A thiol-inducible and quick-response DNA cross-linking agent

Three new 2,4-dinitrobenzenesulfonyl derivatives 1–3 were successfully prepared for the first time using a simple process. They were efficiently triggered by thiols (glutathione and l-cysteine) to release the corresponding phenol derivatives (4–6) within 5?min. The quick response of 1–3 toward thiols was determined by ¹H NMR and HPLC. Moreover, our results indicated that 1 could induce DNA cross-linking in the presence of glutathione, probably due to the quinone methide formation of phenol intermediate 4 followed by departure of 2,4-dinitrobenzenesulfonyl group.     

Synthesis of 2-,4,-6-, and/or 7-substituted quinoline derivatives as human dihydroorotate dehydrogenase (hDHODH) inhibitors and anticancer agents: 3D QSAR-assisted design

Following our research for human dihydroorotate dehydrogenase (hDHODH) inhibitors as anticancer agents, herein we describe 3D QSAR-based design, synthesis and in vitro screening of 2-,4,-6-, and/or 7-substituted quinoline derivatives as hDHODH inhibitors and anticancer agents. We have designed 2-,4,-6-, and/or 7-substituted quinoline derivatives and predicted their hDHODH inhibitory activity based on 3D QSAR study on 45 substituted quinoline derivatives as hDHODH inhibitors, and also predicted toxicity. Designed compounds were docked into the binding site of hDHODH. Designed compounds which showed good predictive activity, no toxicity, and good docking score were selected for the synthesis, and in vitro screening as hDHODH inhibitors in an enzyme inhibition assay, and anticancer agents in MTT assay against cancer cell lines (HT-29 and MDA-MB-231). Synthesized compounds 7 and 14 demonstrated IC₅₀ value of 1.56?µM and 1.22?µM, against hDHODH, respectively, and these are our lead compounds for the development of new hDHODH inhibitors and anticancer agents.     

Structure-activity relationship of leucyladenylate sulfamate analogues as leucyl-tRNA synthetase (LRS)-targeting inhibitors of Mammalian target of rapamycin complex 1 (mTORC1)

Leucyl-tRNA synthetase (LRS) plays an important role in amino acid-dependent mTORC1 signaling, which is known to be associated with cellular metabolism and proliferation. Therefore, LRS-targeting small molecules that can suppress mTORC1 activation may provide an alternative strategy to current anticancer therapy. In this work, we developed a library of leucyladenylate sulfate analogues by extensively modifying three different pharmacophoric regions comprising adenine, ribose and leucine. Several effective compounds were identified by cell-based mTORC1 activation assays and further tested for anticancer activity. The selected compounds mostly exhibited selective cytotoxicity toward five different cancer cell lines, supporting the hypothesis that the LRS-mediated mTORC1 pathway is a promising alternative target to current therapeutic approaches.     

Discovery of 4′-OH-flurbiprofen Mannich base derivatives as potential Alzheimer’s disease treatment with multiple inhibitory activities

A series of 4′-OH flurbiprofen Mannich base derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound 8n demonstrated the best inhibitory effects on self-induced Aβ_1-42 aggregation (65.03% at 25.0?μM). Moreover, this representative compound also exhibited good antioxidant activity, biometal chelating ability and anti-neuroinflammatory activity in vitro. Furthermore, compound 8n displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 8n as promising candidate for further development of multi-functional drugs against AD.     

Chemical synthesis and functional characterization of a new class of ceramide analogues as anti-cancer agents

Deregulation of ceramide metabolism is a hallmark of human cancer. Ceramide analogues thereby represent a new class of anti-cancer agents. We aimed at developing effective and low toxic ceramide analogues and synthesized a new class of ceramide analogues starting from l-threonine. Several analogues exhibit potent cytotoxicity against human cancer cells in vitro with IC₅₀ as low as 4.8?μM. These ceramide analogues decreased xIAP and Bcl-xL level and exhibited significant sensitization activity to overcome human cancer cell resistance to TRAIL, a cancer-selective agent that are being tested in human clinical trials. Furthermore, we determined that these ceramide analogues effectively suppress human cancer xenograft growth in vivo with no significant toxicity at the efficacious dose. Therefore, we have developed a simple and effective method to synthesize functional ceramide analogues using l-threonine as starting material and these analogues have the great potential to be further developed as anti-cancer agents in human cancer therapy.     

