Structural requirements for the interaction of combretastatins with tubulin: how important is the trimethoxy unit?

A series of combretastatins possessing both a trimethoxy unit and other substituents on ring A has been synthesised and tested for cytotoxicity and their ability to interact with the protein tubulin. All previous studies have indicated that the trimethoxy unit is essential for interaction with tubulin. The studies herein show that molecules possessing functionalities other than trimethoxy can also interact with tubulin. Importantly a trimethyl substituted agent 52a has shown reduced cytotoxicity, but increased potency in its ability to inhibit the assembly of tubulin.     

Kinetics of the formation of primary products of cumeme cracking over a partially exchanged LaY-Zeolite

The kinetics of formation of primary products from cumene cracking over a partially exchanged LaNaY catalyst have been studied at 400, 450, and 500°C. It has been found that in both the fully and the partially exchanged LaNaY zeolite catalysts the nature of active sites is the same. The higher activity of the fully exchanged catalyst is attributed to a higher concentration of the active sites. It has also been found that an increase in exchange level leads to an increase in the number of both Bronsted and Lewis active sites, but in somewhat different proportions. A comparatively slight increase in the decay rate constant is observed over the same increase in the level of exchange.     

Synthesis and antitumor activity of 1,8-diaminoanthraquinone derivatives

Continuing our ongoing studies on cytotoxic substances, a series of regioisomeric disubstituted aminoanthraquinone (DAAQ) derivatives have been synthesized as cytotoxic activity based on a proposed bioactive amino conformation. To assess the biological activity of amino-substitution in the side-chains of anthraquinone located at positions 1 and 8 of the anthraquinone ring system. The aim of the study was to determine if members of the anthraquinone family could be used as adjuncts to increase the growth inhibiting effect of anticancer agents in rat glioma C6 cells, human hepatoma G2 cells and 2.2.15 cells. In vitro cytotoxicity data is reported for the compounds and some indications of structure--activity relationships have been discerned. A number of compounds were found to have good cytotoxicity against proliferation in these three cell lines. This has led to the discovery some of the DAAQ as a conformationally constrained structure possessing anticancer properties that displays cytotoxicity for these above cell lines and is being investigated further.     

Study on the synthesis and cytotoxicity of new quinophenoxazine derivatives

We have synthesized several new quinophenoxazine analogues and tested their cytotoxicity activities. The results showed that the compounds, 4a and 4b, possessing phenyl ring in the structure have almost same pharmacological capacity with A-62176. This finding suggests that the phenyl ring portion is important to this series of compounds for the activity expression.     

New ent-kaurene-type diterpenoids possessing cytotoxicity from the New Zealand liverwort Jungermannia species

Two new ent-kaurene-type and a new rearranged ent-kaurene-type diterpenoids possessing cytotoxicity against a human leukemia cell line have been isolated from the New Zealand liverwort Jungermannia species, together with previously known ent-kaurene-type diterpenoids. Their structures were established based on extensive NMR techniques.     

Unexpected influence of stereochemistry on the cytotoxicity of highly efficient Ti(IV) salan complexes: new mechanistic insights

The effect of stereochemistry on the cytotoxicity of highly active and hydrolytically stable N-methylated Ti(IV) salan complexes is reported. Four bis(isopropoxo) complexes incorporating N-methylated salan ligands with different aromatic substitution patterns have been prepared in racemic and optically active forms for the first time by ligand-to-metal chiral induction from trans-diaminocyclohexyl-based chiral ligands. The configuration of the metal center that derives from that of the ligand has an enormous influence on cytotoxicity, with the racemic mixture mostly being more active than the single enantiomers that are of either similar or different activity. This implies that the active species is a salan-bound heterochiral polynuclear compound, interacting with a chiral target. Four additional complexes of achiral salan and chiral labile sec-butoxo ligands, analyzed as racemic and as homochiral, revealed no influence of stereochemistry, supporting early dissociation of the labile ligands to give the polynuclear products.     

