Steroid Sulphatase and Its Inhibitors: Past,Present, and Future

Steroid sulphatase (STS), involved in the hydrolysis of steroid sulphates, plays an important role in the formation of both active oestrogens and androgens. Since these steroids significantly impact the proliferation of both oestrogen- and androgen-dependent cancers, many research groups over the past 30 years have designed and developed STS inhibitors. One of the main contributors to this field has been Prof. Barry Potter, previously at the University of Bath and now at the University of Oxford. Upon Prof. Potter’s imminent retirement, this review takes a look back at the work on STS inhibitors and their contribution to our understanding of sulphate biology and as potential therapeutic agents in hormone-dependent disease. A number of potent STS inhibitors have now been developed, one of which, Irosustat (STX64, 667Coumate, BN83495), remains the only one to have completed phase I/II clinical trials against numerous indications (breast, prostate, endometrial). These studies have provided new insights into the origins of androgens and oestrogens in women and men. In addition to the therapeutic role of STS inhibition in breast and prostate cancer, there is now good evidence to suggest they may also provide benefits in patients with colorectal and ovarian cancer, and in treating endometriosis. To explore the potential of STS inhibitors further, a number of second- and third-generation inhibitors have been developed, together with single molecules that possess aromatase–STS inhibitory properties. The further development of potent STS inhibitors will allow their potential therapeutic value to be explored in a variety of hormone-dependent cancers and possibly other non-oncological conditions.     

Purification,crystallization, and X-ray diffraction analysis of succinyl-diaminopimelate desuccinylase from Wolbachia endosymbiont of Brugia malayi

Lymphatic filariasis (LF) is a debilitating mosquito-borne parasitic disease caused by Brugia malayi in humans in the lymphatic system. Although limited drugs are available to treat this disease, these drugs are only effective against the larvae of Brugia malayi. As resistance has been reported to the available drugs, a new antifilarial drug is needed with better prognostic features, a short period of time of use, and efficiency at preventing adult worm survival. In this study, we have targeted succinyl-diaminopimelate desuccinylase (DapE) from the Wolbachia endosymbiont of Brugia malayi (WBm), which is involved in the production of lysine and meso-diaminopimelic acid, an essential component for the formation of bacterial cell walls, and plays a vital role in pathogen survival. Deletion of DapE gene is lethal to WBm since the organism has no alternative pathway for lysine biosynthesis. Here, the expression, purification, and crystallization of DapE are reported. The crystals of DapE, with an estimated solvent content of 50.76%, diffract synchrotron X-rays to a resolution of 2.3 Å and belong to the space group C222₁, with unit-cell parameters of a = 51.78, b = 78.83, and c = 216.20 Å. The X-ray absorption spectroscopy further confirms that zinc atoms are incorporated in DapE.     

Overview of Inositol and Inositol Phosphates on Chemoprevention of Colitis-Induced Carcinogenesis

Chronic inflammation is one of the most common and well-recognized risk factors for human cancer, including colon cancer. Inflammatory bowel disease (IBD) is defined as a longstanding idiopathic chronic active inflammatory process in the colon, including ulcerative colitis and Crohn’s disease. Importantly, patients with IBD have a significantly increased risk for the development of colorectal carcinoma. Dietary inositol and its phosphates, as well as phospholipid derivatives, are well known to benefit human health in diverse pathologies including cancer prevention. Inositol phosphates including InsP₃, InsP₆, and other pyrophosphates, play important roles in cellular metabolic and signal transduction pathways involved in the control of cell proliferation, differentiation, RNA export, DNA repair, energy transduction, ATP regeneration, and numerous others. In the review, we highlight the biologic function and health effects of inositol and its phosphates including the nature and sources of these molecules, potential nutritional deficiencies, their biologic metabolism and function, and finally, their role in the prevention of colitis-induced carcinogenesis.     

Ruthenium‐Catalyzed Metathesis Cascade Reactions in Natural Products Synthesis

In this account, we provide a brief summary of recent developments in ruthenium‐catalyzed metathesis cascade reactions towards the total synthesis of natural products. We also highlight recent progress from our own laboratory regarding the synthesis of securinega alkaloids and humulanolides, which has resulted in the development of novel ruthenium‐catalyzed metathesis cascade reactions. Inspired and guided by the pioneering and elegant research conducted in this area, we developed a regio‐controlled relay dienyne metathesis cascade reaction and a cyclobutene‐promoted RCM/ROM/RCM cascade reaction for the synthesis of securinega alkaloids and humulanolides, respectively.     

