One-Pot Multi-Component Synthesis and Biological Evaluation of Novel Indole-Pyrimidine Derivatives as Potent Anti-Cancer and Anti-Microbial Agents

Russian Journal of Bioorganic Chemistry - A series of novel hybrids of indole-pyrimidine moieties were synthesized and evaluated for their in vitro anti-cancer, in vitro anti-bacteria and...     

Synthesis of Quinoxlines Containing 1,2,3-Triazoles and Their Anti-Bacterial and Anti-Cancer Activity

Russian Journal of Bioorganic Chemistry - A series of 1-((1aryl)-1H-1,2,3-triazol-4-yl)methyl)quinoxalin-2(1H)-ones have been synthesized in moderate to high yields and evaluated for their...     

Study of Malformin C,a Fungal Source Cyclic Pentapeptide,as an Anti-Cancer Drug

Malformin C, a fungal cyclic pentapeptide, has been claimed to have anti-cancer potential, but no in vivo study was available to substantiate this property. Therefore, we conducted in vitro and in vivo experiments to investigate its anti-cancer effects and toxicity. Our studies showed Malformin C inhibited Colon 38 and HCT 116 cell growth dose-dependently with an IC₅₀ of 0.27±0.07μM and 0.18±0.023μM respectively. This inhibition was explicated by Malformin C’s effect on G2/M arrest. Moreover, we observed up-regulated expression of phospho-histone H2A.X, p53, cleaved CASPASE 3 and LC3 after Malformin C treatment, while the apoptosis assay indicated an increased population of necrotic and late apoptotic cells. In vivo, the pathological study exhibited the acute toxicity of Malformin C at lethal dosage in BDF1 mice might be caused by an acute yet subtle inflammatory response, consistent with elevated IL-6 in the plasma cytokine assay. Further anti-tumor and toxicity experiments proved that 0.3mg/kg injected weekly was the best therapeutic dosage of Malformin C in Colon 38 xenografted BDF1 mice, whereas 0.1mg/kg every other day showed no effect with higher resistance, and 0.9mg/kg per week either led to fatal toxicity in seven-week old mice or displayed no advantage over 0.3mg/kg group in nine-week old mice. Overall, we conclude that Malformin C arrests Colon 38 cells in G2/M phase and induces multiple forms of cell death through necrosis, apoptosis and autophagy. Malformin C has potent cell growth inhibition activity, but the therapeutic index is too low to be an anti-cancer drug.     

Essential Oils as Potent Source of Nematicidal Compounds

Bioassay tests were conducted to find out the nematicidal activity of eight essential oils against Meloidogyne incognita (Kofoid and White) Chitwood at four concentrations. Maximum activity was recorded in oils of Eucalyptus citriodora , Eucalyptus hybrida and Ocimum basilicum followed by Pelargonium graveolens , Cymbopogon martinii, Mentha arvensis, Mentha piperita and Mentha spicata oils, respectively. The eucalyptus ( E. citriodora and E. hybrida ) and Indian basil ( O. basilicum ) oils were highly toxic to M. incognita even at the lower concentrations, namely 500 and 250 ppm. The remaining oils were also toxic to the nematode but at different amounts.     

Carnivorous Plants as a Source of Potent Bioactive Compound: Naphthoquinones

Carnivorous plants are among the curiosities of nature being different from the normal plants in their mode of nutrition. These plants have fascinated several researchers for centuries. They are also characterized by synthesis of bioactive compounds which are used as a mechanism for self defense. These compounds possess a broad spectrum of biological activities such as antiparasitic, antibacterial, insecticidal, fungicidal, anti-inflammatory, antipyretic, antiproliferative activities. Although, several antimicrobial drugs have been introduced during the recent decades, the problems of microbial infections resistant to synthetic pesticides still exist which necessitate the introduction of novel antimicrobial agents with additional modes of actions than the currently available therapeutic agents. Naphthoquinones are one of the most studied bioactive compounds which have been reported to inhibit the growth of proliferative cells and microbes. Efforts have been made to induce the biosynthesis of naphthoquinone in different species of carnivorous plants. It has been demonstrated that the accumulation of naphthoquinones in carnivorous plants was increased by injecting chitin into the plant tissues. Also, their biosynthesis could be enhanced by the incorporation of elicitors in in vitro cultures of plants. In the present review, we discuss the applications of naphthoquinones and its biosynthesis in carnivorous plants.     

尿液作为新型生物标志物来源的探索

机体各种变化是生物标志物研究的核心内容.因为机体固有的稳态调控机制,在血液中早期产生的变化容易被清除.而在尿液中不存在稳态调控机制,允许容纳更多的变化因素存在.尤其在疾病发生的早期阶段,从尿液中更有可能发现新型的早期生物标志物.在尿液生物标志物研究中,亦应当考虑药物的影响.使用尿液生物标志物研究路线图,能够有效规避各种影响因素对于尿液生物标志物研究的干扰;同时,结合膜处理新技术,有利于经济、高效地大规模收集尿液样本,促进尿液生物标志物的大规模研究.另外,本文介绍了最容易在尿液中体现出变化的肾脏疾病生物标志物的研究进展.尿液生物标志物的研究,将赋予人类在疾病预防、诊断、治疗及预后监测等诸多方面实现更多进步的可能性.     

