一个8-O-4'新木脂素化合物的对映选择性合成

报道了一条立体选择性合成赤式8-O-4'新木脂素的新路线. 以Sharpless双羟化反应构筑2个手性中心, 经过几步转化, 得到关键中间体6, 通过Mitsunobu反应进行偶联, 可以得到单一赤式的8-O-4'新木脂素化合物. 通过此路线, 立体选择性地合成了一个天然8-O-4'新木脂素的赤式异构体.     

1'-C-氰基-2',3',5'-三-O-苯甲酰基-β-D-呋喃胸苷的声化学合成

本文首次应用超声波技术合成了1'-C-氰基-2',3',5'-三-O-苯甲酰基-β-D-呋喃胸苷, 反应时间1h, 产率96-100%, 与通常的化学合成方法相比, 反应速度及产率大辐度提高。     

2',3'-二脱氧-2',3'-二去氢鸟嘌呤核苷构象稳定性的理论研究

采用密度泛函方法在B3LYP/6-31＋G**水平上研究了2',3'-二脱氧-2',3'-二去氢鸟嘌呤核苷分子(D4G)的构象. 分别研究在气相中的孤立分子和一水合物异构体的相对稳定性和异构体之间的相互转变过程, 分析了水分子的参与对D4G异构体的相对稳定性和几何结构参数以及自然电荷的影响. 结果表明, 孤立的D4G分子在气相中存在8种稳定构象, 其中构象d4g-2是所有构象中最稳定的, 气相中D4G主要以d4g-2存在. 气相中各构象的相对稳定性为: d4g-2＞d4g-1＞d4g-5＞d4g-3＞d4g-6＞d4g-4＞d4g-8＞d4g-7. 计算得到的各构象键长和键角数据与实验值接近. 一个水分子的加入对D4G分子的构型参数有所影响, 基本不改变D4G分子各构象的稳定性顺序, 但构象转变的能垒有所提高. 氢键在分子构象中发挥了重要作用.     

2',3'-二脱氧-2',3'-二去氢鸟嘌呤核苷构象稳定性的理论研究

采用密度泛函方法在B3LYP/6-31＋G**水平上研究了2',3'-二脱氧-2',3'-二去氢鸟嘌呤核苷分子(D4G)的构象. 分别研究在气相中的孤立分子和一水合物异构体的相对稳定性和异构体之间的相互转变过程, 分析了水分子的参与对D4G异构体的相对稳定性和几何结构参数以及自然电荷的影响. 结果表明, 孤立的D4G分子在气相中存在8种稳定构象, 其中构象d4g-2是所有构象中最稳定的, 气相中D4G主要以d4g-2存在. 气相中各构象的相对稳定性为: d4g-2＞d4g-1＞d4g-5＞d4g-3＞d4g-6＞d4g-4＞d4g-8＞d4g-7. 计算得到的各构象键长和键角数据与实验值接近. 一个水分子的加入对D4G分子的构型参数有所影响, 基本不改变D4G分子各构象的稳定性顺序, 但构象转变的能垒有所提高. 氢键在分子构象中发挥了重要作用.     

核苷2‘或3’—（硫代）膦酸酯的合成

通过（硫代）亚磷酸二酯与酮核苷的羰基的加成反应合成了2'位或3'（硫代）膦酰修饰的核苷，在这一加成反应中，只检测和分离到一种异构体。文中对该异构体的构型进行了讨论。     

2',3'-O-二苯甲酰尿嘧啶核糖核苷U(BZ)~2单晶的制备和晶体结构测定

制备了2',3'-O-二苯甲酰基尿嘧啶核糖核苷U(BZ)~2,并在DMF溶液中培养得到单晶.单晶经X射线衍射测定,属三斜晶系,空间群为P1.晶胞参数a=5.734(1)A,b=10.124(3)A, C=11.905(3)A,α=73.07(2),β=84.36(2),γ=81.61(2),Z-1.用CAD-4四园仪收集衍射数据.用直接法解晶体结构,用块对角矩阵最小二乘法修正,对3154个独立反射.最终R=0.070.U(BZ)~2的碱基相对于糖环为β构型,两个苯甲酰基在空间上远离 5'-OH,使5'-OH周围空隙较大,因而苯甲酰基作为Ur的2',3'-羟基的保护基,对5'-OH的反应不存在立体障碍.     

