白藜芦醇及其衍生物和类似物抗肿瘤研究进展

白藜芦醇具有广泛的生物学活性,尤其是抗肿瘤作用备受关注,得到了广泛研究。同时,为了提高生物利用度,并获得更高的抗肿瘤活性,有关其衍生物与类似物的研究也大量开展。本文对白藜芦醇的结构及理化性质、抗肿瘤作用机制、毒性、代谢动力学、白藜芦醇衍生物和类似物的抗肿瘤活性及作用机制,以及制备方法进行了回顾。作为一类很有希望的的新型抗肿瘤药物,有关白藜芦醇及其衍生物和类似物还存在许多需要继续研究的问题,包括生物作用机制、结构与活性的关系不明确、生物利用度与疗效之间存在的矛盾以及体内药代动力学研究的缺乏等,还需要系统开展作用机制、毒理学和代谢动力学研究以及动物体内试验。     

Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells

Despite the continuous developments in pharmacology and the high therapeutic effect of new treatment options for patients with hematological malignancies, these diseases remain a major health issue. Our study aimed to synthesize, analyze in silico, and determine the biological properties of new melphalan derivatives. We obtained three methyl esters of melphalan having in their structures amidine moieties substituted with thiomorpholine (EM–T–MEL), indoline (EM–I–MEL), or 4-(4-morpholinyl) piperidine (EM–MORPIP–MEL). These have not yet been described in the literature. The in vitro anticancer properties of the analogs were determined against THP1, HL60, and RPMI8226 cells. Melphalan derivatives were evaluated for cytotoxicity (resazurin viability assay), genotoxicity (alkaline comet assay), and their ability to induce apoptosis (Hoechst33342/propidium iodide double staining method; phosphatidylserine translocation; and caspase 3/7, 8, and 9 activity measurements). Changes in mitochondrial membrane potential were examined using the specific fluorescence probe JC–1 (5,5′,6,6′-tetrachloro-1,1′,3,3′–tetraethylbenzimidazol carbocyanine). The EM–T–MEL derivative had the highest biological activity, showing higher cytotoxic and genotoxic properties than the parent drug. Moreover, it showed a high ability to induce apoptosis in the tested cancer cells. This compound also had a beneficial effect in peripheral blood mononuclear cells (PBMC). In conclusion, we verified and confirmed the hypothesis that chemical modifications of the melphalan structure improved its anticancer properties. The conducted study allowed the selection of the compound with the highest biological activity and provided a basis for chemical structure-biological activity analyses.     

卡拉胶的生物活性及分子修饰研究进展

卡拉胶作为一种结构独特的硫酸多糖,具有多种生物活性,但因分子量过大,使其在生物医药领域的应用受到限制。文章简要介绍了近年来有关卡拉胶抗病毒、抗肿瘤、抗凝血等生物活性的研究,进一步介绍了卡拉胶分子修饰及其衍生物生物活性的研究进展。     

<Emphasis Type="Italic">Jatropha</Emphasis> Diterpenes: a Review

Terpenes are the largest group of phytochemicals that exhibit diverse functions in mediating antagonistic and beneficial interactions in, and among, organisms. For many years the abundance and distribution of terpenoid compounds in plants have benefitted both nature and human civilization. Jatropha species, belonging to the family Euphorbiaceae, are a rich source of terpenoid compounds. Among the terpenes, diterpenoid compounds have dominated the research area in Jatropha species with respect to their novel chemical structures and medicinal values. The present review describes the chemistry and biological activities of an array of Jatropha diterpenes. The diterpenes isolated from Jatropha species belongs to rhamnofolane, daphnane, lathyrane, tigliane, dinorditerpene, deoxy preussomerin and pimarane skeletal structures. Among the 68 diterpenes collated in this review, the biological activity of compounds varied distinctly—the majority of the diterpenes exhibited cytotoxic, antitumor and antimicrobial activities in vitro. To name a few, jatrophone, spruceanol and jatrophatrione exhibited antitumor properties against P338 lymphocytic leukemia and japodagrol against KB carcinoma cells. Whereas, curcusone B exhibited anti-invasive effects against cholangiocarcinoma cells. The phorbol esters (Jatropha factor C1–C6) and Jatropherol exhibited insect deterrent/cytotoxic properties. Many diterpenes (jatrophalactam, faveline derivatives, multifolone, curcusone, jatrophone derivatives etc.) showed in-vitro cytotoxic activity, while japodagrin, jatrogrossidione derivatives and jatropholone derivatives exhibited antimicrobial activities. Jatropha diterpenoids having a wide spectrum of bioactivity could form lead compounds or could be used as templates for the synthesis of new compounds with better biological activity for utilization in the pharmaceutical industries.     

