查尔酮类化合物生物活性研究进展

查尔酮类化合物以1,3-二苯基丙烯酮为基本骨架结构,为多种药用植物的有效成分,具有广泛的生物学活性,因此人们对此类化合物进行了大量研究。了解该类化合物的药理作用机制和构效关系,可为新药设计和开发提供先导化合物或药物资源。现对查尔酮类化合物的抗肿瘤、抗寄生虫、抗HIV、抗炎等多种生物学活性的药理作用机制及构效关系进行了综述。     

Use of computational tools in the field of food safety

In this article we give an overview of how computational methods are currently used in the field of food safety by national regulatory bodies, international advisory organisations and the food industry. Our results show that currently the majority of stakeholders in the field of food safety do not apply computational methods on a routine basis, mainly because of a lack of in-house expertise. Some organisations, however, are very experienced in their use and have developed specialised in-house approaches. Despite this variable situation, computational tools are widely perceived to be a useful tool to support regulatory assessments and decision making in the field of food safety. Recognized, however, is a widespread need to develop guidance documents and software tools that will promote and harmonise the use of computational methods, together with appropriate training.     

Case studies to test: A framework for using structural, reactivity, metabolic and physicochemical similarity to evaluate the suitability of analogs for SAR-based toxicological assessments

A process for evaluating analogs for use in SAR (Structure-Activity Relationship) assessments was previously published (Wu et al. 2010). Subsequently, this process has been updated to include a decision tree for estrogen binding (from US EPA) and flags for developmental and reproductive toxicity (DART). This paper presents the results of blinded case studies designed to test this updated framework. The results of these case studies support the conclusion that the process outlined by Wu et al. (2010) can be successfully applied to develop surrogate values for risk assessment. The read across results generated by the process were shown to be protective when compared to the actual toxicity data. Successful application of the approach requires significant expertise as well as discipline to not overstep the boundaries of the defined analogs and the rating system. The end result of this rigor can be the inability to read across all endpoints for all chemicals resulting in data gaps that cannot be filled using read across, however, this reflects the current state of the science and is preferable to making non-protective decisions. Future work will be targeted towards expanding read across capabilities. Two examples of a broader category approach are also shown.     

Recent developments in the synthesis and biological activity of muramylpeptides

Derivatives of muramyl dipeptide (MDP) are considered as immunostimulants and adjuvants in the immunotherapy of cancer and infections. The interest in these compounds is mainly related to a high variety of their structure and biological properties. Here, we describe the synthesis and biological activity of several recently developed classes of MDP analogues. We also report potential of these analogues in the treatment of cancer and infectious diseases in experimental systems and cancer patients.     

Recent developments in human papillomavirus diagnosis and therapy in genital neoplasia

Infection with certain types of human papillomavirus (HPV) is casually associated with the development of cervical cancer and other anogenital neoplasia. There is increasing evidence of a wider association with other epithelial cancers. The availability of recombinant molecular biological techniques has circumvented the difficulties in studying the virus life cycle that is critically dependent on the differentiation of the epithelial target cell. From an understanding of the virology and cell biology of HPV infection, prospects for diagnostic and screening procedures in cervical neoplasia are being tested. The prize is the cost effective estimation of risk from HPV infection. New approaches need to be compared to existing and proven, although not perfect, smear test screening methods for prevention of cervical cancer. Novel research and development activities aimed at treating HPV infections in early premalignant lesions are utilising aspects of interference with early viral gene expression, or their co-ordinate cellular targets. Many immunological approaches with the goal of prevention of infection (prophylactic vaccination) or therapy of early cervical lesions are being tested. A virus-like particle composed of HPV L1 or L1/L2 capsid proteins, formulated to generate neutralising antibodies, is a key technology. Chimeric variations delivering other target antigens that can stimulate cytotoxic T-lymphocyte (CTL) activity may have wider applications in cancer treatments. Immunotherapeutic strategies aimed at treating late stage disease by optimising the stimulation of CTL versus HPV oncogenes is another major area of activity. Clinical trials testing the safety and efficacy of some of these inventions are in progress.     

Recent developments in the discovery of melanin-concentrating hormone antagonists: novel antiobesity agents

The discovery in the mid 1990s that melanin-concentrating hormone (MCH) is a strong appetite stimulant has led to a rapid increase in interest in this peptide. Significant evidence now exists establishing the key role that MCH plays in controlling food intake and energy homeostasis. Interest was further heightened by the discovery of two G-protein-coupled receptors (GPCRs) that were bound to, and activated by, MCH. Of these two receptors, only one, the MCH1 receptor, is expressed in rodents and as a result most of the efforts to identify MCH antagonists have focused on this receptor. Significant medicinal chemistry programmes from a number of companies have produced a variety of drug-like, low molecular weight MCH antagonists, a number of which have shown highly promising efficacy in a variety of animal models of food intake and body weight.     