Pd-基金属-酸-碱多功能催化剂的制备及其丙酮一步法合成MIBK性能研究

甲基异丁基酮 (MIBK) 是一种重要的化学品, 广泛应用于涂料以及有机合成领域, 下游产品包括特种涂料溶剂、高品质脱蜡溶剂和高性能橡胶防老剂等. 近年来随国民经济的快速发展, 甲基异丁基酮的年需求量与价格逐年上升, 应用领域也不断拓宽. 因此, 开展 MIBK 绿色合成工艺的研究对提高原子经济性、打破国际技术壁垒以及满足国内市场需求具有重要意义. 目前生产 MIBK 最绿色、高效的生产方法是丙酮一步法, 包括缩合、脱水以及加氢等一系列反应过程, 该工艺顺利实施的关键在于所使用的催化剂. 根据丙酮一步法合成 MIBK 反应特点, 所用催化剂表面必须具备多种催化活性中 心, 从而保证缩合、脱水以及加氢反应的顺利进行, 实现从反应物到产物的高效转化. 因此, 高活性和高选择性多功能催化剂的制备是提高 MIBK 生产效率的有效途径.本文采用浸渍法将具有加氢活性的贵金属 Pd 负载在表面具有丰富酸性位点或碱性位点的固体酸或固体碱氧化物载体上, 制备了 Pd/MOx(M = Ti, Ce, Al, Si, La, Ca和Mg) 双功能催化剂, 并用于丙酮一步法合成 MIBK 反应中. 结果表明, Pd基金属-酸/碱双功能催化剂均可以催化该连串反应的进行, 其性能高于 Pd 基金属-酸双功能催化剂, 其中 Pd/MgO 催化剂上丙酮转化率为30.67%, MIBK 产率可达27.61%. 构效关系研究显示, 催化剂表面酸性位点和碱性位点对于该连串反应的各反应步骤催化性能有所不同, 其中碱性位点有利于丙酮缩合反应, 而酸性位点有利于二丙酮醇脱水反应, 且强路易斯碱性中心位点可以更好的催化缩合反应的进行, 同时中强度路易斯酸性中心位点具有最佳的催化脱水反应的能力. 此外, 表面具有最强路易斯碱性中心位点 Pd/La2O3催化剂并未表现出最高的MIBK产率, 说明在丙酮一步法合成MIBK反应中, Pd基双功能催化剂表面各位点间的协同对其催化性能具有重要的影响.本文进一步采用水热法和沉淀沉积法制备了系列MgTiOx、MgAlOx和CaTiOx二元复合氧化物 (MMO) 以及 CaMgAlOx和 TiMgAlOx三元MMO, 并以其为载体, 通过浸渍焙烧还原制备 Pd 基多功能催化剂, 并用于丙酮一步法合成MIBK反应中,发现Pd/MgAl-MMO多功能催化剂具有最高的催化活性及 MIBK 产率. 对其表面多功能位点数量进行调变, 并通过 XRD、CO2-TPD、NH3-TPD、吡啶红外、CO2红外和HRTEM等进行表征, 结果表明, 经过450 ℃焙烧酸碱中心摩尔量比为0.4的0.1%Pd/Mg3Al-MMO多功能协同催化剂三种催化活性中心位点协同作用最佳, 其丙酮转化率为38.20%, MIBK产率可达31.63%. Pd/Mg3AlMMO多功能协同催化剂三种活性位点接近性研究表明, 在多功能催化剂中分离酸中心活性位点、碱中心活性位点以及加氢活性位点后, 获得的双功能催化剂产率均明显下降, 说明Pd/Mg3Al-MMO多功能催化剂在三种活性位点相互接近时才能更好催化反应的进行. 根据多功能催化剂构效关系研究结果, 对各催化活性中心的密度及分布进行调控, 结果显示, 通过沉淀沉积法制备的Pd/Mg3Al-MMO催化剂性能进一步提高, 丙酮转化率为42.11%, 产率高达37.20%.     

Proteasome inhibitors: an expanding army attacking a unique target

Proteasomes are large, multisubunit proteolytic complexes presenting multiple targets for therapeutic intervention. The 26S proteasome consists of a 20S proteolytic core and one or two 19S regulatory particles. The 20S core contains three types of active sites. Many structurally diverse inhibitors of these active sites, both natural product and synthetic, have been discovered in the last two decades. One, bortezomib, is used clinically for treatment of multiple myeloma, mantle cell lymphoma, and acute allograft rejection. Five more recently developed proteasome inhibitors are in trials for treatment of myeloma and other cancers. Proteasome inhibitors also have activity in animal models of autoimmune and inflammatory diseases, reperfusion injury, promote bone and hair growth, and can potentially be used as anti-infectives. In addition, inhibitors of ATPases and deubiquitinases of 19S regulatory particles have been discovered in the last decade.     

Selective inhibition of 6-phosphogluconate dehydrogenase from Trypanosoma brucei

A number of triphenylmethane derivatives have been screened against 6-phosphogluconate dehydrogenase from Trypanosoma brucei and sheep liver. Some of these compounds show good inhibition of the enzymes and also selectivity towards the parasite enzyme. Modelling was undertaken to dock the compounds into the active sites of both enzymes. Using a combination of DOCK 3.5 and FLEXIDOCK a correlation was obtained between docking score and both activity for the enzymes and selectivity. Visualisation of the docked structures of the inhibitors in the active sites of the enzymes yielded a possible explanation of the selectivity for the parasite enzyme.     