Synthesis,Cytotoxicity, Induction of Apoptosis,and Interaction with DNA of Dinuclear Platinum(II) Complexes

Six dicarboxylato‐bridged dinuclear platinum(II) complexes S1 – S6 , with a newly designed chiral ligand, 2‐{[(1R,2R)‐2‐aminocyclohexyl]amino}propanoic acid ( HL ), were prepared and spectrally characterized. The in vitro cytotoxicity of all resulting platinum(II) complexes was evaluated against human HCT‐116, MCF‐7, and HepG‐2 tumor cell lines. The results show that all compounds exhibit positive biological activity toward HCT‐116 and MCF‐7 cell lines, of which complexes S3 , S4 , and S5 , with succinate and its derivatives as bridges, showing better activity than the positive controls. Moreover, double‐dyeing flow cytometric resection experiments indicate that the target compounds inhibit tumor cell growth by inducing apoptosis; gel electrophoresis experiments demonstrate the compounds′ ability to prompt pET22b plasmid DNA degradation in almost the same way as oxaliplatin.     

Zinc Coordination Compounds with Benzimidazole Derivatives: Synthesis,Structure, Antimicrobial Activity and Potential Anticancer Application

Developing new, smart drugs with the anticancer activity is crucial, especially for cancers, which cause the highest mortality in humans. In this paper we describe a series of coordination compounds with the element of health, zinc, and bioactive ligands, benzimidazole derivatives. By way of synthesis we have obtained four compounds named C1, C2, C4 and C4. Analytical analyses (elemental analysis (EA), flame atomic absorption spectrometry (FAAS)), spectroscopic (Fourier transform infrared spectroscopy (FT-IR), mass spectrometry (MS)) and thermogravimetric (TG) methods and the definition of crystal structures were used to explore the nature of bonding and to elucidate the chemical structures. The collected analytical data allowed the determination of the stoichiometry in coordination compounds, thermal stability, crystal structure and way of bonding. The cytotoxicity effect of the new compounds as a potential antitumor agent on the glioblastoma (T98G), neuroblastoma (SK-N-AS) and lung adenocarcinoma (A549) cell lines and human normal skin fibroblasts (CCD-1059Sk) was also determined. Cell viability was determined by the MTT assay. The results obtained confirmed that conversion of ligands into the respective metal complexes significantly improved their anticancer properties. The complexes were screened for antibacterial and antifungal activities. The ADME technique was used to determine the physicochemical and biological properties.     

Cytostatic activity of 1,10-phenanthroline derivatives generated by the clip-phen strategy

The cytostatic activities of a series of twelve 1,10-phenanthroline (Phen) derivatives and of their copper complexes were studied on L1210 murine leukemia cells. Large increases in the biological activity were observed for compounds of the 3-Clip-Phen series, in which two Phen moieties were bridged at their C3 positions by an alkoxy linker, the 3-pentyl-Clip-Phen derivative showing an IC(50) value of 130 nM while Phen shows an IC(50) value of 2500 nM under the same conditions. IC(50) values seemed to be modulated not only by the position, the nature, and the length of the linker of Clip-Phen but also by hydrophobicity. Since copper complexes of Phen are chemical nucleases and nucleic acids are thus a potential target for these compounds, the corresponding copper complexes were also studied. Copper complexation of the 3-Clip-Phen ligands did not increase their biological activities. Attempts to vectorize 3-Clip-Phen derivatives with a DNA binder such as spermine or with a cell-penetration peptide failed to increase their biological activity relative to the original 3-Clip-Phen series.     

