Biocatalysis: synthesis of chiral intermediates for drugs

Chirality is a key factor in the safety and efficacy of many drug products and thus the production of single enantiomers of drug intermediates has become increasingly important in the pharmaceutical industry. Chiral intermediates and fine chemicals are in high demand for the bulk preparation of drug substances and agricultural products. There has been an increasing awareness of the enormous potential of the use of microorganisms and microorganism-derived enzymes for the transformation of synthetic chemicals with high chemo-, regio- and enantioselectivities. In this article, biocatalytic processes are described for the synthesis of chiral intermediates for drugs.     

专利视角下我国医药中间体应用技术发展态势研究

目的:协助企业了解医药中间体行业相关的技术点和发展趋势,为医药中间体应用技术提供新的发展思路和技术支持.方法:将医药中间体涉及的核心技术列为研究对象并分为四级,检索国家知识产权局专利检索系统(SIPO)及合享(INCOPAT)、智慧芽(PatSnap)专利数据库中2020年2月2日之前公开/公告的医药中间体专利数据.运...     

添加兴奋剂相关化学成分的中西药复方制剂说明书分析

为了解兴奋剂相关中西药复方制剂的含量控制现状,对添加兴奋剂相关化学成分的中西药复方制剂质量标准及说明书进行了分析。介绍了已被直接添加到中西药复方制剂的7种兴奋剂相关化学成分,梳理了269个有效批准文号,共涉及47个品种。得到的主要结论为添加兴奋剂相关化学成分的中西药复方制剂,其药品规格或说明书中未能完全体现所含化学药的含量,存在一定的安全隐患,特别在联合用药时,可能增加不良反应风险,同时可能导致运动员误服兴奋剂。建议对中西药复方制剂中的化学药成分及毒性成分进行控制,制定含量范围,为进一步完善质量标准和说明书提供参考,并充分引起医药行业对兴奋剂相关问题的重视。     

《新编国家中成药》收载品种中含化学药成分的统计与思考

目的确保用药安全、有效。方法对《新编国家中成药》所收载的含化学药成分的中成药进行列表、统计、分类。结果5017种中成药中含化学药成分的有160种,占3.19%;含化学药成分的中成药主要集中在抗感冒药、止咳平喘药、胃肠疾病治疗药物上;部分中成药说明书未按规定说明所含化学药成分。结论药品生产单位应完善中成药说明书中化学药成分相关信息;医师与药师应熟知相关信息,确保用药安全、有效。     

The application of structure-based assessment to support safety and chemistry diligence to manage genotoxic impurities in active pharmaceutical ingredients during drug development

Starting materials and intermediates used to synthesize pharmaceuticals are reactive in nature and may be present as impurities in the active pharmaceutical ingredient (API) used for preclinical safety studies and clinical trials. Furthermore, starting materials and intermediates may be known or suspected mutagens and/or carcinogens. Therefore, during drug development due diligence need be applied from two perspectives (1) to understand potential mutagenic and carcinogenic risks associated with compounds used for synthesis and (2) to understand the capability of synthetic processes to control genotoxic impurities in the API. Recently, a task force comprised of experts from pharmaceutical industry proposed guidance, with recommendations for classification, testing, qualification and assessing risk of genotoxic impurities. In our experience the proposed structure-based classification, has differentiated 75% of starting materials and intermediates as mutagenic and non-mutagenic with high concordance (92%) when compared with Ames results. Structure-based assessment has been used to identify genotoxic hazards, and prompted evaluation of fate of genotoxic impurities in API. These two assessments (safety and chemistry) culminate in identification of genotoxic impurities known or suspected to exceed acceptable levels in API, thereby triggering actions needed to assure appropriate control and measurement methods are in place. Hypothetical case studies are presented demonstrating this multi-disciplinary approach.     

Development and validation of a general non-digestive method for the determination of palladium in bulk pharmaceutical chemicals and their synthetic intermediates by graphite furnace atomic absorption spectroscopy

A simple, selective, sensitive, accurate and relatively inexpensive method for the determination of palladium in bulk pharmaceutical chemicals (BPC) and their synthetic intermediates by graphite furnace atomic absorption spectroscopy has been developed and validated. Sample preparation by direct dissolution of sample in 70% nitric acid is simple and effective without adverse effects. The limit of detection and the limit of quantitation of the method were determined to be 0.7 ppm and 2 ppm respectively in BPC.     

