Design,Synthesis and Molecular Docking Studies of Some Tetrahydropyrimidine Derivatives as Possible Fascin Inhibitors

Eight derivatives of tetrahydropyrimidine scaffold were designed and prepared as hybrid compounds possessing the structural features of both monastrol as an anticancer drug and nifedipine as a fascin blocking agent. All of the compounds were evaluated for their cytotoxic potency and the ability to inhibit 4T1 breast cancer cells migration. Then, they were investigated in silico for their ability to inhibit the fascin protein using molecular docking simulation. The most potent compound was 4d and the weakest one was 4a according to the in vitro cytotoxicity assay. The corresponding IC₅₀ values were 193.70 and 248.75 μm , respectively. The least cytotoxic compound ( 4a ) was one of the strongest ones in binding to the fascin binding site according to the molecular docking results. 4a and 4e inhibited the 4T1 cells migration better than other compounds. They were more potent than nifedipine in inhibiting the migration process. In silico studies proved 4h to be the most potent fascin inhibitor in terms of ΔG_bind although it was not inhibiting migration. The controversy between the in vitro and in silico results may cancel the theory of the involvement of the fascin inhibition in the migration inhibition. However, the considerable antimigratory effects of some of the synthesized compounds encourage performing further in vivo experiments to introduce novel tumor metastasis inhibitors.     

利用回交导入系剖析水稻苗期和分蘖期耐盐性的遗传重叠

以籼稻品种IR64为受体,来自伊朗的粳稻农家品种Binam为供体培育的99个BC2F8回交导入系为材料,定位了水稻在2叶1心期和分蘖期控制耐盐相关性状的数量性状基因座（QTL）．共检测到影响苗期叶片盐害级别、幼苗存活天数和地上部钾、钠离子浓度的QTL 13个,影响分蘖期株高、分蘖数和地上部鲜重的QTL 22个．多数分蘖期QTL对盐胁迫表现出明显的表达差异,根据表达情况将这些QTL分成3组,第1组为在对照条件下表达的11个QTL;第2组为在对照和盐胁迫条件下共同表达的5个QTL,其中有3个（QPh5,QPh8,QTn9）在两种环境下的基因效应大小和方向一致,其表达受盐胁迫影响较小;第3组为受盐胁迫诱导表达的6个QTL．检测到13个影响胁迫与对照差值即性状稳定性的QTL,除QPh4,QTn2和QFw2a外,其余10个基因座增加性状稳定性或提高耐盐性的等位基因均来自Binam．上述受盐胁迫影响较小的3个QTL和影响性状稳定性的13个QTL对耐盐性有贡献,属耐盐QTL．比较苗期和分蘖期耐盐QTL的分布,发现多数（69％）影响苗期和分蘖期的耐盐QTL在遗传上相互独立,仅在第1,2,8和11染色体的4个相同或相邻区域定位到影响两个时期的耐盐QTL,表明苗期和分蘖期的耐盐性存在部分的遗传重叠．通过标记辅助选择将苗期和分蘖期的重要耐盐QTL进行累加,或针对苗期和分蘖期的重叠耐盐QTL进行选择,有可能培育出苗期和分蘖期均耐盐的水稻品种．     

Design,Synthesis, Molecular Docking,and Molecular Dynamics Simulation Studies of Novel 3-Hydroxypyridine-4-one Derivatives as Potential Acetylcholinesterase Inhibitors

Researchers have focused on inhibiting acetylcholinesterase for Alzheimer's disease treatment. In this study, some novel AChE inhibitors were synthesized using hydroxypyridin-4-one plus benzylpiperidine scaffolds which were evaluated using Ellman's method. Accordingly, ((1-(4-methoxyphenethyl)piperidin-4-yl)amino)methyl)-5-hydroxy-1-methylpyridin-4(1H)-one (VII_d) showed weaker but promising AChE inhibition compared to donepezil (IC₅₀=143.090 nM). The average RMSD values of VII_d was found to be 2.25 indicated less structural changes in the active site residues. The phenyl group of the phenyl-ethyl-N-piperidine moiety of VII_d formed hydrophobic interactions with Trp285 and Tyr340. There was a π-cation interaction between nitrogen atom of piperidine ring and Phe294. Another π-cation interaction was found between type 2 amine of linker and Trp85. Piperidine ring interacted with Tyr336, Tyr123, and Phe337 through hydrophobic interactions. Indeed, the VII_d was predicted to be absorbed across the gastrointestinal tract, though it may be pumped out by P-gp. Indeed, VIId can permeate through the blood brain barrier. MD simulation studies revealed that benzyloxy moiety plays a role similar to benzylpiperidine moiety of donepezil in binding to the active site residues. Also, carbonyl group functioned similar to indanone ketone group. Overall; further research on VII_d may lead to introduction of a novel class of AChE inhibitors.     