白藜芦醇及其类似物和衍生物的药理学研究进展

对白藜芦醇的化学结构及理化性质、抗肿瘤作用机制、遗传毒性、代谢动力学以及白藜芦醇类似物和衍生物的抗肿瘤活性及作用机制进行了综述。     

壳聚糖类金属配合物的合成及应用

壳聚糖是一种氨基取代多糖,无毒、可降解,具有良好的生物活性和生物相容性,分子结构中的羟基和氨基可与金属配位形成配合物,多数配合物的生物活性（抑菌、清除氧自由基和吸附低分子量毒物等）与壳聚糖的相比,均有不同程度的提高,综述了壳聚糖类金属配合物的合成方法和在医学、医药领域中的应用。     

Homogeneous catalysts for ethylene polymerization based on bis(imino)pyridine complexes of iron, cobalt, vanadium and chromium

Results of a comparative study of ethylene polymerization activity and the structure of polyethylene (PE) produced over homogeneous catalysts based on bis(imino)pyridine complexes with close ligand frameworks and different transition metal centers (Fe(II), Co(II), Cr(III) and V(III)) are reported. The effects of the activator nature and polymerization conditions on the activity of these complexes and the resulting PE structure (molecular weight, molecular weight distribution, content of methyl and vinyl groups) have been studied. The experimental data obtained under comparable conditions demonstrate a pronounced effect of transition metal center on the catalytic properties of bis(imino)pyridine complexes (polymerization activity, copolymerization reactivity, thermal stability, PE structure, composition of optimal activator, formation of single-site or multiple-site catalytic system).     

Phenanthroline derivatives with improved selectivity as DNA-targeting anticancer or antimicrobial drugs

Phenanthroline derivatives are of interest due to their potential activity against cancer, and viral, bacterial, and fungal infections. In a search for highly specific antitumor and antibacterial compounds, we report the activities of 1,10-phenanthroline-5,6-dione (phendione or L(1)), dipyrido[3,2-a:2',3'-c]phenazine (dppz or L(2)), and their corresponding platinum complexes ([PtL(1)Cl2] and [PtL(2)Cl2]), and provide the solid-state 3D structure for [PtL(1)Cl2]. It is generally known that a toxic metal ion coordinated to an active organic moiety leads to a synergistic effect; however, we report herein that the platinum complexes [PtL(1)Cl2] and [PtL(2)Cl2] have weaker activities relative to those of the free ligands, especially against bacteria. Testing these agents against a variety of human cancer cell lines revealed that L(1) and [PtL(1)Cl2] were at least as active as cisplatin against several of the cell lines (including a cisplatin-resistant cell line). The absence of antibacterial activity of [PtL(1)Cl2] removes the detrimental effect of phenanthrolines toward intestinal flora, suggesting a highly promising new strategy for the development of anticancer drugs with reduced side effects.     

Polymerization of Methylthiirane initiated by platinum(II)- and palladium(II)-complexes

Summary Some complexes derived from platinum(II) and palladium(II) initiate stereospecific polymerization of methylthiirane in homogeneous phase.When the metal environment is chiral no stereoelective polymerization occurs. The mechanism of polymerization initiated by platinum complexes seems to be similar to those proposed for zinc or cadmium derivatives whereas analogies are apparent between palladium and some aluminum derivatives, especially in the formation of great amounts of disulfide bonds during the polymerization.     

Application of molecular topology for the prediction of reaction yields and anti-inflammatory activity of heterocyclic amidine derivatives

Topological-mathematical models based on multiple linear regression analyses have been built to predict the reaction yields and the anti-inflammatory activity of a set of heterocylic amidine derivatives, synthesized under environmental friendly conditions, using microwave irradiation. Two models with three variables each were selected. The models were validated by cross-validation and randomization tests. The final outcome demonstrates a good agreement between the predicted and experimental results, confirming the robustness of the method. These models also enabled the screening of virtual libraries for new amidine derivatives predicted to show higher values of reaction yields and anti-inflammatory activity.     

