Synthesis and biological evaluation of a folate-targeted rhaponticin conjugate

To improve the therapeutic effect of rhaponticin (RHA), a folate receptor (FR) targeted RHA conjugate was synthesized by utilizing a hydrophilic peptide spacer linked to folic acid (FA) via a releasable disulfide linker. This water-soluble conjugate was found to retain high affinity for FR-positive cells, and it produced specific, dose-responsive activity in vitro. Treatment of FRHA with a reducing agent indicated that the amino-reactive derivative of RHA would be released spontaneously following disulfide bond reduction within the endosomes. FRHA also proved to be active predominantly specific against FR-positive syngeneic and xenograft models in vivo, and possible curative activity resulted with minimal to moderate toxicity. The FRHA conjugate greatly enhanced the therapeutic effects and reduced the toxicity of RHA. In conclusion, FRHA represents a folate-targeted chemotherapeutic that can produce potent activity against established sc tumors. Hence, this report has a great significance in pharmacology and clinical medicine as well as methodology.     

Novel inhibitors of bacterial virulence: Development of 5,6-dihydrobenzo[h]quinazolin-4(3H)-ones for the inhibition of group A streptococcal streptokinase expression

Resistance to antibiotics is an increasingly dire threat to human health that warrants the development of new modes of treating infection. We recently identified 1 (CCG-2979) as an inhibitor of the expression of streptokinase, a critical virulence factor in Group A Streptococcus that endows blood-borne bacteria with fibrinolytic capabilities. In this report, we describe the synthesis and biological evaluation of a series of novel 5,6-dihydrobenzo[h]quinazolin-4(3H)-one analogs of 1 undertaken with the goal of improving the modest potency of the lead. In addition to achieving an over 35-fold increase in potency, we identified structural modifications that improve the solubility and metabolic stability of the scaffold. The efficacy of two new compounds 12c (CCG-203592) and 12k (CCG-205363) against biofilm formation in Staphylococcus aureus represents a promising additional mode of action for this novel class of compounds.     

TRPV1 antagonist with high analgesic efficacy: 2-Thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides

A series of 2-thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Among them, compound 24S showed stereospecific and excellent TRPV1 antagonism of capsaicin-induced activation. Further, it demonstrated strong anti-allodynic in a rat neuropathic pain model. Consistent with its action in vitro being through TRPV1, compound 24S blocked capsaicin-induced hypothermia in mice. Docking analysis of 24S with our hTRPV1 homology model was performed to identify its binding mode.     

Discovery of XEN445: A potent and selective endothelial lipase inhibitor raises plasma HDL-cholesterol concentration in mice

Endothelial lipase (EL) activity has been implicated in HDL metabolism and in atherosclerotic plaque development; inhibitors are proposed to be efficacious in the treatment of dyslipidemia related cardiovascular disease. We describe here the discovery of a novel class of anthranilic acids EL inhibitors. XEN445 (compound 13) was identified as a potent and selective EL inhibitor, that showed good ADME and PK properties, and demonstrated in vivo efficacy in raising plasma HDLc concentrations in mice.     

Design and bio-evaluation of indole derivatives as potent Kv1.5 inhibitors

Atrial fibrillation (AF) is one of the common arrhythmias that threaten human health. Kv1.5 potassium channel is reported as an efficacious and safe target for the treatment of AF. In this paper, we designed and synthesized three series of compounds through modifying the lead compound RH01617 that was screened out by the pharmacophore model we reported earlier. All of the compounds were evaluated by the whole-patch lamp technology and most of them possessed potent inhibitory activities against Kv1.5. Compounds IIIi and IIIl were evaluated for the target selectivity as well as the pharmacodynamic effects in an isolated rat model. Due to the promising pharmacological behavior, compound IIIl deserves further pharmacodynamic and pharmacokinetic evaluations.     

