Enantioselective Synthesis of Protease Inhibitors and AntiHIV Agents

Part 1: A highly enantio-and diastereoselective Ireland-Claisen rearrangement of chiral C3(acyloxy)-vinyl silanes for the synthesis of anti-disubstituted succinic acid, an important intermediate for matrix metalloprotease inhibitors, has been developed (enantio-and anti/syn selectivities up to 95% and 38/1). The diastereoselectivity of this reaction was found to be sensitive to remote hydroxyl protecting groups, for example, with-OMOM group, the anti/syn ratio was 19/1, while with-OTBDMS, the ratio was 38/1. The resultant Ireland-Claisen rearrangement product was applied to the synthesis of macrocyclic MMP inhibitors, such as SL 422.     

Synthesis of C 2 Symmetric Potential Inhibitors of HIV-1 Protease From D-Mannitol

ABSTRACT

D-Mannitol was used as precursor for the synthesis of acyclic C ₂ symmetric potential HIV-1 protease inhibitors. The 1- and 6-hydroxy groups of D-mannitol were substituted by -NHBoc, -NHValZ, -SAr, -SOAr and -SO₂Ar and the 2-and 5-hydroxy groups were benzylated. In some products one of the central hydroxyl groups was either inverted or deoxygenated. Despite a close structural similarity to previously published inhibitors none of the products showed significant inhibitory activity against HIV-1 protease.

     

基于支持向量学习机的HIV-1蛋白酶抑制剂的活性预测

为了预测人体免疫缺陷蛋白酶抑制剂的活性, 计算了表征分子的组成和拓扑特征的462个分子描述符, 用Kennard-Stone方法和随机方法进行了训练集和测试集设计, 用Monte Carlo 模拟退火方法进行变量筛选, 并分别用神经网络, 逻辑回归, k-近邻和支持向量学习机方法建立了HIV-1蛋白酶的抑制剂模型. 结果表明支持向量学习机优于其余机器学习方法, 用SVM方法所建立的最优模型的最后预测正确率达到98.24%.     

新型蛋白酶抑制剂的合成

以(2S,3S)-1,2-环氧基-3-叔丁氧酰胺基-4-苯丁烷为原料,经N-烷基化、对硝基苯磺酰化、脱去氨基保护基,再与3-叠氮基-3-脱氧胸(腺嘧啶核)苷5-单琥珀酸缩合,合成了新型具有芳香磺酰胺基氨基醇骨架的HIV-1蛋白酶抑制剂--N-{3-[3-叠氮基-3-脱氧胸(腺嘧啶核)苷5-单琥珀酰胺基]-2-羟基-4-苯基丁基}-N-异丁基-4-硝基苯磺酰胺,总收率55.2%,其结构经1H NMR和MS确证.     

Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance

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基于“底物包膜”假说筛选新型HIV-1蛋白酶抑制剂

基于“底物包膜”假说, 以现有HIV-1蛋白酶抑制剂Darunavir为模板构建药效团模型并对中药化学数据库进行搜索; 采用分子对接方法进一步考察化合物与HIV-1蛋白酶结合情况及其与“底物包膜”符合程度, 优先选出两个化合物Annomonicin和去乙酰蟾蜍它灵; 应用分子动力学方法对这两个化合物进行动力学模拟, 观察它们与蛋白酶结合的复合物在动力学过程中的稳定性并计算其结合自由能, 综合评价筛选结果, 最终确定化合物Annomonicin具有更潜在的深入研究价值.     

Indolizine Studies,Part 5: Indolizine-2-carboxamides as Potential HIV-1 Protease Inhibitors[ 1 ]

1,1-Carbonyldiimidazole-promoted coupling of Baylis–Hillman-derived indolizine-2-carboxylic acids with a range of amine and amino acid derivatives has provided access to the corresponding carboxamides in moderate to excellent yield.     

