新的聚合物支载硼氢负离子还原剂系统研究 3: 聚合物支载还原剂III

硼氢化钠的低分子还原系统研究很多,但其聚合物支载还原剂相对来说就很少,而且仅以强碱型阴离子交换树脂来制备的聚合物试剂。为了寻找用途更广泛的、新的聚合物支载还原剂,我们进行了硼氢负离子的聚合物还原系统的研究;发现能用弱酸型阳离子交换树脂制备出新的聚合物支载还原剂。前文报道了用NaBH_4的水溶液和阴离子交换树脂     

Multiple binding modes of the camptothecin family to DNA oligomers

The binding constants of camptothecin, topotecan and its lactone ring-opened carboxylate derivative to DNA octamers were measured by UV and NMR spectroscopy. The self-association of topotecan (TPT) was also measured. The carboxylate form of TPT binds in the same way as the lactone, but more weakly. Titration of TPT into d(GCGATCGC)2 shows a preferred location stacked onto the terminal G1 base. However, the intermolecular NOEs cannot be reconciled with a single conformation of the complex, and suggest a model of a limited number of conformations in fast exchange. MD calculations on four pairs of starting structures with TPT stacked onto the G1-C8 base pair in different orientations were therefore performed. The use of selected experimental "docking" restraints yielded ten MD trajectories covering a wide conformational space. From a combination of calculated free energies, NOEs and chemical shifts, some of the structures produced could be eliminated, and it is concluded that the data are consistent with two major families of conformations in fast exchange. One of these is the conformation found in a crystal of a TPT/DNA/topoisomerase I ternary complex [Proc. Natl. Acad. Sci. USA 2002, 99, 15 387-15 392].     

由藜芦醛合成娃儿藤碱

以藜芦醛(1)、3,4-二甲氧基苯乙酸(2)、(S)-L-脯氨酸(6)等为原料,经8步反应,合成了一种抗肿瘤活性(s)-( )-娃儿藤碱。先由化合物1和2在乙酸酐/三乙胺催化下反应得到3,4-二甲氧基一反式-α-(3′, 4′-二甲氧基苯基)．肉桂酸(3),在0℃、三氟乙酸存在下用VOF_3对其关环成2,3,6,7-四甲氧基-9-羧基菲(4),然后用喹啉作介质,在230℃、无水CuSO_4催化下脱去羧基,得到2,3,6,7-四甲氧基菲(5),再和(S)-N- (三氟乙酰)-L-脯氨酰氯(6b)傅-克反应得到(S)-N-(三氟乙酰基)-2,3,6,7-四甲氧基-9-L-脯氨酰基菲(7),并对产物进行了柱纯化,所得产物在三氟化硼乙醚存在下用三乙基硅烷还原羰基,然后脱去三氟乙酰保护基,最后在盐酸存在下用甲醛闭环得到目标产物(10)。用NMR和MS表征了中间体和目标产物的结构。该合成反应条件温和,总收率为3．5％,产品纯度98．5％(HPLC)。     

Actin-binding marine macrolides: total synthesis and biological importance

Marine organisms produce a fascinating range of structurally diverse secondary metabolites, which often possess unusual and sometimes unexpected biological activities. This structural diversity makes these marine natural products excellent molecular probes for the investigation of biochemical pathways. Recently, a number of novel and stereochemically complex macrolides, having a large macrolactone (22- to 44-membered) ring, that interact with the actin cycloskeleton have been isolated from different marine sources. Actin, like tubulin, is a major component of the cytoskeleton and has important cellular functions. Although the details of these interactions are still under investigation, these marine macrolides are becoming increasingly important as novel molecular probes to help elucidate the cellular functions of actin. Owing to their potent antitumor activities, these compounds, for example the aplyronines, also have potential for preclinical development in cancer chemotherapy. Their appealing molecular structures, with an abundance of stereochemistry, and biological significance, coupled with the extremely limited availability from the marine sources, have stimulated enormous interest in the synthesis of these compounds. This review summarizes the biological properties of these unusual marine natural products and features the recently completed total syntheses of swinholide A, scytophycin C, aplyronine A, mycalolide A--all of these being potent cytotoxic agents that target actin--and a diastereoisomer of ulapualide A. Rather than detailing each individual step of these multistep total syntheses, the different synthetic strategies, key reactions, and methods adopted for controlling the stereochemistry are compared.     