Recent developments in the chemistry and in the biological applications of amidoximes

Amidoximes are compounds bearing both a hydroxyimino and an amino group at the same carbon atom which makes them versatile building blocks for the synthesis of various heterocycles. Their importance in chemistry along with their rich biology, make amidoximes an attractive target for medicinal chemists, biochemists and biologists. Amidoximes and simple O-substituted derivatives possess very important biological activities functioning as antituberculotic, antibacterial, bacteriostatic, insecticidal, elminthicidal, antiviral, herbicidal, fungicidal, antineoplastic, antiarrythmic, antihypertensive, antihistaminic, anxiolytic-antidepressant, anti-inflammatory/antioxidant, antiaggregatory (NO donors) or plant growth regulatory agents. A number of amidoximes has already been used as drugs, or currently being in clinical trials. Their numerous pharmaceutical applications have been recently enriched, due to the fact that some mechanistic pathways, concerning their conversion to amidines, as well as their ability to release NO were clarified, giving a new insight to their mode of action and allowing the design of new therapeutic agents. The main subject of the present review paper is to highlight aspects concerning chemical and biological questions on this interesting class of compounds. Some new synthetic methodologies as well as improvements of previously reported general reactions involving amidoximes, acylated amidoximes, and amidines are presented. The biological applications of amidoximes over the end of 2006 are also extensively reviewed.     

Recent developments of retinoids as therapeutic agents

Retinoids, a group of natural and synthetic retinol (vitamin A) analogues, play an important role in regulating pleiotropic biological events, including growth, differentiation and death of normal, premalignant and malignant cell types, which appears to account for their therapeutic or preventive effects in acne, psoriasis, photoageing, cancer and other diseases. Nuclear retinoic acid receptors and retinoid X receptors are thought to mediate the majority of retinoid biological effects. One effective strategy is to design and synthesise retinoids with receptor selectivity restricted to specific retinoic acid receptors or retinoid X receptor subtypes (α, β and γ) in order to develop novel retinoids with a more favourable therapeutic index and with reduced adverse effects and teratogenic risk. Indeed, retinoid medicinal chemistry has identified ligands that include highly specific antagonists for one of the three RAR subtypes and for retinoid X receptors. Since the retinoid X receptors also serve as heterodimer partners for several other nuclear receptors, including thyroid hormone receptors, vitamin D receptors, peroxisomal proliferator-activator receptors, Farnesoid X receptors and liver X receptors, retinoid X receptor-selective retinoids may have clinical applications for the prevention and treatment of diseases other than dermatological diseases and cancer, such as diabetes, obesity and atherosclerosis.     

Recent developments in the treatment of rheumatoid arthritis with targeted biological agents

Rheumatoid arthritis RA is a chronic systemic autoimmune inflammatory disease characterised by progressive joint damage. The pathophysiological processes involved in inflammatory reactions such as occur in RA and during infections have now been delineated, providing a scientific rationale for the use of biological and/or chemical entities targeted at specific sites of the inflammatory cascade in order to modulate inflammation. Currently available therapies for RA, such as myocrisin and sulfasalazine, were developed empirically without much regard for the basic physiological mechanisms of inflammation, and are not always effective at controlling the disease. The majority of the novel agents being developed for the treatment of RA are biological. However, their clinical effects have been transient, necessitating repeated treatments, many have to be administered parenterally, production costs are very high and some patients have developed antiglobulin responses. Consequently, chemical entities that can be taken orally have been developed. Clinical trials are awaited. Since the immune system is so complex, with pleiotropic cytokines and apparent redundancy in some of the regulatory networks, successful treatment of RA may require the administration of multiple agents targeted at different specific sites of the inflammatory cascade, or of different agents at different stages of the disease, in order to induce disease remission and maintain the response to therapy. However, since cytokines such as TNF-a and IL-1 play important physiological roles in the host's defence systems, chronic inhibition of these cytokines by targeted therapies may be associated with unwanted effects, e.g., infections. Long-term, carefully controlled studies are therefore necessary to assess the safety of selective targeting of processes involved in inflammation. In this chapter the current status and future prospects of these novel and advanced treatment modalities for RA are reviewed.     