Continuous flow reactors for drug discovery

To develop a new generation of drugs, pharmaceutical companies need to be able to synthesize and screen novel chemicals with enhanced speed. New technology that would enable a cost-neutral increase in the number of potential drug candidates would provide a distinct competitive advantage. The miniaturisation of chemical reactors offers many fundamental and practical advantages of relevance to the pharmaceutical industry, which is constantly searching for controllable, information-rich, high-throughput and environmentally friendly methods of producing compounds with a high degree of chemical selectivity. This article reviews the current and future applications of micro reactors that could enhance the drug discovery process.     

Toxicogenomics and drug discovery: will new technologies help us produce better drugs?

Acting on reports in the late 1980s that most drug candidates fail in development, pharmaceutical discovery programmes responded by devising ways to increase the number of chemicals in the pipeline. With discovery now driven primarily by chemistry and high-throughput screening, the biological effects and, in particular, the toxicity of new compounds are largely not appreciated until a compound enters development. Arguably, this paradigm has produced more failures rather than delivering more successes--with more chemicals to examine, much less is known about any single agent before costly development studies are initiated. The emerging field of toxicogenomics is enabling us to ask detailed questions about drug effects very early on, thereby fundamentally changing our approach to drug discovery.     

中国医药化学品出口美国的现状及区域竞争优势

本文系统分析我国医药化学品的现状,并利用区域显示比较优势指数（RRCA）评价了我国医药化学品出口的竞争优势。实证分析显示,尽管中国某些医药化学品在美国市场上拥有较强的竞争力,但整体来讲,中国医药化学品在美国市场的竞争力很低,且仍处于下降的趋势。据此,本文提出了提高中国医药化学品在美国市场竞争力的对策方案。     

药物分析技术应用研究新进展

通过对2012年我国学者在国内外发表的有关药物分析技术应用研究论文进行检索和整理,分类综述针对化学药物、基因工程药物以及中药等各类药物或生物样本的过程分析技术、高通量筛选分析技术、固态性质表征分析技术、杂质谱检测分析技术、体内样本分析技术、中药分析技术、生化药物分析技术等的应用研究新进展。     

Zebrafish eleutheroembryos as an alternative system for screening chemicals disrupting the mammalian thyroid gland morphogenesis and function

The importance and irreversibility of the effects of thyroid hormone deficiency on human brain development highlight the importance of identifying environmental agents that interfere with thyroid gland morphogenesis and function. Zebrafish eleutheroembryos are currently used by many pharmaceutical companies in drug discovery as a vertebrate model, not subjected to regulations for animal experiments, that provides an intermediate step between in vitro and rodent assay. The mechanisms of zebrafish thyroid development are generally comparable to those in humans, and moreover, molecular and functional studies of zebrafish thyroid follicles have demonstrated a high degree of conservation with upper vertebrates, opening up the possibility of designing alternative methods for screening individual chemicals and mixtures that impairing thyroid gland morphogenesis and/or function. Analysis of the intrafollicular thyroxine-content of zebrafish larvae exposed to potential disruptors has proved to be a reliable, physiologically relevant endpoint to estimate effects of chemicals on the mammalian thyroid gland.     

Outsourcing to exploit a key asset

Much has been written and debated about the economic and organizational advantages of outsourcing a growing list of operations in drug discovery. In what has been described as a modular approach to drug discovery, whole sections of the process are now handled very effectively by a wide variety of specialist suppliers to the pharmaceutical industry. Here we report on a novel outsourced solution to the challenge of consolidating and managing some of the key assets residing within a major research organization - its chemical intermediates. At Johnson and Johnson Pharmaceutical Research and Development this resource has been built up over a period of more than 40 years, and is added to daily. The challenge was to provide the company's scientists with a single source for its own and externally procured intermediates; the solution was developed working in partnership with Sigma-Aldrich.     

Recent progress in enzymatic resolution and desymmetrization of pharmaceuticals and their intermediates

The literature since August 2000 is surveyed for interesting and useful examples of the resolution or desymmetrization of pharmaceutical entities, their intermediates and potential drug precursors. Existing, putative and developmental drugs used in various therapeutic areas are discussed.     

Scalable enantioselective processes for chiral pharmaceutical intermediates

The importance and practicality of asymmetric synthesis to obtain enantiomerically pure drug substances has been fully recognized by process chemists of the pharmaceutical industry. Catalytic enantioselective processes would be particularly advantageous, compared to processes requiring stoichiometric amounts of chiral initiators, and would also be of interest from an environmental perspective. Since the commercialization of the Monsanto process for the manufacturing of L-DOPA in the early 1970s, catalytic asymmetric reactions have often been utilized in the commercial production of active pharmaceutical ingredients. This review will focus on recent advances in the development of scalable enantioselective processes for chiral pharmaceutical intermediates.     