Studies on the Physicochemical Properties, Structure and Antitumor Activity of an Oligosaccharide Homologue SnS-2 from the Root of Scrophularia ningpoensis Hemsh

An oligosaccharide homologue named SnS-2 was isolated from the root of Scrophularia ningpoensis Hemsl.SnS-2 was purified by means of gel-permeation chromatography and ion-exchange chromatography. Its physicochemical properties, including carbohydrate content and molecular weight were determined. The structure of SnS-2 was elucidated by chemical methods along with ^1H and ^13C NMR spectroscopy, including two-dimensional DQCOSY and H-detected ^1H, ^13C HMQC experiments. These results show that SnS-2 possesses a backbone consisting of terminal α-Galp-(1→, α-Galp-(1→6), α-Glcp-(1→6) and nonreducing end β-Fruf-(2→. The bioactive assay showed that it could inhibit the growth of Lewis pulmonary carcinoma implanted in mice.     

一种新的质子泵抑制剂苯并咪唑衍生物的合成与表征

以2-巯基苯并咪唑为原料,在碱性条件下与自制的盐酸2-氯甲基-4-(3-甲氧基丙氧基)-3-甲基吡啶缩合得2-{[4-(3-甲氧基丙氧基)-3-甲基吡啶-2-基]甲基硫}-1H-苯并咪唑,再经氧化、成盐反应生成产物2-{[4-(3-甲氧基丙氧基)-3-甲基吡啶-2-基]甲基亚硫酰基}-1H-苯并咪唑钠,总收率66%.此产物通过红外光谱、核磁共振、质谱表征加以确认.     

An experimental and theoretical study of the Cp2VO2CO: use of 13CO3(2-) for structure investigation of d1-metallocene complexes

EPR study has shown that the anticancer agent vanadocene dichloride (Cp2VCl2) interacts with carbonate contained in physiological solutions. Chelate complex Cp2VO2CO (|A(iso)(51V)| = 175.1 MHz, g(iso) = 1.9861) is the only paramagnetic species formed in the range about the physiological pH (5.5-11.0). The super-hyperfine coupling (|a(iso)(13C)| = 24.1 MHz) was evidenced at measurements using 13C labelled carbonate. The structure of carbonate complex was validated by comparison of observed and theoretical calculated HFC tensors (at the density functional level of theory).     

Diorganotin(IV) derivatives of substituted benzohydroxamic acids with high antitumor activity

A series of diorganotin(IV) and dichlorotin(IV) derivatives of 4-X-benzohydroxamic acids, [HL(1) (X = Cl) or HL(2) (X = OCH(3))] formulated as [R(2)SnL(2)] (R = Me, Et, nBu, Ph or Cl; L = L(1) or L(2)), along with their corresponding mixed-ligand complexes [R(2)Sn(L(1))(L(2))] have been prepared and characterized by FT-IR, (1)H, (13)C, and (119)Sn NMR spectroscopy, mass spectrometry, elemental analysis, and melting points. In addition, single-crystal X-ray diffraction analyses were carried out for [Me(2)SnL(2)] (L = L(1) or L(2)), which show coordination structures intermediate between distorted octahedra and bicapped tetrahedra. The hydroxamate ligands are asymmetrically coordinated by the oxygen atoms, the carbonyl oxygen atom is further away from the metal center than the other oxygen atom. The complexes are stable monomeric species; most of them are soluble not only in chlorohydrocarbon solvents, but also in alcohols and hydroalcoholic solutions. In polar solvents, the mixed-ligand complexes gradually decompose into the corresponding single-ligand complex couples. The complexes exhibit in vitro antitumor activities (against a series of human tumor cell lines) which, in some cases, are identical to, or even higher than, that of cisplatin. For the dialkyltin complexes, the activity increases with the length of the carbon chain of the alkyl ligand and is higher in the case of the chloro-substituted benzohydroxamato ligand. The [nBu(2)Sn(L(1))(2)] complex displays a high in vivo activity against H22 liver and BGC-823 gastric tumors, and has a relatively low toxicity.     