新型四氢苯并[4',5']噻吩并[3',2'∶5,6]吡啶并[4,3-d]嘧啶类化合物衍生物的合成及抗肿瘤活性

本文以环己酮为原料,通过氮杂Wittig反应合成了一系列结构新颖的取代四氢苯并噻吩并吡啶并嘧啶衍生物,并采用MTT法考察所合成目标化合物对CNE2、KB、MGC-803、MCF-7和PC3这5种肿瘤细胞的抑制活性。初步的生物活性结果表明,目标化合物对5种肿瘤细胞均有抑制活性,尤其是对胃癌MGC-803细胞展现出了更强的抑制活性。其中3-(4-氟苯基)-2-((4-氟苯基)氨基)-5-甲基-8,9,10,11-四氢苯并[4',5']噻吩并[3',2':5,6]吡啶并[4,3-d]嘧啶-4(3H)-酮[化合物8c,IC_(50)=(0. 9±0. 25)μmol·L~(-1)]对MGC-803的活性最强,是5-氟尿嘧啶[IC_(50)=(18. 4±1. 43)μmol·L~(-1)]的20倍;同时,目标化合物对正常的胃黏膜上皮细胞GES-1没有毒性。四氢苯并[4',5']噻吩并[3',2':5,6]吡啶并[4,3-d]嘧啶类化合物具有良好的抗肿瘤活性,值得进一步深入研究。     

5'-脱氧-5'-氟-5-氟尿核苷的合成和性质

叙述了5'-脱氧-5'-氟尿核苷和5'-脱氧-5'-氟-5-氟尿核苷的合成, 并比较了它们以及尿核苷和5-氟尿核苷的一些性质。     

核苷2′或3′-(硫代)膦酸酯的合成

通过(硫代)亚磷酸二酯与酮核苷的羰基的加成反应合成了2′位或3′位(硫代)膦酰修饰的核苷,在这一加成反应中,只检测和分离到一种异构体.文中对该异构体的构型进行了讨论.     

高异三尖杉酯碱的合成及其立体异构体的分离鉴定

2-氧代-6-甲基庚酰基三尖杉碱(3)与0-(1-甲氧基异丙基)羟基乙酸甲酯(4)在强碱性试剂二异丙胺锂(LDA)存在下,起亲核加成反应,反应中间体5在室温用酸性丙酮水解,得到一种新的三尖杉酯类生物碱一一高异三尖杉酯碱(6c)及其立体异构体(6a、6b、6d)的混合物,产率56%、通过制备薄层层析分得这四个立体异构体,它们的1H NMR和异三尖杉酯碱及其立体异构体的1H NMR类似,推定了它们的绝对构型。初步药理试验表明,高异三尖杉酯碱及其立体异构体的混合物对白血病L7712的DNA合成有明显的抑制作用。     

2-芳胺基-5-[5'-氨基-1'-(4"-氯苯基)-1',2',3'-三唑-4'-基]-1,3,4-噻二唑的合成

1-[5'-氨基-1'-(4"-氯苯基)-1,2,3-三唑-4'-甲酰基]-4-芳基-3-氨基硫脲在浓硫酸催化下环化得到2-芳胺基-5-[5'-氨基-1'-(4"-氯苯基)-1',2',3',-三唑-4'-基]-1,3,4-噻二唑2a-i, 依此法合成了九个标题化合物, 收率为30-74%。化合物2i的结构用X-光衍射单晶分析确证。     

Synthesis and properties of a novel bridged nucleic acid with a P3'' --> N5'' phosphoramidate linkage, 5''-amino-2'',4''-BNA

5'-Amino-2',4'-BNA, a novel analogue of BNA series compounds, was successfully synthesized, and its incorporated oligonucleotides showed potent duplex- and triplex-forming ability and resistance against snake venom phosphodiesterase.     