Recent developments in ghrelin receptor (GHS-R1a) agonists and antagonists

The 28 amino acid polypeptide, ghrelin, is a novel neuroendocrine hormone synthesised primarily in the stomach. It stimulates growth hormone (GH) secretion, increases food intake and appetite and promotes body weight gain by decreasing fat mass metabolism, particularly in rodent models. The pharmacological properties of this peptide are mediated by the type 1a growth hormone secretagogue receptor (GHS-R1a), a G-protein-coupled receptor localised predominantly in the pituitary gland and hypothalamus. The discovery of new agents that either mimic or modulate the actions of ghrelin via the GHS-R1a has attracted considerable interest in recent years. Many peptidyl and peptidomimetic GHS-R1a agonists such as growth hormone-releasing peptides (GHRPs) and growth hormone secretagogues (GHSs) that stimulate GH secretion and increase plasma levels of insulin-like growth factor-1 (IGF-1) have been identified. First generation GHSs have undergone extensive clinical evaluation in humans, but have shown disappointing results in the treatment of diseases such as frailty, the age-related decline in body composition. Several of these compounds were found to increase adiposity in rodent models. Second generation dipeptidyl and third generation small molecule GHSs have recently been profiled in various animal models. A third generation of GHS with partial agonist activity at the GHS-R1a showed anabolic activity in rodent models, increasing fat-free (muscle) mass rather than fat mass. A few GHS-R1a receptor antagonists have been disclosed, although these compounds have exhibited poor selectivities or weak affinities for the receptor. Since endogenous ghrelin appears to play an important role in the long-term regulation of energy balance, GHS-R1a antagonists may be useful in the prevention of weight gain, following weight loss, or in the treatment of obesity, a pathological condition characterised by excess adiposity. This review describes the pharmacology of select ghrelin receptor modulators and highlights new ghrelin receptor agonists and antagonists that have appeared in the literature from 1999 – 2002.     

新型噁唑烷酮类抗菌药物的研究进展

目的阐述唑烷酮类抗菌药物的最新研究进展。方法根据近期关于新的唑烷酮类抗菌药物研究开发现状的29篇相关文献,对唑烷酮的3位芳基和5位侧链的结构改造特点进行整理和归纳。结果与结论大多数化合物具有提高的抗G+菌活性,部分化合物显示出抗G-菌的活性。另外,还介绍了一类具有扩大的抗菌谱的唑烷酮与其他类型抗菌药物形成的拼合化合物。     

The onus of cannabinoids in interrupting the molecular odyssey of breast cancer: A critical perspective on UPRER and beyond

Cannabinoids, commonly used for medicinal and recreational purposes, consist of various complex hydrophobic molecules obtained from Cannabis sativa L. Acting as an inhibitory molecule; they have been investigated for their antineoplastic effect in various breast tumor models. Lately, it was found that cannabinoid treatment not only stimulates autophagy-mediated apoptotic death of tumor cells through unfolded protein response (UPR^ER) activated downstream effectors, but also imposes cell cycle arrest. The exploitation of UPR^ER tumors as such is believed to be a major molecular event and is therefore employed in understanding the development and progression of breast tumor. Simultaneously, the data on clinical trials following administration of cannabinoid is currently being explored to find its role not only in palliation but also in the treatment of breast cancer. The present study summarizes new achievements in understanding the extent of therapeutic progress and highlights recent developments in cannabinoid biology towards achieving a better cure of breast cancer through the exploitation of different cannabinoids.     

Use of linear free energy relationships in toxicology: prediction of partition coefficients of volatile lipophilic compounds

A relationship between the partition coefficient (P) and the boiling point (T_Bp, expressed in degrees Kelvin) was derived as . The relationship is based on the Clausius-Clapeyron equation and is valid for volatile lipophilic compounds, when one of the phases is air. Specific tissue/air and whole animal/air partition coefficients, as published in the literature, were used to validate the equation.     

Recent developments in the treatment of tuberculosis

The history of chemotherapy of tuberculosis commenced in 1944 with the discovery of streptomycin. Currently, short-course chemotherapy comprising rifampicin, isoniazid, pyrazinamide and ethambutol/streptomycin administered under directly observed settings for 6 months (initially all four drugs followed by the former two drugs), constitutes the cornerstone treatment for pulmonary tuberculosis. Multi-drug resistant tuberculosis requires alternative chemotherapy, ideally in the form of individualised regimens, for management. To improve on the duration of chemotherapy for drug-susceptible tuberculosis and to achieve better treatment for multi-drug resistant tuberculosis as well as latent tuberculosis infection, there arises a genuine need for new drugs. The quest for new agents is, however, impeded by obstacles. Hopefully, tackling these through collaborative public-private partnerships on an international scale will lead to a fruitful outcome.     