Carbohydrate-Derived Dienes as Building Blocks for Pharmaceutically Relevant Molecules

Carbohydrate-based dienes are valuable building blocks for a variety of highly functionalized carbo- and oxa-cycles by virtue of their high degree of inherent stereochemical information, and suitability in various synthetic transformations. Research into the chemistry of carbohydrate-based dienes has been expanding over the last decades due to its unique applications in the construction of diverse and complex structural frameworks. In this review, we describe the main transformations of this interesting class of molecule and highlight their utility in the construction of diverse ring systems important for drug development.     

腹腔镜手术联合药物治疗子宫内膜异位症的临床疗效分析

目的评价腹腔镜手术联合药物治疗子宫内膜异位症的临床疗效。方法选取东莞市第三人民医院于2015年1月至2017年1月收治的150例子宫内膜异位症患者,按随机盲选法分为两组,对照组75例给予腹腔镜手术治疗,观察组75例给予腹腔镜手术联合药物治疗,对比两组临床治疗效果。结果在治疗总有效率方面,观察组为94.67%,明显要比对照组的70.67%高,两组数据差异有统计学意义(P<0.05)。在不良反应发生率方面,观察组为5.33%,明显要比对照组的22.67%低,两组数据差异有统计学意义(P<0.05)。结论对于子宫内膜异位症患者,采取腹腔镜手术联合药物进行治疗,具备显著疗效,能够降低不良反应发生率,因此,值得在临床中采纳及应用。     

Multifunctional 8‐Hydroxyquinoline‐Appended Cyclodextrins as New Inhibitors of Metal‐Induced Protein Aggregation

Mounting evidence suggests a pivotal role of metal imbalances in protein misfolding and amyloid diseases. As such, metal ions represent a promising therapeutic target. In this context, the synthesis of chelators that also contain complementary functionalities to combat the multifactorial nature of neurodegenerative diseases is a highly topical issue. We report two new 8‐hydroxyquinoline‐appended cyclodextrins and highlight their multifunctional properties, including their Cu^II and Zn^II binding abilities, and capacity to act as antioxidants and metal‐induced antiaggregants. In particular, the latter property has been applied in the development of an effective assay that exploits the formation of amyloid fibrils when β‐lactoglobulin A is heated in the presence of metal ions.     

Controlling the shape of the molecular weight distribution for tailored tensile and rheological properties in thermoplastics and thermoplastic elastomers

Thermoplastics and thermoplastic elastomers compose roughly 80 percent of all polymeric materials manufactured today and play an important role in numerous sectors of modern society. While the effects of molecular weight and dispersity (Ð) on the tensile and rheological properties of these materials are well-known, only recent studies have evidenced the profound influence of the shape of the molecular weight distribution (MWD) on polymer properties. This development is largely due to the emergence of new synthetic strategies to control higher moments of the MWD. In this Perspective, we describe recent advancements by our group in understanding the effect of MWD shape on the mechanical and rheological properties of thermoplastics and thermoplastic elastomers. We highlight means to exploit MWD shape for improved processability and performance and discuss future directions in this field.     

Enantioselectivity Effects in Clinical Metabolomics and Lipidomics

Metabolomics and lipidomics have demonstrated increasing importance in underlying biochemical mechanisms involved in the pathogenesis of diseases to identify novel drug targets and/or biomarkers for establishing therapeutic approaches for human health. Particularly, bioactive metabolites and lipids have biological activity and have been implicated in various biological processes in physiological conditions. Thus, comprehensive metabolites, and lipids profiling are required to obtain further advances in understanding pathophysiological changes that occur in cells and tissues. Chirality is one of the most important phenomena in living organisms and has attracted long-term interest in medical and natural science. Enantioselective separation plays a pivotal role in understanding the distribution and physiological function of a diversity of chiral bioactive molecules. In this context, it has been the goal of method development for targeted and untargeted metabolomics and lipidomic assays. Herein we will highlight the benefits and challenges involved in these stereoselective analyses for clinical samples.     