DIRECT PHOTO-AFFINITY LABELING OF CYCLIC NUCLEOTIDE BINDING PROTEINS WITH GUANOSINE-3'',5''-MONOPHOSPHATE

Abstract— Radioactivity from [³H]-guanosine-3',5'-monophosphate was shown to become stably linked to proteins in testis extracts during ultraviolet irradiation. Adenosine-3',5'-monophosphate competitively inhibited incorporation into these proteins. Guanosine-3',5'-monophosphate had a lower affinity for binding sites than did adenosine-3',5'-monophosphate. Similar peptides were photo-labeled with [³H]-guanosine-3',5'-monophosphate and [3H]-adenosine-3',5'-monophosphate. Guanosine-3',5'-monophosphate was more efficiently incorporated than was adenosine-3',5'-monophosphate. Extracts from a number of tissues incorporated both cyclic nucleotides photochemically.     

2',3'-双脱氢-2',3'-双脱氧胸苷(d4T)5'-硫代磷酰氨基酸酯的合成和谱学分析

HIV逆转录酶是治疗艾滋病的有效靶点，核苷-磷酰氨基酸酯是HIV逆转录酶的 有效抑制剂，但是这类化合物容易在体内被核酸酶水解。本研究设计合成了对核酸 酶具有抵抗作用的2',3'-双脱氢-2',3'-双脱氧胸苷5'-硫代磷酰氨基酸酯化合物， 这类化合物可以有效地透过细胞膜经过细胞激酶的作用，进入HIV逆转录酶的作用 位点，病毒实验表明该类化合物对MT-4细胞具有较好的抗HIV病毒活性。报道了2', 3'-双脱氢-2',3'-双脱氧胸苷5'-硫代磷酰氨基酸酯化合物的合成，及利用NMR， IR和ESI-MS谱进行的结构表征和构象分析。     

四氢苯并[4',5']噻吩并[3',2':5,6]吡啶并[4,3-d]嘧啶-4(3H)-酮的合成、晶体结构及杀菌活性

通过氮杂Wittig反应合成了一系列结构新颖的未见文献报道的取代四氢苯并[4',5']噻吩并[3',2':5,6]吡啶并[4,3-d]嘧啶-4(3H)-酮化合物6, 产物的结构通过核磁共振氢谱、质谱、红外光谱、元素分析的确证. 为进一步了解此类化合物的结构, 对化合物6c进行了X射线单晶衍射. 初步杀菌活性测定结果表明, 该类化合物具有较好的杀菌活性和选择性. 如6f在50 mg/L浓度时, 对黄瓜灰霉菌的抑制率为98%.     

2-芳胺基-5-[5'-氨基-1'-(4''-氯苯基)-1', 2', 3'-三唑-4'-基]——-1, 3, 4-恶二唑的合成

利用1-[5'-氨基-1'-(4'-氯苯基)-1', 2', 3'-三唑-4'-甲酰基]-4-芳基氨基硫脲在汞盐Hg(OAc)2-HOAc中加热缩合, 制得11种新的2-芳胺基-5-[5'-氨基-1'-(4'-氯苯基)-1', 2', 3'-三唑-4'-基]---1, 3, 4-恶二唑。所有化合物的结构经元素分析, IR、MS以及1H NMR确认。选择代表物作生测试验, 结果表明, 2b, 2k中MIC3.1mg/L时, 对大肠杆菌及金黄色葡萄球菌繁殖有明显抑制。     