Influence of Complexation of Thiosemicarbazone Derivatives with Cu (II) Ions on Their Antitumor Activity against Melanoma Cells

A series of thiosemicarbazone derivatives was prepared and their anti-tumor activity in vitro was tested. The X-ray investigation performed for compounds T2, T3 and T5 confirmed the synthesis pathway and assumed molecular structures of analyzed thiosemicarbazones. The conformational preferences of the thiosemicarbazone system were characterized using theoretical calculations by AM1 method. Selected compounds were converted into complexes of Cu (II) ions. The effect of complexing on anti-tumor activity has been investigated. The copper(II) complexes, with Schiff bases T1, T10, T12, T13, and T16 have been synthesized and characterized by chemical and elemental analysis, FTIR spectroscopy and TGA method. Thermal properties of coordination compounds were studied using TG-DTG techniques under dry air atmosphere. G361, A375, and SK-MEL-28 human melanoma cells and BJ human normal fibroblast cells were treated with tested compounds and their cytotoxicity was evaluated with MTT test. The compounds with the most promising anti-tumour activity were then selected and their cytotoxicity was verified with cell cycle analysis and apoptosis/necrosis detection. Additionally, DNA damages in the form of a basic sites presence and the expression of oxidative stress and DNA damage response genes were evaluated. The obtained results indicate that complexation of thiosemicarbazone derivatives with Cu (II) ions improves their antitumor activity against melanoma cells. The observed cytotoxic effect is associated with DNA damage and G2/M phase of cell cycle arrest as well as disorders of the antioxidant enzymes expression.     

Conjugation of Cisplatin Analogues and Cyclooxygenase Inhibitors to Overcome Cisplatin Resistance

Cyclooxygenase (COX) is an enzyme involved in tumorigenesis and is associated with tumor cell resistance against platinum‐based antitumor drugs. Cisplatin analogues were conjugated with COX inhibitors (indomethacin, ibuprofen) to study the synergistic effects that were previously observed in combination treatments. The conjugates ensure concerted transport of both drugs into cells, and subsequent intracellular cleavage enables a dual‐action mode. Whereas the platinum(II) complexes showed cytotoxicities similar to those of cisplatin, the platinum(IV) conjugates revealed highly increased cytotoxic activities and were able to completely overcome cisplatin‐related resistance. Although some of the complexes are potent COX inhibitors, the conjugates appear to execute their cytotoxic action via COX‐independent mechanisms. Instead, the increased lipophilicity and kinetic inertness of the conjugates seem to facilitate cellular accumulation of the platinum drugs and thus improve the efficacy of the antitumor agents. These conjugates are important tools for the elucidation of the direct influence of COX inhibitors on platinum‐based anticancer drugs in tumor cells.     

基于5-FU开发抗肿瘤药物的最新进展

5-氟尿嘧啶及其衍生物是临床上一类抗瘤谱广、效率高的抗代谢药物。寻求高效低毒、高选择性和高靶向性的5-氟尿嘧啶衍生物是目前抗肿瘤药物研究领域的一个热点。本文对5-氟尿嘧啶的各种结构修饰及其生物活性研究进行了总结,将为5-氟尿嘧啶衍生物的研究产生较大的促进作用。     

Mechanism of Anticancer Action of Novel Imidazole Platinum(II) Complex Conjugated with G2 PAMAM-OH Dendrimer in Breast Cancer Cells