Cytochrome P450 enzymes in the generation of commercial products

Cytochrome P450 enzymes are remarkably diverse oxygenation catalysts that are found throughout nature. Although most of the interest in the pharmaceutical industry has focused on the role of cytochrome P450s in drug development, these enzymes also offer potential in the discovery not only of drugs, but also of other useful chemicals. Potential applications range from the use of cytochrome P450s as drug targets, to the use of randomly generated mutants of cytochrome P450s to produce libraries of new chemicals and drugs.     

微生物转化技术在现代医药工业中的应用

对微生物转化技术在现代医药工业应用上的独特优势。特别是在手性药物或药物中间体制备、借助微生物转化手段实施组合生物催化在新药筛选方面发挥的积极作用进行了阐述分析，并结合作者自身近年来在该技术领域的实践和收获对数个相关课题作了介绍。     

Hydroformylation and carbonylation processes: new trends in the synthesis of pharmaceuticals

The synthesis of complex organic molecules by catalytic transformations has made a significant impact on the development of new routes to a variety of pharmaceutical intermediates and optically active drugs. Carbonylation and hydroformylation reactions using metal complex catalysts are particularly attractive in this context as they provide clean, atom-efficient routes for the synthesis of molecules with carboxylic acid, aldehyde and amide functional groups to replace stoichiometric, multi-step routes using toxic and hazardous reagents. This review presents an update of recent research demonstrating the novel features of catalytic carbonylation and hydroformylation reactions and the current state of their development. Besides the expanding applications of carbonylation reactions, their unique features, such as high regioselectivity, high enantioselectivity (using appropriate chiral ligands) and their combination with other reactions to facilitate tandem (one-pot) synthesis, are highly promising. Clearly, the future direction is toward the synthesis of enantiomerically pure drug molecules and intermediates by asymmetric catalysis if the challenges of catalyst-product separation and the development of chiral ligands at a lower cost can be met.     

A rapid bioassay for chemicals that induce pro-oxidant states

A new bioassay has been developed that allows rapid, sensitive detection of chemicals such as paraquat and adriamycin, which manifest their acute toxicity, mutagenicity or carcinogenicity by inducing a pro-oxidant state in vivo. Submitochondrial particles isolated from bovine myocardium are used to catalyze NADH-dependent enzymatic reduction of these chemicals to free radicals. The highly reactive species generated in this system reduce molecular dioxygen to the superoxide anion radical, which is detected spectrophotometrically using the adrenochrome reaction. The anticancer drug adriamycin, the herbicides paraquat and diquat, the analytical dye sulfonazo III, and the experimental carcinogen 4-nitroquinoline-N-oxide have been used to test the sensitivity of this new method. This assay can be used to screen fresh water samples for the presence of pollutants that can generate oxygen-centered free radicals in vivo, or to test newly synthesized chemicals for this activity, and may therefore be valuable for environmental monitoring and preliminary toxicity evaluation of industrial or pharmaceutical products.     

Tight junction modulator and drug delivery

Recent progress in pharmaceutical technology based on genomic and proteomic research has provided many drug candidates, including not only chemicals but peptides, antibodies and nucleic acids. These candidates do not show pharmaceutical activity without their absorption into systemic flow and movement from the systemic flow into the target tissue. Epithelial and endothelial cell sheets play a pivotal role in the barrier between internal and external body and tissues. Tight junctions (TJs) between adjacent epithelial cells limit the movement of molecules through the intercellular space in epithelial and endothelial cell sheets. Thus, a promising strategy for drug delivery is the modulation of TJ components to allow molecules to pass through the TJ-based cellular barriers. In this review, we discuss recent progress in the development of TJ modulators and the possibility of absorption enhancers and drug-delivery systems based on TJ components.     

脂肪酶在手性药物中间体制备中的应用

近几年来，生物催化剂在有机合成中的应用已经成为一个比化学方法更吸引人的技术。尤其脂肪酶在有机合成中经常表现出极高的立体选择性，因此它们经常被用于制备光学活性化合物。文章详细介绍了脂肪酶在制备单一手性药物中间体中的应用，其中包括在实验室研究中的例子和在医药工业中已经形成一定生产规模的实例。