Mating preferences of two species of Eccritotarsus (Hemiptera: Miridae)

ABSTRACT

Eccritotarsus spp. are biological control agents that have been sourced from Brazil and Peru to control water hyacinth in South Africa. These agents have been released in over 30 sites and were thought to be the same species. The sequencing of mitochondrial DNA and interbreeding experiments have since confirmed the cryptic species to be separate species. The Brazilian population remains E. catarinensis while the Peruvian population is now E. eichhorniae. This paper assessed the mating behaviour of both species, to investigate behavioural traits that have resulted in reproductive isolation, which could have led to speciation. Mating choices in a form of no-choice, bi-choice and multi-choice tests were conducted within and between species in a 3:1, 2:1 and 1:1 sex ratio. The E. eichhorniae pair had more single and multiple copula incidences, higher average total copula duration and higher copula latency while the E.catarinensis♀×E.eichhorniae♂ pair had less single and multiple copula incidences, lower average total copula duration and lower copula latency. When the E.eichhorniae♀ and E.catarinensis♂ were given their respective choices, they only mated with conspecifics. However, when E.eichhorniae♀ are crossed with E.catarinensis♂ they do not produce offspring. These results suggest that interbreeding will be limited in South Africa.     

磁性纳米材料的生物医学应用进展

以四氧化三铁为代表的医用磁性纳米材料具有独特的磁学性能、表面易功能化、良好的生物学相容性等特点,在纳米医学相关领域展现出巨大的应用前景,特别是近年来它作为可介导外场的智能材料,在材料设计和生物医学应用方面均取得了突破性的进展.鉴于此,本文围绕磁性氧化铁纳米材料的生物医学应用,着重介绍近年来其在磁共振影像探针、磁热和磁力效应的生物医学应用、诊疗一体化以及纳米酶催化等领域的研究进展,并对磁性纳米材料在生物医学领域未来的发展方向进行了展望.     

微生态制剂在胃肠道疾病中的临床应用

微生态制剂(microbial ecological agents, MEA)是利用益生菌及其代谢产物而制成的一种药物制剂。MEA主要是通过补充有益的微生物来重建人体肠道内的菌群平衡,以治疗多种胃肠道疾病。现就近年来MEA在胃肠道中的作用机制,以及在防治炎症性肠病、与抗生素相关的腹泻、幽门螺杆菌感染和慢性肝病等疾病中的临床应用作一概述,为更好地开发和利用MEA治疗疾病奠定基础。     

芽孢杆菌dhs-330-021菌粉的制备及稳定性研究

目的:利用喷雾干燥工艺制备芽孢杆菌dhs-330-021菌粉,并研究菌粉的活性及稳定性。方法:以脱脂乳、海藻糖、β-环糊精和谷氨酸钠为保护剂,采用喷雾干燥(条件为:进口温度100℃,出口温度50～60℃,进样速度2～4mL/min)制备芽孢杆菌菌粉,以喷干存活率和菌粉活菌数为指标,选择最佳制备条件。结果:获得喷干保护剂配方为脱脂乳10.0%、海藻糖6.0%、β-环糊精13.0%、谷氨酸钠15.0%,喷干存活率为65.9%,菌粉活菌数为1.38×109CFU/g,存放180 d后菌粉活菌数为1.03×10~9CFU/g。结论:喷雾干燥工艺可以用于芽孢杆菌dhs-330-021菌粉的制备,获得的菌粉稳定性较好。     

CoMFA and CoMSIA 3D-QSAR analysis of diaryloxy-methano-phenanthrene derivatives as anti-tubercular agents

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series (44 compounds) of diaryloxy-methano-phenanthrene derivatives as potent antitubercular agents. The best predictions were obtained with a CoMFA standard model (q (2)=0.625, r (2)=0.994) and with CoMSIA combined steric, electrostatic, and hydrophobic fields (q (2)=0.486, r (2)=0.986). Both models were validated by a test set of seven compounds and gave satisfactory predictive r (2) values of 0.999 and 0.745, respectively. CoMFA and CoMSIA contour maps were used to analyze the structural features of the ligands to account for the activity in terms of positively contributing physicochemical properties: steric, electrostatic, and hydrophobic fields. The information obtained from CoMFA and CoMSIA 3-D contour maps can be used for further design of phenanthrene-based analogs as anti-TB agents. The resulting contour maps, produced by the best CoMFA and CoMSIA models, were used to identify the structural features relevant to the biological activity in this series of analogs. Further analysis of these interaction-field contour maps also showed a high level of internal consistency. This study suggests that introduction of bulky and highly electronegative groups on the basic amino side chain along with decreasing steric bulk and electronegativity on the phenanthrene ring might be suitable for designing better antitubercular agents.