HIV-1蛋白酶与抑制剂作用的结合自由能计算

HIV-1蛋白酶是治疗艾滋病的重要靶标酶之一. 采用分子动力学模拟, 运用MM-PBSA方法计算了HIV-1蛋白酶与三个抑制剂BE4, BE5和BE6的结合自由能, 结果表明抑制剂P₁/ 位置的苄基上双氟原子的不同位置对结合自由能产生不同的影响. 通过能量分解的方法考察了HIV-1蛋白酶的主要残基与三个抑制剂间的相互作用与识别, 结果表明三个抑制剂以相同的作用模式与HIV-1蛋白酶结合, 计算结果与实验结果基本吻合.     

Ligand-Free Suzuki Coupling of Arylboronic Acids with Methyl (E)-4-Bromobut-2-enoate: Synthesis of Unconventional Cores of HIV-1 Protease Inhibitors

An effective ligand-free Suzuki coupling protocol to unite methyl (E)-4-bromobut-2-enoate with several arylboronic acids has been accomplished. Thus, a number of variously functionalized methyl 4-arylcrotonates have been achieved in high to excellent yields under mild conditions. This method enables the preparation of diverse aryl-substituted cores of HIV-1 protease inhibitors.     

Stereoselective Synthesis of HIV-1 Protease Inhibitor, DMP 323

DMP 323, a potent HIV-1 protease inhibitor, has been synthesized by an efficient stereoselective process, amenable to large scale preparations. The core C(2) symmetric diol was synthesized by a stereoselective pinacol coupling of CBZ protected D-phenylalanine. Judicious selection of protecting groups allowed cyclic urea formation under mild conditions, enhanced the ease of bis-alkylation, and led to intermediates which were easily purified without chromatography. Additionally, a one-pot, high yield process was developed to prepare the alkylating agent, 4-[(triphenylmethoxy)methyl]benzyl chloride from 1,4-benzenedimethanol.     

Synthetic Studies of an Analogue of HIV-1 Protease Inhibitors of Didemnaketals:Construction of the C1-C8 Intermediate

ThedidenlnaketalsAandBhaveprovedtobesignificantinhibitorstoHIV-Iprotease'.UPtotilepresent.however,nosuccessfulsynthesishasbeenreported.Inconnectiollx'l,lthOLlrs}'ntheticstudiesoftheiranalogLles,wehavereportedasuccesslillsynthesisofthesimilarilltermediateof32.Hereinwewouldpresentanefficientprocedureforthediastereoselectivesynthesisofanotherintermediate4.Basedoiltileretrosyntheticanalysis,theintermediate4couldbesynthesizedfromllaturalI.-(-)-nlelltllollebecauseofthevaltlablechiralCSmethyl.…     

Design and Enantioselective Synthesis of Phosphonates as Enzyme Inhibitors

Abstract

The serine proteases [1] form an important group of hydrolytic enzymes essential to a variety of biological activities ranging from food digestion to blood clotting. However their uncontrolled activity is also known to be implicated in a number of pathological conditions including emphysema, cystic fibrosis, cancer and myocardial infarction. Their selective control is therefore an important goal and could offer a basis for the rational design of therapeutic agents.     

q~2引导构象选择CoMFA方法研究HIV－1RT抑制剂

对未知受体结构的药物设计其主导方法CoMFA来说，柔性目标分子的多种构象 造成了问题的复杂性。本文介绍交叉验证参数R~2(q~2)引导的构象选择CoMFA方法 ，选择化合物的最佳构象。将一组47个HIV－1 RT抑制剂进行有、无构象选择的 CoMFA分析来作评价。根据化合物的活性、毒性、选择性指数（毒性／活性比）等 实验数据得到的模型，其交叉验证参数q~2为0.7以上，非交叉验证的相应参数为0. 94以上，最后，还经过试验集化合物验证该模型的预测能力，置信度（1－α）＞ 0.99。     

Enantioselective Synthesis of (1R,2S) and (1S,2S) Dehydrocoronamic Acids

Thanks to the successive use of two esterases with different regioselectivities and conventional organic chemistry we have synthesized (1R,2S) and (1S,2S) dehydrocoronamic acids.