Recent developments in the therapy of phaeochromocytoma

The basic principles of treatment for phaeochromocytomas and paragangliomas are to block the effects of high catecholamines and make the patient safe for surgical removal of the tumour. The traditional preoperative medical preparation uses the non-selective α-adrenoceptor blocker phenoxybenzamine and a β-adrenoceptor blocker, propranolol. Other agents have been used effectively, including selective α-adrenoceptor blockers, doxazosin and prazosin, and calcium channel antagonists. There have been no trial comparing regimens and there is some controversy as to the best regimen. Major advances have been made in laparoscopic and laparoscopic-assisted surgery. Cortical-sparing adrenalectomy has been used in some centres for familial phaeochromocytomas. High-dose [¹³¹I]-metaiodobenzylguanidine therapy and combined [¹³¹I]-metaiodobenzylguanidine and chemotherapy are promising new developments for the malignant disease. All patients should be followed indefinitely because the recurrence or malignancy rate is ≥ 10% over a prolonged follow up.     

Recent developments in the treatment of sepsis

Despite advances in supportive care, septic shock remains a major cause of morbidity and mortality. With the identification of the systemic inflammatory response as a major component in the pathogenesis of the septic shock syndrome, much of the recent work has focused on modulating this response. This includes antiendotoxin therapies in patients with Gram-negative sepsis, and therapies to modulate the pro-inflammatory mediators produced in response to infection, such as TNF-α, platelet-activating factor and complement. High-flow haemofiltration has the potential advantage of clearing both endotoxin and pro-inflammatory mediators. Antithrombotic strategies have been investigated and have yielded the first major success in the treatment of sepsis with activated protein C. Nitric oxide produces the cardiovascular features of sepsis and investigators have looked at both reducing its production and mopping up the excess. Attempts to reduce apoptosis have been a new focus in the treatment of sepsis. There have also been recent developments in supportive care suggesting a role for vasopressin and replacement corticosteroid therapy.     

Synthesis and biological studies of catechol ether type derivatives as potential phosphodiesterase (PDE) IV inhibitors

New series of catechol ether type derivatives 5, 6 have been synthesized and applied to biological tests. Even though it is a preliminary data, some of our target molecules show the promising result against PDE IV inhibition. SAR and biological studies with synthetic compounds will be discussed in detail.     

Recent developments in analytical determination of furosemide

Furosemide (FUR), a drug that promotes urine excretion, is used in the pharmacotherapy of various diseases and is considered as a doping agent in sports. FUR is a powerful diuretic (water pill). This medicine is used to treat excessive fluid accumulation and swelling (edema) of the body caused by heart failure, cirrhosis, chronic kidney failure, and nephrotic syndrome. Owing to its extensive use as a powerful diuretic, FUR has long attracted the attention of many analysts. A variety of analytical methods have been proposed for the determination of FUR in biological fluids and pharmaceutical samples. The revision includes the most relevant analytical methodologies used in its determination from the nineties decade at present.     

以贝壳为钙源的焦谷氨酸钙抗疲劳功效研究

摘 要：目的 验证一种新型补钙剂--焦谷氨酸钙（calcium L-pyroglutamate, CAP）的抗疲劳作用。方法 选取正常雄性昆明小鼠作为实验动物,腹腔注射脂多糖形成炎症模型,随机分组并通过观察小鼠负重游泳时间,血清尿素氮（BUN）、乳酸（LA）水平,血清乳酸脱氢酶（LDH）活性,血清肿瘤坏死因子α（TNF-α）,白介素10（IL-10）、白介素1β（IL-1β）,肝糖原、肌糖原以及肌肉组织中丙二醛（MDA）含量,超氧化物歧化酶（SOD）活性,综合评价焦谷氨酸钙的抗疲劳作用。结果 与模型组相比,高、低剂量组小鼠负重游泳时间显著延长（P<0.05或P<0.01）,焦谷氨酸钙高剂量组BUN水平显著下降（P<0.01）,血清LA水平显著下降,血清LDH活性显著提升,血清TNF-α,IL-1β浓度显著降低,IL-10浓度显著提高,肝、肌糖原含量显著升高,肌肉SOD活性显著升高,MDA含量显著下降。结论 焦谷氨酸钙具有显著抗疲劳效果,其作用机制可能与调节能量代谢,抗氧化应激活性以及抗炎症活性有关,可以作为一种潜在的抗疲劳药物。