手性药物的方法 ,它又可分为化学催化不对称合成法和酶催化不对称法。     

手性双膦配合物用于均相催化不对称氢化

手性双膦配体２,２’－双（二苯基膦基）－１,１’联萘与钌、铑离子形成的配合物可作为高效均相催化剂,用于烯烃和羰基的高对映造反性氢化,或烯烃的对映造反性异构化。本文对此领域的研究状况进行简介。     

手性螺环膦配体催化的不对称氢化反应在天然产物及药物合成中的应用

手性螺环膦配体具有合成方便、结构多样等特点。这类配体与过渡金属形成的络合物能够催化多种不同底物的不对称氢化反应,表现了优异的对映选择性。同时,这些反应也被应用于天然产物和药物分子的合成中。     

手性二胺配体在不对称催化反应中的应用

手性二胺类配体因其良好催化活性和对映选择性得到了广泛研究。本文综述了近期手性二胺配体在不对称反应中的应用进展。     

不对称烷基化反应在药物及生物活性化合物 合成中的应用

该文从合成光学活性化合物的3种手性诱导方式——手性源诱导的不对称反应、手性助剂诱导的不对称反应及不对称催化反应来介绍近年来不对称烷基化反应在药物及生物活性化合物合成中的应用。     

手性拆分技术及其在手性药物合成中的应用新进展

手性拆分是获得手性药物的重要途径,该文对经典的结晶法拆分、动力学拆分和色谱分离法拆分等手性拆分方法的新进展进行综述,并介绍膜拆分法、萃取拆分法等新技术在手性药物合成中的应用。     

不对称全合成技术（一）——金属催化的不对称氢化

不对称合成(又称为手性合成)在制药工业中应用的重要性比其它化学合成领域都要大得多，因为目前在开发的新药当中有80％是带有手性碳的化合物分子。在众多手性分子的合成当中，其核心是过渡金属手性催化剂。常用的过渡金属是铑、钯、铟和钛，与金属配位的手性     

工业规模的过渡金属催化不对称氢化研究进展

过渡金属催化不饱和化合物的不对称氢化是获得手性化合物较经济、较有效的途径。经过数十年卓有成效的不对称催化基础研究,以过渡金属催化不对称氢化为核心技术,成功实现了许多手性化合物,如手性氨基酸、手性醇、手性胺、手性羧酸等的工业规模制备。该文主要概述近20年来工业规模的过渡金属催化不对称氢化含有碳-氧双键(C=O)、碳-碳双键(C=C)以及碳-氮双键(C=N)的不饱和化合物以构建相应的手性药物或活性关键中间体的方法。     

不对称aldol反应及其在天然产物全合成中的应用

不对称aldol反应是天然产物全合成领域中应用最为广泛的反应之一。本文重点介绍近5年来应用于天然产物全合成中的、由手性辅基及手性催化剂介导的不对称aldol反应。     

不对称合成技术（五）——生物催化的手性合成及拆分

自然界中大部分分子是手性纯的,其范围从简单的氨基酸和糖类一直延伸到由细菌、植物和其它有机体制造的美丽而又巨大的复杂分子。因此。你简直不敢想象自然界的手性合成技术会比人类高明如此之多。最近几年,越来越多化学家从大自然的“书”本中学到用细菌、细胞和分离酶催化来完成化学反应和分离单一对映体。他们也能用有效的合成转化来制造原先通过纯化学方法合成困难的（甚至是无法获得）手性化合物。     

手性叔丁基亚磺酰胺的制备方法及其在药物合成中的应用

手性叔丁基亚磺酰胺是近年来发展起来的一种新型医药中间体,也是合成手性胺类药物及其中间体的关键手性源,其相关研究受到研究人员的广泛关注。综述手性叔丁基亚磺酰胺的制备方法以及该化合物在药物合成领域中的应用情况。     

金纳米粒及其在药物传递系统中的应用研究进展

近年来,随着纳米材料科学的蓬勃发展,金纳米粒由于具有独特的光学和物理性质以及毒性小、比表面积大、表面可功能化修饰、易与药物分子结合等特点,其作为载体在药物传递系统中的应用已引起广泛关注。综述金纳米粒的特性、合成方法、体内分布与毒性以及在不同药物传递系统中的应用研究。     