Characterization of a Novel Anti-Cancer Compound for Astrocytomas

The standard chemotherapy for brain tumors is temozolomide (TMZ), however, as many as 50% of brain tumors are reportedly TMZ resistant leaving patients without a chemotherapeutic option. We performed serial screening of TMZ resistant astrocytoma cell lines, and identified compounds that are cytotoxic to these cells. The most cytotoxic compound was an analog of thiobarbituric acid that we refer to as CC-I. There is a dose-dependent cytotoxic effect of CC-I in TMZ resistant astrocytoma cells. Cell death appears to occur via apoptosis. Following CC-I exposure, there was an increase in astrocytoma cells in the S and G2/M phases. In in vivo athymic (nu/nu) nude mice subcutaneous and intracranial tumor models, CC-I completely inhibited tumor growth without liver or kidney toxicity. Molecular modeling and enzyme activity assays indicate that CC-I selectively inhibits topoisomerase IIα similar to other drugs in its class, but its cytotoxic effects on astrocytoma cells are stronger than these compounds. The cytotoxic effect of CC-I is stronger in cells expressing unmethylated O⁶-methylguanine methyltransferase (MGMT) but is still toxic to cells with methylated MGMT. CC-I can also enhance the toxic effect of TMZ on astrocytoma when the two compounds are combined. In conclusion, we have identified a compound that is effective against astrocytomas including TMZ resistant astrocytomas in both cell culture and in vivo brain tumor models. The enhanced cytotoxicity of CC-I and the safety profile of this family of drugs could provide an interesting tool for broader evaluation against brain tumors.     

Use of Laccase as a Novel, Versatile Reporter System in Filamentous Fungi

Laccases are copper-containing enzymes which oxidize phenolic substrates and transfer the electrons to oxygen. Many filamentous fungi contain several laccase-encoding genes, but their biological roles are mostly not well understood. The main interest in laccases in biotechnology is their potential to be used to detoxify phenolic substances. We report here on a novel application of laccases as a reporter system in fungi. We purified a laccase enzyme from the ligno-cellulolytic ascomycete Stachybotrys chartarum. It oxidized the artificial substrate 2,2′-azino-di-(3-ethylbenzthiazolinsulfonate) (ABTS). The corresponding gene was isolated and expressed in Aspergillus nidulans, Aspergillus niger, and Trichoderma reesei. Heterologously expressed laccase activity was monitored in colorimetric enzyme assays and on agar plates with ABTS as a substrate. The use of laccase as a reporter was shown in a genetic screen for the isolation of improved T. reesei cellulase production strains. In addition to the laccase from S. charatarum, we tested the application of three laccases from A. nidulans (LccB, LccC, and LccD) as reporters. Whereas LccC oxidized ABTS (K_m= 0.3 mM), LccD did not react with ABTS but with DMA/ADBP (3,5-dimethylaniline/4-amino-2,6-dibromophenol). LccB reacted with DMA/ADBP and showed weak activity with ABTS. The different catalytic properties of LccC and LccD allow simultaneous use of these two laccases as reporters in one fungal strain.     

6-Cyclopropylpurines as Novel Potent Analogs of Cytokinins

6-Alkynyl-, trans-6-alkenyl-, trans-6-cyclopropyl-and 6-alkylpurines structurally related to the cytokinin 6-benzylaminopurine (BAP) have been synthesized and examined with a radish cotyledon assay as plant growth stimulators. The growth stimulation obtained with the 6-alkylpurines trans-cyclopropylpurines was very close to that obtained with BAP, and the trans-styrylpurines were somewhat less effective. The fact that the conformationally locked cyclopropanes exhibit growth-stimulating effects comparable to the flexible 6-alkylpurines and to BAP, supports the hypothesis that the orientation of the NH-CH₂ bond in “the active conformation” of BAP is close to anti, which means that the torsion angle C(6)-N(6)-CH₂-C is approximately 180 degrees.     

食用菌多糖的提取纯化及生物活性研究进展

食用菌多糖因具有抗氧化、免疫调节、抗肿瘤、降血糖、降血脂等生物活性而备受关注。食用菌多糖的结构影响其生物活性,具有(1→3)、(1→4)、(1→6)及混合糖苷键的β-D-葡聚糖是高活性食用菌多糖的结构特征之一,展现出提高抗氧化酶活性、促进分泌抗癌因子、刺激脾脏和胸腺细胞增殖等不同功能。酸碱、超声波及微波、Sevag法、树脂法、亲和层析等不同提取纯化方法会影响食用菌多糖得率,同时会改变食用菌多糖结构,影响其生物活性。详述食用菌多糖的提取纯化方法及其对结构与活性的影响,食用菌多糖的组成结构和构效关系,以及食用菌多糖在抗氧化、抗肿瘤、免疫调节、降血糖和降血脂等方面的功能、结构特征及生物活性,并提出了食用菌多糖形成的分子机制、多糖活性位点修饰、多糖代谢动力学等未来研究方向。     

