1-[(乙氧基)甲基]-6-(1-萘甲基)胸腺嘧啶的合成

HEPT是抑制HIV-1逆转录酶的潜在活性化合物。1-[(乙氧基)甲基]-6-(1-萘甲基)胸腺嘧啶是HEPT的类似物,通过增加6位取代基的位阻可提高药效。文献设计并合成了该化合物,并对关键中间体(d)的合成及脱羟基反应作了初步讨论。     

基于分子对接的6-萘甲基取代HEPT类HIV-1逆转录酶抑制剂构效关系研究

采用分子对接方法得到了一系列6-萘甲基取代HEPT类逆转录酶抑制剂分子与HIV-1逆转录酶复合物模型,从中抽取出抑制剂分子的活性构象,进一步应用CoMFA和CoMSIA方法建立了具有较好预测能力的3D-QSAR模型,深入探讨了这些化合物的定量构效关系,为进一步的药物设计奠定了良好的基础.另外,以化合物13及其相应的β异构体24为代表,结合量子化学从头算分子轨道理论方法考察了它们的前线轨道,为阐明α和β系列化合物的活性差异提供了理论依据.     

HEPT类逆转录酶抑制剂的三维定量构效关系

利用比较分子力场分析(CoMFA)方法对32个HEPT类HIV-1逆转录酶抑制剂(RTIs)的三维定量构效关系(3D-QSAR)进行了分析,建立了HIV-1逆转录酶抑制剂的3种3D-QSAR模型,发现影响其生物活性的主要因素为立体场因素,这与HIV-1RT的非底物结合部位(NNBS)的疏水性环境相吻合.进一步分析表明,适当长度的1-位侧链对保持化合物的抗病毒活性致关重要;增大5-位取代基的体积可增强生物活性;在1-位苄氧甲基的对位引入大体积基团有利于提高活性.同时考察立体场、静电场与生物活性的关系,表明,CoMFA模型为最佳预测模型,其交叉验证系数R_CV²=0.870,传统相关系数R²=0.986,标准偏差SE=0.146,F=294.546.用此模型预测了检验组3个HEPT类化合物的-lgEC₅₀,R_pred²=0.850,表明模型具有很好的预测能力,可为HEPT类HIV-1逆转录酶抑制剂的结构优化提供理论指导.     

3-取代苄氧基-6-(取代-1H-吡唑-1-基)哒嗪的合成与生物活性

3-氯-6-肼基哒嗪分别与乙酰丙酮和3-二甲胺基丙烯醛反应, 合成了中间体3-氯-6-(3,5-二甲基-1H-吡唑-1-基)哒嗪(2)和3-氯-6-(1H-吡唑-1-基)哒嗪(4), 它们与多种取代苄醇反应, 得到了一系列未见报道的3-取代苄氧基-6-(取代-1H-吡唑-1-基)哒嗪, 其结构均经1H NMR, IR和元素分析确证. 初步的生物活性测试结果表明, 所合成的化合物对油菜和稗草均具有一定的抑制作用.     

Chemistry of HIV-1 virucidal Pt complexes having neglected bidentate sp2 N-donor carrier ligands with linked triazine and pyridine rings. synthesis, NMR spectral features, structure, and reaction with guanosine

Complexes of the types LPtCl2 and [L2Pt]X2 [L = substituted 3-(pyridin-2'-yl)-1,2,4-triazine] were synthesized and characterized by NMR spectroscopy and, for the first time, by X-ray crystallography in an effort to determine the coordination properties of this novel class of inorganic medicinal agents possessing HIV-1 virucidal activity. The agents containing either one or two sp2 N-donor bidentate ligands are referred to as ptt (platinum triazine) agents. The X-ray structures of three LPtCl2 compounds revealed the expected pseudo-square-planar geometry. The X-ray structure of [(pyPh2t)2Pt](BF4)2 [pyPh2t = 3-(pyridin-2'-yl)-5,6-diphenyl-1,2,4-triazine] has the expected trans relationship of the unsymmetrical L and is essentially planar, an unusual property for a Pt(II) complex with two bidentate sp2 N donors. HIV-1 is an RNA virus; the guanosine ribonucleoside (Guo) binds (MepyMe2t)PtCl2 at both (inequivalent) available coordination sites to form [(MepyMe2t)Pt(Guo)2]2+ [MepyMe2t = 3-(4'-methylpyridin-2'-yl)-5,6-dimethyl-1,2,4-triazine]. This adduct has four nearly equally intense Guo H8 signals attributed to two pairs of head-to-tail (HT) and head-to-head (HH) conformers, which interchange rapidly within each pair. However, equilibration between pairs requires rotation of the Guo cis to the MepyMe2t pyridyl ring, and the H6' proton on this ring projects toward the Guo and hinders Guo rotation about the Pt-N7 bond. Thus, the HT/HH pairs do not interchange; such behavior is rare. Guo did not add to [(MepyMe2t)2Pt]2+, a result suggesting the possibility that the virucidal activity of LPtCl2 and [L2Pt]2+ ptt agents arises respectively from covalent and noncovalent (possibly intercalative interactions favored by [L2Pt]2+ planarity) binding to biomolecular targets.     

Design,Synthesis and Antitumor Activity of a Novel Series of PAC-1 Analogues

A novel series of first procaspase activating compound(PAC-1) analogues was designed, synthesized and evaluated for antitumor activity towards two cell lines[human promyelocytic leukemia cell line(HL60) and human embryonic lung fibroblast cell line(HLF)] by the MTT[3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazo-liumromide] method in vitro. The structures of all the compounds were confirmed by ¹H NMR, MS and elemental analysis. Among the compounds synthesized,(E)-2-[(3-{[4-(tert-butyl)benzyl](methyl)amino}propyl)(methyl)amino]-N'-[4-(diethylamino)-2-hydroxybenzylidene]acetohydrazide(compound 6n) exhibits a good anti-proliferative activity to the majority of tumor cells tested, and selectively cleaves cancer cells. Thus, compound 6n was identified as promising lead compound for further structural modification.