Exploring pyrimidine-substituted curcumin analogues: Design,synthesis and effects on EGFR signaling

Epidermal growth factor receptor (EGFR) is an effective molecular target of anti-cancer therapies. Curcumin inhibits cancer cell growth in vitro by suppressing gene expression of EGFR and reduces tumor growth in various animal models. To overcome instable and insoluble properties of curcumin as therapeutics, we designed and synthesized six novel pyrimidine-substituted curcumin analogues with or without a hydroxyl group originally present in curcumin. The cell viability tests indicated that IC₅₀ of the analogues containing hydroxyl group were 3 to 8-fold lower than those of the analogues without hydroxyl group in two colon cancer cell lines tested. Western blot analysis indicates the analogues containing hydroxyl group inhibited expression and tyrosine phosphorylation of EGFR. Further protein analyses showed that the analogues had anti-cellular proliferation, pro-apoptosis, and cell cycle arrest properties associated with suppressed EGFR expression. These results indicate that the hydroxyl groups in curcumin and the analogues were critical for observed biological activities.     

琥珀酸脱氢酶或琥珀酰辅酶A合成酶缺失促进大肠杆菌积累5-氨基乙酰丙酸

5-氨基乙酰丙酸 (ALA) 是生物体内四吡咯类化合物的合成前体,在农业及医药领域应用广泛,是极具开发价值的高附加值生物基化学品。目前利用外源C4途径的重组大肠杆菌发酵生产ALA的研究主要利用LB培养基并添加葡萄糖和琥珀酸、甘氨酸等合成前体,成本较高。琥珀酸在C4途径中以琥珀酰辅酶A的形式直接参与ALA的合成。文中在以葡萄糖为主要碳源的无机盐培养基中研究了琥珀酰辅酶A下游代谢途径琥珀酸脱氢酶编码基因sdhAB和琥珀酰辅酶A合成酶编码基因sucCD缺失对ALA积累的影响。与仅表达异源ALA合成酶的对照菌株相比,sdhAB和sucCD缺失菌株ALA的产量分别提高了25.59%和12.40%,且ALA的积累不依赖于琥珀酸的添加和LB培养基的使用,从而大幅降低了生产成本,显示出良好的工业应用前景。     

新型猪瘟疫苗研究进展

猪瘟是由猪瘟病毒引起猪的一种急性、热性和高度接触性传染病.该病呈世界性分布,给世界养猪业造成了巨大的经济损失.目前,疫苗接种仍然是防控猪瘟的主要手段.虽然传统的猪瘟弱毒疫苗(如C株)安全有效,但猪瘟的临床表现发生了很大变化,呈现典型猪瘟和非典型猪瘟共存、隐性感染和持续感染并现,免疫失败的现象时有报道,且不能区分野毒感染和免疫接种.因此,研制安全、高效、能区分野毒感染和疫苗免疫动物(DIVA)的新型猪瘟疫苗极为必要.文中就近年来开发的核酸疫苗、病毒活载体疫苗、基于蛋白/肽的疫苗、基因缺失疫苗、嵌合瘟病毒疫苗等新型DIVA猪瘟疫苗作一综述.     

ALDH2, a novel protector against stroke?