Highly upregulated in liver cancer (HULC): An update on its role in carcinogenesis

Highly upregulated in liver cancer (HULC) was initially recognized during the screening of a hepatocellular carcinoma (HCC)-specific gene library. Further studies demonstrated its aberrant upregulation in several other tumor types. The oncogenic roles of this long noncoding RNA (lncRNA) have been verified through expression studies as well as functional studies. Moreover, the results of knockdown experiments have indicated diminished carcinogenic effects of cancer cell line in nude mice following HULC silencing. More recent studies have shown that expression levels of this lncRNA might be used as diagnostic biomarkers in cancer patients. Moreover, mechanistical studies have revealed associations between HULC and two HCC-related viruses namely hepatitis B and C viruses. Taken together, HULC can be regarded as a therapeutic target not only for HCC but also for a variety of human malignancies. In the current review, we summarized the recent literature about the role of HULC in the carcinogenesis and its potential application in cancer diagnosis and prognosis.     

Dissection of genetic overlap of salt tolerance QTLs at the seedling and tillering stages using backcross introgression lines in rice

QTLs for salt-tolerance(ST)related traits at the seedling and tillering stages were identified using 99 BC2F8 introgression lines(IL)derived from a cross between IR64(indica)as a recurrent parent and Binam(japonica)from Iran as the donor parent.Thirteen QTLs affecting survival days of seedlings(SDS), score of salt toxicity of leaves(SST),shoot K concentration(SKC)and shoot Na concentration(SNC) at the seedling stage and 22 QTLs underlying fresh weight of shoots(FW),tiller number per plant(TN) and plant height(PH)at the tillering stage were identified.Most QTLs detected at the tillering stage showed obvious differential expression to salt stress and were classified into three types based on their differential behaviors.Type I included 11 QTLs which were expressed only under the non-stress condition.Type II included five QTLs expressed in the control and the salt stress conditions,and three of them(QPh5,QPh8 and QTn9)had similar quantity and the same direction of gene effect,suggesting their expression was less influenced by salt stress.Type III included six QTLs which were detectable only under salt stress,suggesting that these QTLs were apparently induced by the stress.Thirteen QTLs affecting trait difference or trait stability of ILs between the stress and non-stress conditions were identified and the Binam alleles at all loci except QPh4,QTn2 and QFw2a decreased trait difference.The three QTLs less influenced by the stress and 13 QTLs affecting trait stability were considered as ST QTLs which contributed to ST.Comparing the distribution of QTLs detected at the seedling and tillering stages,most(69%)of them were genetically independent.Only four were the same or adjacent regions on chromosomes 1,2,8 and 11 harboring ST QTLs detected at the two stages,suggesting that partial genetic overlap of ST across the two stages occurs.It is likely,therefore,to develop ST rice variety for both stages by pyramiding of ST QTLs of different stages or selection against the overlapping QTLs between the two stages via marker-assisted selection(MAS).     

Synthesis of Some Benzothiazole Derivatives Based on 3-Hydroxypyridine-4-one and Benzaldehyde and Evaluation of Their β-Amyloid Aggregation Inhibition Using both Experimental Methods and Molecular Dynamic Simulation

Some novel inhibitors based on the (benzo[d]thiazol-2-yl)-1-phenylmethanimine derivatives were designed to reduce the aggregation process in Alzheimer's disease. These structures seem to mimic stilbene-like scaffold, while the benzothiazole moiety “locks” the thioflavin T binding site. Other inhibitors were designed based on 2-((benzo[d]thiazol-2-ylimino)methyl)-5-(benzyloxy)-1-methylpyridin-4(H)-one derivatives. Benzo[d]thiazol-2-amine derivatives were prepared by the reaction of aniline derivatives with ammonium thiocyanate in the presence of bromine/acetic acid. Then, the reaction of amines with benzaldehyde derivatives and 5-(benzyloxy)-1-methyl-4-oxo-1,4-dihydropyridine-2-carbaldehyde gave the desired compounds. The plate reader-based fibrillation assay was done to evaluate the inhibition of Aβ aggregation. Also, molecular dynamic simulation was carried out to clarify the interaction manner of the designed compounds with Aβ formation. The biological evaluation proved 5a and 7e as the best inhibitor of the Aβ aggregation. compound 5a in the concentration of 50 μM inhibited Aβ fibril formation better than 7e . MD simulation elucidated that the Aβ aggregation inhibitors in different concentrations represented different binding conformations throughout the entire or in one area of Aβ. MD showed the ligands in lower concentrations accumulate in an area of Aβ aggregations and separate one fibril from the aggregated Aβ. On the contrary, in higher concentrations, the ligands tend to be located through the entire Aβ.