The ubiquitin system,disease, and drug discovery

Abstract

The ubiquitin system of protein modification has emerged as a crucial mechanism involved in the regulation of a wide array of cellular processes. As our knowledge of the pathways in this system has grown, so have the ties between the protein ubiquitin and human disease. The power of the ubiquitin system for therapeutic benefit blossomed with the approval of the proteasome inhibitor Velcade in 2003 by the FDA. Current drug discovery activities in the ubiquitin system seek to (i) expand the development of new proteasome inhibitors with distinct mechanisms of action and improved bioavailability, and (ii) validate new targets. This review summarizes our current understanding of the role of the ubiquitin system in various human diseases ranging from cancer, viral infection and neurodegenerative disorders to muscle wasting, diabetes and inflammation. I provide an introduction to the ubiquitin system, highlight some emerging relationships between the ubiquitin system and disease, and discuss current and future efforts to harness aspects of this potentially powerful system for improving human health.

Publication history

Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).

     

Design,Synthesis, and Evaluation of Bioactive Small Molecules

Collaborative research projects between chemists, biologists, and medical scientists have inevitably produced many useful drugs, biosensors, and medical instrumentation. Organic chemistry lies at the heart of drug discovery and development. The current range of organic synthetic methodologies allows for the construction of unlimited libraries of small organic molecules for drug screening. In translational research projects, we have focused on the discovery of lead compounds for three major diseases: Alzheimer's disease (AD), breast cancer, and viral infections. In the AD project, we have taken a rational‐design approach and synthesized a new class of tricyclic pyrone (TP) compounds that preserve memory and motor functions in amyloid precursor protein (APP)/presenilin‐1 (PS1) mice. TPs could protect neuronal death through several possible mechanisms, including their ability to inhibit the formation of both intraneuronal and extracellular amyloid β (Aβ) aggregates, to increase cholesterol efflux, to restore axonal trafficking, and to enhance long‐term potentiation (LTP) and restored LTP following treatment with Aβ oligomers. We have also synthesized a new class of gap‐junction enhancers, based on substituted quinolines, that possess potent inhibitory activities against breast‐cancer cells in vitro and in vivo. Although various antiviral drugs are available, the emergence of viral resistance to existing antiviral drugs and various understudied viral infections, such as norovirus and rotavirus, emphasizes the demand for the development of new antiviral agents against such infections and others. Our laboratories have undertaken these projects for the discovery of new antiviral inhibitors. The discussion of these aforementioned projects may shed light on the future development of drug candidates in the fields of AD, cancer, and viral infections.     

Click polymerization: The aurora of polymer synthetic methodology

As an emerged efficient polymerization methodology, the click polymerization plays a significant role in the area of polymer and materials sciences. Similar to the click reaction, the click polymerization enjoys the advantages of high efficiency, mild reaction conditions, and high regio- and stereo-selectivity etc. In this highlight, we summarize the recent progress on click polymerizations, with focus on the alkyne-based ones. The challenges and opportunities in this area are also briefly discussed. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 616–621     

Mapping N6-Methyladenosine (m6A) in RNA: Established Methods,Remaining Challenges,and Emerging Approaches

N⁶-Methyladenosine (m⁶A) is the most abundant internal modification in eukaryotic mRNA. Specific m⁶A reader and eraser proteins link this modification to many aspects of mRNA metabolism and regulate its levels in a dynamic way. Precise localization and quantification in varying biological samples is, therefore, relevant to understand the functional role of m⁶A and mechanisms governing its regulation. In this Minireview, we summarize established and emerging concepts for m⁶A mapping. Starting with the seminal m⁶A-sequencing techniques based on immunoprecipitation, we will highlight technical improvements by photo-cross-linking and remaining challenges. As an alternative, antibody-free approaches will be presented. These include wild-type or engineered m⁶A-sensitive enzymes and chemical biology approaches combining substrate analogues, chemical derivatization, and enzymatic steps to trace m⁶A. Finally, single-molecule sequencing as a new avenue for direct detection of mRNA modifications will be discussed.     

Recent Progress in Bioconjugation Strategies for Liposome-Mediated Drug Delivery

In nanoparticle (NP)-mediated drug delivery, liposomes are the most widely used drug carrier, and the only NP system currently approved by the FDA for clinical use, owing to their advantageous physicochemical properties and excellent biocompatibility. Recent advances in liposome technology have been focused on bioconjugation strategies to improve drug loading, targeting, and overall efficacy. In this review, we highlight recent literature reports (covering the last five years) focused on bioconjugation strategies for the enhancement of liposome-mediated drug delivery. These advances encompass the improvement of drug loading/incorporation and the specific targeting of liposomes to the site of interest/drug action. We conclude with a section highlighting the role of bioconjugation strategies in liposome systems currently being evaluated for clinical use and a forward-looking discussion of the field of liposomal drug delivery.     