A QSAR model of PAHs carcinogenesis based on thermodynamic stabilities of biactive sites

Polycyclic aromatic hydrocarbons (PAHs) have been adopted to study the carcinogenesis of chemicals experimentally and theoretically. A model of carcinogenic activity of 48 PAHs was obtained based on the calculated relative thermodynamic stabilities of epoxide and carbonium intermediates of the PAHs. Using both epoxyl-energy and cationized-energy of two active sites, the model reasonably predicts the carcinogenic activity of these PAHs and shows a good ability to distinguish between carcinogenic and noncarcinogenic PAHs. Furthermore, the model suggests that double active sites and their distance characteristics are important factors in the chemical carcinogenesis of PAHs. The physical meaning of the energies corresponding addition reactions with DNA is also discussed.     

Catalytic activities of modified hydrolytic enzymes in organic media : syntheses of optically active trifluoromethylated compounds

Modifications of hydrolytic enzymes by incorporation of fluorine-containing molecules have been found to improve the catalytic activity of the parent enzymes. Syntheses of optically active compounds possessing a trifluoromethyl group, via enzymatic chiral Michael addition reaction and synthesis of heterocycles, have been undertaken in organic solvents.     

The importance of the long type 1 copper-binding loop of nitrite reductase for structure and function

The long 15-residue type 1 copper-binding loop of nitrite reductase has been replaced with that from the cupredoxin amicyanin (7 residues). This sizable loop contraction does not have a significant effect on the spectroscopy, and therefore, the structures of both the type 1 and type 2 Cu(II) sites. The crystal structure of this variant with Zn(II) at both the type 1 and type 2 sites has been determined. The coordination geometry of the type 2 site is almost identical to that found in the wild-type protein. However, the structure of the type 1 centre changes significantly upon metal substitution, which is an unusual feature for this class of site. The positions of most of the coordinating residues are altered of which the largest difference was observed for the coordinating His residue in the centre of the mutated loop. This ligand moves away from the active site, which results in a more open metal centre with a coordinating water molecule. Flexibility has been introduced into this region of the protein. The 200 mV increase in the reduction potential of the type 1 copper site indicates that structural changes upon reduction must stabilise the cuprous form. The resulting unfavourable driving force for electron transfer between the two copper sites, and an increased reorganisation energy for the type 1 centre, contribute to the loop variant having very little nitrite reductase activity. The extended type 1 copper-binding loop of this enzyme makes a number of interactions that are important for maintaining quaternary structure.     

Schilancidilactones A and B: two novel tetranortriterpenoids with an unprecedented skeleton from Schisandra lancifolia

Schilancidilactones A (1) and B (2), two novel tetranortriterpenoids possessing an unprecedented skeleton, have been isolated from the stems of Schisandra lancifolia. Their structures were elucidated on the basis of extensive spectroscopic analysis. The relative configurations of 1 were further determined by single-crystal X-ray crystallography. Compounds 1 and 2 were tested for their cytotoxicity against four tumor cell lines NB4, A549, SH-SY5Y, and PC-3, and compound 1 was further tested for its anti-HIV-1 activity.     

Rubriflordilactones A and B, two novel bisnortriterpenoids from Schisandra rubriflora and their biological activities

[STRUCTURE: SEE TEXT] Rubriflordilactones A (1) and B (2), two novel highly unsaturated rearranged bisnortriterpenoids possessing a biosynthetically modified aromatic D-ring, were isolated from the leaves and stems of Schisandra rubriflora. Their structures were established on the basis of extensive spectroscopic methods, including two-dimensional NMR techniques, and confirmed by X-ray crystallographic analysis. Compound 1 showed weak anti-HIV-1 activity, and compound 2 exhibited an EC50 value of 9.75 microg/mL (SI=12.39) against HIV-1 replication with low cytotoxicity.     

Synthesis of daunorubicin analogues containing truncated aromatic cores and unnatural monosaccharide residues

The anthracycline antibiotics daunorubicin and doxorubicin have been used widely as anticancer drugs, but their cardiotoxicity limits their clinical use. We describe here the preparation of a small panel of daunorubicin analogues in which the anthraquinone core is replaced with simpler aromatic moieties that lack a quinone functionality. The targets consist of a functionalized 1,2,3,4-tetrahydro-naphthalene or 1,2,3,4-tetrahydro-anthracene core bound to one of three monosaccharides: daunosamine, acosamine, or 4-amino-2,3,6-trideoxy-l-threo-hexopyranose. Key steps in the synthesis included an enantioselective ring opening of benzo-fused norbornene derivatives for the preparation of the core structures and the use of silver hexafluorophosphate-promoted thioglycoside activation in the glycosylation of these cores. Evaluation of these compounds against the MCF-7 cancer cell line demonstrated that the identity of the carbohydrate moiety appeared to have little influence on the cytotoxicity. Moreover, the analogues with the 1,2,3,4-tetrahydro-naphthalene core showed no cytotoxicity, while those possessing the 1,2,3,4-tetrahydro-anthracene moiety were more active. The IC50 values for the latter group of compounds were in the range of 94-134 microM, compared to 17 microM for doxorubicin and 5 microM for daunorubicin.     