In a recent paper published in Cell Research, an association between expression of mitochondrial aldehyde dehydrogenase (ALDH2), a mitochondrial chaperon expressed in the brain, and the prevalence of stroke is revealed. This finding indicates that ALDH2 may serve as a potential endogenous neuroprotective target and a promising therapeutic strategy for the management of stroke.Stroke is one of the leading causes of death and a major reason of adult chronic disability as well as age-related cognitive decline and dementia¹. Ischemic stroke represents > 80% of all stroke incidences with the remaining 20% due to primary hemorrhage. Proper management of the conventional risk factors for stroke, such as high blood pressure, elevated blood cholesterol, cigarette smoking, carotid stenosis, diabetes mellitus and heart failure, may reduce the incidence of stroke only to a certain degree, suggesting the existence of undiscovered or undefined risk factors^1,2. The unidentified risk factors for stroke, in conjunction with unsatisfactory control of known risk factors (e.g., high cholesterol and hypertension), may explain the intimate clinical challenge or failure for stroke management. To this end, identification of novel risk factors may hold promises in the development of strategies for prevention and treatment of stroke. Ample evidence has implicated the importance of genetic predisposition in the onset and progression of stroke². More recently, genome-wide association study (GWAS) approach has transformed the genetics of many complex chronic diseases and is just beginning to impact the field of stroke³. Genetic variants predisposing to ischemic stroke have been revealed by GWAS, such as two loci associated with atrial fibrillation (PITX2 and ZFHX3) linked to cardioembolic stroke and a locus on chromosome 9p21 tied to large-vessel stroke^1,4,5. Nonetheless, the precise contribution of genetics to the etiology of stroke, in particular various stroke subtypes, remains somewhat elusive. Gene candidates that have been identified to be associated with stoke warrant further validation in a large independent data set to consolidate their causative role in the pathogenesis of stroke.In a recent paper published in Cell Research, Guo and colleagues performed an unbiased proteomic examination and unveiled a unique role of deficiency in mitochondrial aldehyde dehydrogenase (ALDH2), the so-called “facial flash gene” responsible for detoxification of toxic aldehydes such as 4-hydroxy-2-nonenal (4-HNE), in the pathogenesis of stroke⁶. In their study, overexpression or activation of ALDH2 conferred neuroprotection through clearance of 4-HNE whereas ALDH2 knockdown mitigated the neuroprotective property of PKCɛ. The PKCɛ-ALDH2 pathway was shown to mediate neuroprotection offered by moderate ethanol intake. Serum 4-HNE levels were inversely correlated with lifespan and elevated plasma 4-HNE levels were observed for at least 6 months following stroke onset. Perhaps the most intriguing evidence is that much higher initial plasma 4-HNE levels were associated with development of stroke in an 8-year follow-up study. These findings favor a likely role of ALDH2 in the prevalence of stroke or stroke-prone subjects, and furthermore, its therapeutic potential as a target in the management of stroke (Figure 1).Open in a separate windowFigure 1Schematic diagram depicting the possible interplay between ischemic stroke and elevated serum 4-HNE levels. Serum 4-HNE levels positively correlates with stroke injury and remains elevated after stroke. Deficiency and activation of ALDH2 significantly accentuates and attenuates stroke-associated cerebral ischemia injury, respectively.ALDH2 is a human gene found on chromosome 12. All Caucasians are homozygous for ALDH2 while approximately 50% of Asians are heterozygous and possess only one normal copy of the ALDH2 gene and one mutant copy encoding an inactive mitochondrial isozyme⁷. A recent meta-analysis of GWAS identified a tight association between ALDH2 genetic mutation and elevated blood pressure, a known risk factor for stroke, in Asian decedents⁸. This is supported by the recent observation favoring a crucial role for ALDH2 in the regulation of cardiovascular homeostasis in diabetes, alcoholism, endoplasmic reticulum stress, arrhythmias and ischemia-reperfusion injury^9,10,11. Stroke is known to interrupt mitochondrial function and promote mitochondrial swelling and depolarization, leading to ultimate neuronal cell death¹². ALDH2 exerts a major role in aldehyde detoxification in mitochondria, and attenuates or ablates neuronal mitochondrial damage. Reactive aldehydes, including MDA, 4-HNE and 1-palmitoyl-2-oxovaleroyl phosphatidyl choline (POVPC), all of which are potential substrates for ALDH2, are elevated in ischemic stroke injury^1,12. Higher levels of 4-HNE and MDA were found in the serum of stroke-prone hypertensive rats compared with normotensive WKY rats⁶. Interestingly, only 4-HNE, but not MDA, was elevated in stroke-prone hypertensive rats compared with hypertensive rats, suggesting a role of 4-HNE as a possible biomarker for stroke.Given that approximately 40% of the East Asian population carries an ALDH2*2 mutant allele with dramatic reduction in ALDH2 enzymatic activity, the current observation suggest that ALDH2 mutation serves as a risk factor for stroke⁶. Unlike its reported role in the heart, little information is available for ALDH2 in the brain and cerebrovascular function. Like all animal studies, caution needs to be taken to translate experimental findings to a clinical setting. It is noteworthy that the animal outcome studies were performed at a relatively short period after stroke. A longer time window should be essential to the ultimate assessment of stroke injury. Further studies are needed to uncover the precise mechanism behind the regulation of ALDH2 in stroke.