Poly(glycoamidoamine)s: Cationic glycopolymers for DNA delivery

Polymer science is playing an exciting role in inspiring and advancing novel discoveries in the area of genetic drug delivery. Polymeric materials can be synthesized and chemically tailored to bind and compact nucleic acids into viral‐like nanoparticles termed polyplexes that can deliver genetic materials into cells. This article highlights our work in this area to synthesize and study a novel class of cationic glycopolymers that we have termed poly(glycoamidoamine)s (PGAAs). The design of these materials has been inspired by many previous works in the literature. Carbohydrate comonomers have been incorporated into these structures to lower the toxicity of the delivery vehicle, and oligoamine moieties have been added to yield a cationic backbone that facilitates strong DNA binding, compaction, cellular uptake, and delivery of genetic material. PGAAs have been designed to vary in the carbohydrate size, the hydroxyl number and stereochemistry, the amine number, and the presence or absence of heterocyclic groups. Through structure–bioactivity studies, we have discovered that these materials are highly biocompatible, and each specific feature plays a large role in the observed delivery efficacy. Such structure–property studies are important for increasing our understanding of how the polymer chemistry affects the biological activity for the clinical development of polymer‐based therapeutics. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 6895–6908, 2006     

先导化合物的发现——整合计算机虚拟筛选、化学合成和生物测试方法

先导化合物的发现在药物研究中起关键作用。基于分子对接的虚拟筛选是创新药物研究的新方法和新技术,已成为一种与高通量筛选互补的方法,广泛应用于先导化合物的发现中。本文将结合本课题组的研究实例,综述了通过计算机虚拟筛选、化学合成和生物测试相结合的方法来发现先导化合物的一些研究工作。     

Size‐dependent Tumor Response to Photodynamic Therapy and Irinotecan Monotherapies Revealed by Longitudinal Ultrasound Monitoring in an Orthotopic Pancreatic Cancer Model

Longitudinal monitoring of tumor size in vivo can provide important biological information about disease progression and treatment efficacy that is not captured by other modes of quantification. Ultrasound enables high‐throughput evaluation of orthotopic mouse models via fast acquisition of three‐dimensional tumor images and calculation of volume with a reasonable degree of accuracy. Herein, we compare orthotopic pancreatic tumor volume measurements determined by ultrasound with volume measured by calipers and tumor weight, and found strong correlations between the three modalities over a large range of tumor sizes, suggesting ultrasound can accurately quantify tumor volumes in this model. Furthermore, we demonstrate the unique ability of longitudinal treatment monitoring to reveal a tumor size‐dependent response to Benzoporphyrin Derivative photodynamic therapy (BPD‐PDT) and irinotecan. Small tumors (5–35 mm³) were found to respond well to a single round of PDT, while large tumors (35–65 mm³) showed no response to the same treatment. These results highlight the role that tumor size can play in preclinical interpretation of treatment response and more generally suggest that careful evaluation of subtle biological features such as this must be carefully considered in order to grant a more comprehensive understanding of disease biology in vivo.     

Design,identification, antifungal evaluation and molecular modeling of chlorotetaine derivatives as new anti-fungal agents

Abstract

It is feasible to rationally modify existing bioactive components for new drug development, achieving molecules with improved biological activities. In this study, rational modification of chlorotetaine was carried out following in silico molecular modelling to enhance interactions between the fungal oligopeptide transmembrane transporter PTR22 and the ligand. The peptide obtained with the lowest docking energy, Lys-chlorotetaine (LC), displayed an improved antifungal effect compared with chlorotetaine. The lowest minimum inhibitory concentration observed against a tested pathogen was 1.47?µg/mL (Candida krusei CBS573), which was satisfactory. To thoroughly explore the detailed interactions between the transporter and LC, molecular dynamics simulation was also performed, which revealed that LC could bind to the transporter via different intermolecular interactions from chlorotetaine, and predicted electrostatic interactions (salt-bridges) would enable the more efficient release of LC. This study provides a simple and reliable method for the rational modification of oligopeptide antibiotics.