New insights on the active species and mechanism of cytotoxicity of salan-Ti(IV) complexes: a stereochemical study

Following the discovery of cisplatin, much effort has been devoted to the exploration of transition metal complexes as cytotoxic agents. We have recently introduced the highly efficient C(2)-symmetrical salan-Ti(IV) family of complexes, demonstrating high cytotoxicity toward colon and ovarian cells and enhanced hydrolytic stability in mixed organic/water solutions. The effect of stereochemistry is hereby reported, by comparing the cytotoxic activity and hydrolysis of pure enantiomers and their racemic mixture for four complexes of this family with different aromatic substitutions: para-Me, para-Cl, ortho-Cl, and ortho-OMe. These complexes include the trans-diaminocyclohexyl bridge, which enables ligand-to-metal chiral induction to give solely the Δ isomer when starting from the R,R ligand and vice versa. Different activity is obtained for the different stereochemical forms (Δ, Λ, and rac) in two of the four complexes, where for the other two either all forms are inactive or all are highly active. Additionally, where not all are of similar activity, the racemic mixture is the least active of the three. We therefore conclude that the salan ligand is essential for the fruitful biological interaction, which probably involves a chiral cellular target. The activity of the racemate differing from that expected from a simple mixture of enantiomers operating separately may be explained by the involvement of a polynuclear active species, where different metal centers might be of different configurations. This is particularly supported by the different polynuclear products of hydrolysis obtained from an optically pure complex and from the racemic one, as analyzed crystallographically. The former is an all-R,R chiral C(1)-symmetrical homodimer, while the latter is an achiral R,R-S,SC(i)-symmetrical heterodimer obtained through chiral recognition.     

Microwave-assisted synthesis of 2-styrylquinoline-4-carboxylic acid derivatives to improve the toxic effect against Leishmania (Leishmania) amazonensis

The identification of new compounds is urgent to develop safe and efficacious candidates for leishmaniasis treatment, especially from natural products as a potential source of active molecules against neglected tropical parasite diseases. Inspired by the efficacious quinoline alkaloid microbial effects, we have previously reported the synthesis and biological activity of 2-phenylquinoline-4-carboxylic acids and poly-substituted quinolines against parasites. In this work, a series of eighteen 2-styryl-4-quinolinecarboxylic acids were synthesized under microwave irradiation settings obtaining from good to excellent yields (60%-90%), shorter reaction times (2 minutes), and eco-friendly experimental conditions. All these products were evaluated against infective forms of Leishmania (Leishmania) amazonensis, such as promastigotes and intracellular amastigotes, based on cytotoxicity assays, including host macrophage infection assays. Compounds 4 and 5 possessing a 2-chloro or 4-chlorostyryl moiety, respectively, were considered the most promising antileishmanial agents due to the parasite killing effect in intracellular forms inside infected macrophages. Thus, our results revealed that the 2-styryl-4-quinolinecarboxylic acid backbone structure was essential for the activity against intracellular pathogens like L. (L.) amazonensis.     

Detitanation of MgCl2‐supported Ziegler‐Natta catalysts for the study of active sites organization

Thermal treatments under vacuum of conventional supported Ziegler‐Natta precatalysts (MgCl₂/TiCl₄/Dibutylphthalate) were conducted to gradually remove titanium to modify the active sites distribution. Only limited detitanations of precatalysts were achieved paying attention not to chemically alter the internal donor (T < 150 °C). Used in combination with the required cocatalyst and external donor in the propylene slurry polymerization, the modified precatalysts exhibited a drop of activity versus decreasing titanium content but the distributed polymer properties are almost not affected (a slight narrowing of molecular weight distribution was observed). After a titanium chloride secondary impregnation (possibly done in presence of an additional Lewis base), activity resumed but polymer properties are once again unchanged. These findings highlight the difficulty to separate the different families of active sites and lead us to propose a cluster organization of titanium active sites. Active sites are composed of titanium clusters having a size distribution at the precatalyst surface, possessing a critical operating size and operating collectively in polymerization. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 5461–5470, 2008