Transition metal coordination compounds play an important role in the treatment of neoplastic diseases. However, due to their low selectivity and bioavailability, as well as the frequently occurring phenomenon of drug resistance, new chemical compounds that could overcome these phenomena are still being sought. The solution seems to be the synthesis of new metal complexes conjugated with drug carriers, e.g., dendrimers. Numerous literature data have shown that dendrimers improve the bioavailability of the obtained metal complexes, solving the problem of their poor solubility and stability in an aqueous environment and also breaking down inborn and acquired drug resistance. Therefore, the aim of this study was to synthesize a novel imidazole platinum(II) complex conjugated with and without the second-generation PAMAM dendrimer (PtMet2–PAMAM and PtMet2, respectively) and to evaluate its antitumor activity. Cell viability studies indicated that PtMet2–PAMAM exhibited higher cytotoxic activity than PtMet2 in MCF-7 and MDA-MB-231 breast cancer cells at relatively low concentrations. Moreover, our results indicated that PtMet2–PAMAM exerted antiproliferative effects in a zebrafish embryo model. Treatment with PtMet2–PAMAM substantially increased apoptosis in a dose-dependent manner via caspase-9 (intrinsic pathway) and caspase-8 (extrinsic pathway) activation along with pro-apoptotic protein expression modulation. Additionally, we showed that apoptosis can be induced by activating POX, which induces ROS production. Furthermore, our results also clearly showed that the tested compounds trigger autophagy through p38 pathway activation and increase Beclin-1, LC3, AMPK, and mTOR inhibition. The high pro-apoptotic activity and the ability to activate autophagy by the imidazole platinum(II) complex conjugated with a dendrimer may be due to its demonstrated ability to reverse multidrug resistance (MDR) and thereby increase cellular accumulation in breast cancer cells.     

Complex of cisplatin with biocompatible poly(ethylene glycol) with pendant carboxyl groups for the effective treatment of liver cancer

Cisplatin was incorporated into polymeric carriers through the coordination of Pt with the carboxylic groups of methoxy‐poly(ethylene glycol) (mPEG)‐block‐poly[(2‐carboxy‐ethylsulfanyl)‐propyl glycidyl ether] (PCPGE). The mPEG‐b‐PCPGE/Pt complexes with a Pt content of 14 wt % could self‐assemble into spheric micelles with diameter of about 80 nm in aqueous solution. The effective internalization of the polymer platinum micelles by the cells via an endocytosis mechanism was confirmed by confocal laser scanning microscopy and flow cytometry. The antitumor activity of the polymeric micelles was similar to that of cisplatin in vitro. The in vivo blood clearance of platinum was studied, and the results show that the micelles exhibited longer blood circulation than the free cisplatin. The biodistribution of cisplatin and its micelles in mice was studied through the measurement of the Pt content in plasma, organs, and tumors, especially in tumor cell DNA. Their antitumor activity in vivo, assessed in mice bearing H22 liver cancers, showed that the micelles exhibited greater antitumor efficacy than free cisplatin. Therefore, this polymer platinum micelle is a promising candidate as a smart antitumor drug carrier for malignancy therapy in future clinical applications. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40764.     

Microemulsions in the preparation of highly active combustion catalysts

Catalytic activity in combustion of toluene in toluene–air mixtures and physical–chemical properties of platinum catalysts prepared from reverse microemulsions (water-in-oil) and by classical impregnation from water solutions of H₂PtCl₆ were studied. Microemulsion catalysts were more active than those prepared classically from water solutions. Size of Pt in classically impregnated catalysts was three times higher than that of catalysts prepared from microemulsions. In case of microemulsion preparation method, platinum is located near the pellet surface or its position in the pellet can be optimised. The effect of oil used in microemulsion system seems to be negligible for the activity of the catalysts with 0.1 wt.% Pt.     

A New Class of Luminescent Platinum(II) Complexes of 1,3-Bis(N-alkylbenzimidazol-2′-yl)benzene-Type Ligands and Their Application Studies in the Fabrication of Solution-Processable Organic Light-Emitting Devices

A novel class of luminescent platinum(II) bzimb (1,3-bis(N-alkylbenzimidazol-2′-yl)benzene) complexes has been designed and synthesized. With the incorporation of various substituents on the anionic phenyl ring of the bzimb ligand, the emission color can be readily tuned. Their photophysical, electrochemical and electroluminescence properties have been studied. These platinum(II) bzimb complexes have been demonstrated to be capable of serving as phosphorescent dopants. Efficient solution-processable OLEDs (organic light-emitting devices), with a maximum external quantum efficiency of up to 4.85 %, can be achieved. This class of platinum(II) bzimb complexes represents a promising class of phosphorescent dopants for solution-processable OLEDs.