Asymmetric Synthesis and Enantiospecificity of Binding of 2-(1,2,3,4-Tetrahydro-1-isoquinolyl)-ethanol Derivatives to μ and κ Receptors

A number of 2-(1,2,3,4-tetrahydro-1-isoquinolyl)-ethanol derivatives 7a—e have been synthesized in diastereomerically and enantiomerically pure form and have been evaluated for their binding affinity at μ and κ opioid receptors. The amido ketones 5a—c and ent- 5a—c , which were accessible by employing 3b and ent- 3b for Asymmetric Electrophilic Amidoalkylation reactions, served as starting compounds. Upon reduction of 5a—c and ent- 5a—c the amido alcohols l- 6a—c , u- 6a—c , ent-l- 6a—c and ent-u- 6a—c were obtained. Hydrolysis of these compounds yielded the secondary amino alcohols l- 7a—c , u- 7a—c , ent-l- 7a—c and ent-u- 7a—c and upon reductive methylation of l- 7b—c , u- 7b—c , ent-l- 7b—c and ent-u- 7b—c with CH₂O and NaCNBH₃ the tertiary amino alcohols l- 7d—e , u- 7d—e , ent-l- 7d—e and ent-u- 7d—e were obtained. The binding affinities of the final compounds l- 7a—e , u- 7a—e , ent-l- 7a—e and ent-u- 7a—e at both the μ and the κ receptor were strongly dependent on their stereochemistry. In each case isomers exhibited higher affinity at the μ than at the κ receptor. For the secondary amino alcohols 7a—c the affinity at the μ receptor followed the stereochemical order l- 7 > ent-l- 7 > ent-u- 7 > u- 7 whereas for the tertiary amino alcohols the order l- 7 > u- 7 > ent-l- 7 > ent-u- 7 was found. The stereoisomers l- 7d and l- 7e of the tertiary amino alcohols were found to be the most active compounds the latter exhibiting a K_i value of 7.17 which is close to that of Morphine (K_i = 1.64). In an in vivo model, the Writhing Test, both compounds l- 7d and l- 7e displayed high analgetic activity.     

The Enantiomers of the Valproic Acid Analogue 2-n-Propyl-4-pentynoic Acid (4-yn-VPA): Asymmetric Synthesis and Highly Stereoselective Teratogenicity in Mice

The teratogenic activities of R( +)- and S( – )-2-n-propyl-4-pentynoic acid (R and S-4-yn-VPA), the enantiomers of the highly teratogenic valproic acid (VPA) analogues (±)-4-yn-VPA, were investigated in mice. The enantiomers were prepared via asymmetric synthesis, each in three steps employing the chiral auxiliaries (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone and S-4-benzyl-2-oxazolidinone. The determination of the absolute configurations and the optical purities is described. R( + )-4-yn-VPA contained 7%, and S( – )-4-yn-VPA 8%, of the respective antipodes. The aqueous solutions of the sodium salts of R- and S-4-yn-VPA were administered as single i.p. injections during early organogenesis in the mouse (day 8 of gestation) using the induction of exencephaly as the teratological end point. Dose/exencephaly curves indicated that S-4-yn-VPA is 7.5 times more teratogenic than its antipode, 1.9 times more teratogenic than (±)-4-yn-VPA and 3.9 times more teratogenic than the parent drug VPA. In contrast, the neurotoxicity (maternal toxicity) of the 4-yn-VPA enantiomers was found to be independent of the stereo-chemical configuration and lower than achieved after VPA administration. Due to its low neurotoxicity and highly Stereoselective neural tube-inducing activity, S-4-yn-VPA should prove an important tool for the investigation of molecular mechanism of the teratogenic action in this class of compounds; R-4-yn-VPA could act as the negative control in these studies.     