Synthesis and antitumor activity of camptothecin- 4β-triazolopodophyllotoxin conjugates

Abstract

Two new compounds (9 and 10) having a camptothecin (CPT) analog conjugated to the 4β-azido-4-deoxypodophyllotixin analog by untilizing the copper-catalyzed azide-alkyne cycloadditon (CuAAC) reaction, and were evaluated for their cytotoxicity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW480) using the MTT (3-(4,5-dimethyl-thiahiazo-2-yl)-2,5-diphenyltetrazolium bromide) assay. Two novel conjugates shown weak cytotoxicity, compound 10 showed highly potent against HL-60 cell line tested, with IC₅₀ value 17.69?±?0.19?μM. This compound suggested its potential as anticancer agents for further development.

     

Synthesis, biochemical properties and molecular modelling studies of organometallic specific estrogen receptor modulators (SERMs), the ferrocifens and hydroxyferrocifens: evidence for an antiproliferative effect of hydroxyferrocifens on both hormone-dependent and hormone-independent breast cancer cell lines

A series of ferrocene derivatives based upon the structure of the antiestrogenic drug tamoxifen or of its active metabolite hydroxytamoxifen has been prepared and named by analogy ferrocifens and hydroxyferrocifens. This series includes 1-[4-(O(CH(2))(n)NMe(2))phenyl]-1-phenyl-2-ferrocenyl-but-1-ene and 1-[4-(-O(CH(2))(n)NMe(2))phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene, with n=2, 3, 5 and 8, and 1-[4-(-O(CH(2))(2)NMe(2))phenyl]-1-(4-hydroxyphenyl)-2-ferrocenylethene. Most of these molecules have been synthesised by McMurry cross-coupling of the appropriate ketones, except for the ethene complexes, which were prepared by a four-step reaction sequence starting from the ferrocenylacetic acid. All these compounds were obtained as mixtures of Z and E isomers. The isomers were separated in the cases of the ferrocenyl derivatives of tamoxifen and hydroxytamoxifen (n=2). No isomerisation of the Z and E isomers occurred in DMSO after one day, while a 50:50 mixture of the isomers was obtained within one hour in chloroform. The X-ray structure of (E)-1-[4-(-O(CH(2))(2)NMe(2))phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene has been determined. The relative binding affinity (RBA) values of the hydroxyferrocifens for the estrogen receptor alpha (ERalpha) was good to moderate, with values decreasing progressively with the length of the basic chain. The RBA values found for the estrogen receptor beta (ERbeta) are equal to or slightly less than those found for the alpha form. The lipophilicity of the hydroxyferrocifens are superior to the values found for estradiol and increase with lengthening of the chain. The antiproliferative effects of the four hydroxyferrocifens with n=2, 3, 5 and 8 were studied on four breast cancer cell lines (MCF7, MDA-MB231, RTx6 and TD5) possessing different levels of ERalpha. On MCF7 cells containing high levels of ERalpha, hydroxyferrocifens behave as antiestrogens. At a molarity of 1 microM the effect is close to that of hydroxytamoxifen (used for reference) when n=2 or 5, more marked when n=3, and weaker when n=8. Ferrocene alone has no effect. For the MDA-MB231 cells, classed as a hormone-independent breast cancer cell line, on the other hand, the hydroxyferrocifens show remarkable antiproliferative behaviour while the hydroxytamoxifen is completely inactive. Hydroxyferrocifens therefore show the unique property of being active both on hormone-dependent and on hormone-independent breast cancer cell lines. The molecular modelling study provides some clues for understanding of the antagonist effect of these molecules, while an additional cytotoxic effect due to the vectorised ferrocenyl unit is revealed in some occasions.