METHYLALLOPSORALEN-THYMINE 3,4- and 4'',5''-MONOADDUCTS FORMED IN THE PHOTOREACTION WITH DNA

Abstract— Two new allopsoralens, i.e. 4,7.5'-trimethylallopsoralen and 4,7,4'-trimethylallopsoralen have been irradiated (365 nm) in the presence of DNA. The DNA so treated was hydrolyzed and among the products of its hydrolysis new 3,4- and 4',5'-monocycloadducts between the two furocoumarins and thymine have been isolated. The monoadducts have been characterized on the basis of their spectroscopic properties, of their capacity to undergo photoreversion forming the parent compounds and of the NMR data. A cis-syn conformation has been suggested for both 3,4- and both 4',5'-monoadducts.     

4, 4'', 5''-TRIMETHYL-8-AZAPSORALEN, A NEW-PHOTOREACTIVE AND NON-SKIN-PHOTOTOXIC BIFUNCTIONAL BIOISOSTER OF PSORALEN

Photochemical and photobiological properties of a new isoster of psoralen, 4,4',5'-trimethyl-8-azapsoralen (4,4',5'-TMAP), have been studied. This compound shows a high DNA-photobinding rate, higher than that of 8-methoxypsoralen (8-MOP), forming both monoadducts and inter-strand cross-links. The yield of cross-links, however, is markedly lower than that of 8-MOP. Antiproliferative activity of 4,4',5'-TMAP, in terms of DNA synthesis inhibition in Ehrlich ascites tumor cells, is higher than that of 8-MOP. Mutagenic activity on E. coli WP2 R46+ cells appeared similar to or even lower than that of 8-MOP. This new compound applied on depilated guinea pig skin and irradiated with UVA did not show any skin-phototoxicity. On the basis of these properties 4,4',5'-TMAP appears to be a potential photochemotherapeutic agent.     

A FLOW LINEAR DICHROISM STUDY OF THE ORIENTATION OF 4'',5''-PSORALEN-DNA PHOTOADDUCTS

Abstract— The flow linear dichroism properties of covalent adducts derived from the photochemical binding of various psoralen derivatives to salmon sperm DNA were investigated. The psoralens studied include bifunctional derivatives (8-methoxypsoralen,5-methoxypsoralen, tetrahydropyrido [3,4: 4',5'] psoralen) and monofunctional derivatives (pyrido [3,4-c] psoralen, 7-methylpyrido [3,4-c] psoralen, 3-carbethoxypsoralen). The orientation of the psoralen moieties (furan-side monoadducts) relative to the orientation of the DNA bases was determined. All of the furan-side monoadducts are characterized by a similar orientation, with mean angles between the psoralen moiety and the normals of the planes of the DNA bases ranging between 70° and values close—but not equal—to 90°. The results are consistent with a pseudo-intercalative adduct geometry, most probably involving stacking interactions with the DNA bases.     

TRIPLET EXCITED STATES OF 4'',5''-PHOTOMONOADDUCTS OF 3- CARBETHOXYPSORALEN and 8-METHOXYPSORALEN WITH DNA NUCLEOSIDES

Abstract— Triplet absorption spectra, triplet extinction coefficient and intersystem crossing for 4',5'-monocycloadducts of 3-carbethoxypsoralen (3-CPs) with thymidine (dThd) and uridine (dUrd) in ethanol have been investigated in order to elucidate whether their triplet state properties could be the limitating step for a further photoreaction of 3-CPs monoadducts with DNA nucleosides. The comparison between the triplet characteristics of 4',5'-monoadducts of 3-CPs and those of 8-methoxypsoralen (8-MOP) shows that the quantum yield is much higher in the case of 3-CPs than for 8-MOP. The monofunctionality of 3-CPs cannot therefore be ascribed to the triplet excited states properties of its monoadducts. It is likely that steric hindrance introduced by the bulky carbethoxy group remains a reasonable explanation.