Design,Synthesis, and Bioactivity Evaluation of Novel Rosin Diterpenoid Derivatives as Potential Anti-glioma Agents

Glioma is the most common brain tumor and its treatment options are limited. Abietic acid and dehydroabietic acid are tricyclic diterpenoid oxygen compounds with strong lip solubility and anti-glioma activity. In this study, novel rosin diterpenoid derivatives were designed and synthesized using abietic acid and dehydrogenated abietic acid as lead compounds and their activities against T98G, U87MG, and U251 cells were evaluated by CCK-8 methods. The in vivo activity of compounds with stronger activity in vitro was preliminarily studied through the Zebrafish model. The results showed that the IC₅₀ values of B6 , B8 , B10 , and B12 were 11.47 to 210.6 μM, which were exhibited higher antiproliferative potency against T98G, U87MG, and U251. The scratch experiment showed that B12 inhibited the migration of T98G in a time-dependent and concentration-dependent manner. The results of in vivo activity further explained that B12 could inhibit the proliferation of the T98G. The pKa values of B6 , B8 , B10 , and B12 were 7.17 to 7.35, which were within the ideal range of glioma drugs. The ADME predictions indicated that these derivatives could pass through the blood-brain barrier. In addition, molecular docking primarily explained interaction between compounds and protein. These results suggested that B12 should be a promising candidate that merits further attention in the development of anti-glioma drugs.     

Design and SAR Study of a Novel Class of Nucleotide Analogues as Potent Anti-HCMV Agents

Abstract

We have developed a novel class of 2-phosphonate 1,3-dioxolane nucleotide analogues, from which the guanine derivative displayed weak anti-HCMV activity. Further SAR studies led to the identification of both cis and trans guanine derivatives of tetrahydrofuran analogues as potent anti-HCMV agents, both in vitro and in vivo, compared to ganciclovir and HPMPC.     

Structural Abnormalities in the Hair of a Patient with a Novel Ribosomopathy

We report the biophysical characterization of hair from a patient with a de novo ribosomopathy. The patient was diagnosed with a mutation on gene RPS23, which codes for a protein which comprises part of the 40S subunit of the ribosome. The patient presents with a number of phenotypes, including hypotonia, autism, extra teeth, elastic skin, and thin/brittle hair. We combined optical microscopy, tensile tests, and X-ray diffraction experiments on hair samples obtained from the scalp of the patient to a multi-scale characterization of the hair from macroscopic to molecular length scales and observe distinct differences in the biophysical properties in the patient’s hair when compared to hair from other family members. While no differences were observed in the coiled-coil structure of the keratin proteins or the structure of the intermediate filaments, the patient’s hair was 22% thinner, while the Young’s modulus remained roughly constant. The X-ray diffraction results give evidence that the amount of lipids in the cell membrane complex is reduced by 20%, which well accounts for the other observations. The pathologies characterized by these techniques may be used to inform the diagnosis of similar de novo mutations in the future.     

Synthesis,Molecular Modeling,and Biological Evaluation of Novel Chiral Thiosemicarbazone Derivatives as Potent Anticancer Agents

A series of new chiral thiosemicarbazones derived from homochiral amines in both enantiomeric forms were synthesized and evaluated for their in vitro antiproliferative activity against A549 (human alveolar adenocarcinoma), MCF‐7 (human breast adenocarcinoma), HeLa (human cervical adenocarcinoma), and HGC‐27 (human stomach carcinoma) cell lines. Some of compounds showed inhibitory activities on the growth of cancer cell lines. Especially, compound 17b exhibited the most potent activity (IC₅₀ 4.6 μM) against HGC‐27 as compared with the reference compound, sindaxel (IC₅₀ 10.3 μM), and could be used as a lead compound to search new chiral thiosemicarbazone derivatives as antiproliferative agents. Chirality 27:177–188, 2015. © 2014 Wiley Periodicals, Inc.     

嗜热菌——工业用酶的新来源

综述了嗜热菌和极端嗜热菌产生的热稳定性的淀粉酶、纤维素酶、环糊精酶、木聚糖酶、几丁质酶、葡萄糖异构酶、蛋白酶等的研究进展及其在食品、化工、环保等方面的应用前景。     

Synthesis and Bioactivity of Novel Acetylenic Compounds

The synthesis of novel acetylenic ketone compounds and anti-inflammatory and antimicrobial activities are herein described.     

Novel Synthesis,Reactions, and Biological Study of New Morpholino-Thieno[2,3-c][2,7]Naphthyridines as Anti-Cancer and Anti-Microbial Agents

Russian Journal of Bioorganic Chemistry - The biological uses of 2,7-naphthyridines have sparked great attention in recent years. For this reason, we synthesized a series of novel...