CYP2C19基因多态性与沙利度胺抗肺癌疗效和不良反应的关系研究

目的探讨在肺癌治疗中CYP2C19基因多态性与沙利的疗效和不良反应的关系。方法通过检测患者的CYP2C19的基因型及沙利度胺稳态血药浓度,将患者分成EM组和PM组,比较2组疗效和不良反应的差异。结果 77例肺癌患者PM 13例(16.9%)。EM组和PM组的有效率分别为39.1%、30.8%,中位生存期分别为9.0月和8.0月,1年生存率分别为62.5%、46.2%,P<0.05。EM组恶心呕吐、腹泻、眩晕的发生率低于PM组,P<0.05。PM的平均血药浓度要高于EM组,P<0.05。结论 CYP2C19基因多态性对沙利度胺抗晚期肺癌生存期无明显影响,EM患者能够降低化疗后恶心呕吐反应发生率,提示PM患者宜从低剂量开始服用沙利度胺。     

Synthesis of 2-Fluoro N10-Substituted Acridones and Their Cytotoxicity Studies in Sensitive and Resistant Cancer Cell Lines and Their DNA Intercalation Studies

A series of 2-fluoro N¹⁰-substituted acridone derivatives with varying alkyl side chain length with propyl, butyl substitution, and a tertiary amine group at the terminal end of the alkyl side chain were synthesized and screened against cancer cell lines SW 1573, SW 1573 2R 160 (P-gp substrate) which are non-small lung cancer cell lines, MCF-7, MCF-7/MR (BCRP substrate) are breast cancer cell lines, 2008 WT, 2008MRP1, 2008MRP2, 2008MRP3 are ovarian cancer cell lines, and human embryo kidney cell lines like HEK293, HEK293 MRP4, and HEK293 MRP5i. The propyl-series compounds showed lipophilicity in the range of 1.93 to 4.40 and the butyl series in the range of 2.37 to 4.78. The compounds 4 , 7 , and 8 showed good cytotoxicity against the 60 human cancer cell line panel of the National Cancer Institute, USA. The compounds 14 and 15 showed a better cytotoxicity in most of the cancer cell lines compared to other compounds tested. The DNA-binding properties of the compounds were evaluated based on their affinity or intercalation with CT-DNA measured with absorption titration. The compound 11 bearing planar tricyclic ring linked with a butyl methylpiperazino side chain showed the highest binding affinity with a binding constant (K_i) of 10.38×10 M^–1. Evaluation of the compounds in cell lines with an overexpression of various multidrug resistance-related protein (MRP), P-glycoprotein (P-gp), or Breast Cancer Resistance Protein (BCRP) showed that all compounds are not substrates for any of these transporters.     

心房颤动患者CYP2C9、VKORC1基因多态性与华法林药物敏感度的关系

目的分析心房颤动(AF)患者CYP2C9、VKORC1基因多态性与华法林药物敏感度的关系。方法根据华法林给药累计剂量,将27例AF患者分为低起效剂量组和高起效剂量组;根据达标时间,分为短起效时间组和长起效时间组。比较高、低起效剂量组和长、短起效时间组CYP2C9、VKORC1不同基因型华法林的起效剂量和起效时间。结果高、低起效剂量组rs1057910(CYP2C9*3)及长、短起效时间组VKORC1 rs9923231基因构成差异有统计学意义(P<0.05)。与AA基因型比较,CYP2C9 rs1057910 AC基因型华法林起效剂量降低,VKORC1 rs9923231 GA基因型华法林起效时间缩短(P<0.05)。华法林药物敏感度可分为低度敏感、中度敏感和高度敏感3种。结论应结合临床实际对口服华法林行抗凝治疗的AF患者进行CYP2C9、VKORC1基因多态性检测,以便从基因类型角度合理分配华法林剂量。     

Synthesis of a delta opioid agonist in [2H6], [2H4], [11C], and [14C] labeled forms

In support of a program to develop a treatment for depression, four labeled forms of a delta opioid agonist were prepared. The [²H₄] labeled form was prepared using a relatively straightforward conversion of [²H₄]bromoethanol to [²H₄]N‐methyl‐2‐hydroxyethylamine. The key step in the synthesis of the [²H₆] labeled form involved the Pd‐catalyzed exchange in D₂O of 8‐quinolin‐8‐ol to give [²H₆] 8‐quinolin‐8‐ol. The C‐14 labeled form was synthesized in one step using [¹⁴C]carbonylation, and the C‐11 labeled form was prepared in two steps from ¹¹CH₃I. Copyright © 2011 John Wiley & Sons, Ltd.