[Design Strategy of Biologically Active Compounds Using Various Elements].

Almost all conventional drug discovery research has been based on hydrocarbon-based frameworks and common chemical elements such as nitrogen, oxygen, sulfur, and the halogens. However, triggered by the approval of bortezomib, a boronic acid-containing pharmaceutical agent, the incorporation of functionalities that are not native in biological systems has been intensively investigated. Several other boron-containing pharmaceuticals have also been marketed. Therefore, the inclusion of various elements is one of the most promising strategies for the development of novel and distinctive drug candidates. In this symposium review, the author focused on the 'elements chemistry' approaches for the structural development of biologically active compounds, particularly those involving silicon and phosphorus. The isosteric exchange of Si and C (Si/C-exchange) is one of the most-investigated forms of substituting elements. We revealed the detailed physicochemical impact of Si/C-exchange, and we proposed several applications of silyl functionalities other than the simple Si/C-exchange. Regarding phosphorus, we recently revealed that the P-B substructure can function as the isostere of C-C or Si-C substructures. In addition to these isosteric exchanges, the development of biologically active compounds bearing unique substructures such as carboranes, hydrophobic boron clusters, and ferrocene is introduced. These novel strategies provide several options for structural development, offering great potential for expanding the chemical space of medicinal chemistry.

Biosynthesis, total synthesis, and biological profiles of Ergot alkaloids.

While the use of ergot alkaloids in folk medicine has been practiced for millennia, systematic investigations on their therapeutic potential began about 100 years ago. Subsequently, Albert Hofmann's discovery of lysergic acid diethylamide (LSD) and its intense psychedelic properties garnered worldwide attention and prompted further studies of this compound class. As a result, several natural ergot alkaloids were discovered and unnatural analogs were synthesized, and some were used to treat an array of maladies, including Alzheimer's and Parkinson's disease. While LSD was never commercially approved, recent clinical studies have found it can be an innovative and effective treatment option for several psychiatric disorders. Ongoing biosynthetic and total synthetic investigations aim to understand the natural origins of ergot alkaloids, help develop facile means to produce these natural products and enable their continued use as medicinal chemistry lead structures. This review recounts major developments over the past 20 years in biosynthetic, total synthetic, and pharmaceutical studies. Many ergot alkaloid biosynthetic pathways have been elucidated, with some of them subsequently applied toward "green" syntheses. New chemical methodologies have fostered a fast and efficient access to the ergoline scaffold, prompting some groups to investigate biological properties of natural product-like ergot alkaloids. Limited pharmaceutical applications have yet to completely bypass the undesirable side effects of ergotism, suggesting further studies of this drug class are likely needed and will potentially harness major therapeutic significance.

Computational Approaches to Molecular Properties, Chemical Reactivity, and Drug Virtual Screening.

In the first paragraph of his 1929 paper "Quantum Mechanics of Many-Electron Systems", Dirac wrote that "The underlying physical laws necessary for the mathematical theory of a large part of physics and the whole of chemistry are thus completely known, and the difficulty is only that the exact application of these laws leads to equations much too complicated to be soluble [...].

Technical Considerations for Use of Oligonucleotide Solution API.

The most common approach for the manufacture of oligonucleotides includes isolation of the active pharmaceutical ingredient (API) via lyophilization to provide a solid product, which is then dissolved to provide an aqueous formulation. It is well known from the development and manufacture of large molecules ("biologics") that API production does not always require isolation of solid API before drug product formulation, and this article provides technical considerations for the analogous use of oligonucleotide API in solution. The primary factor considered is solution stability, and additional factors such as viscosity, concentration, end-to-end manufacturing, microbiological control, packaging, and storage are also discussed. The technical considerations discussed in this article will aid the careful evaluation of the relative advantages and disadvantages of solution versus powder API for a given oligonucleotide drug substance.

Striking essential oil: tapping into a largely unexplored source for drug discovery.

Essential oils (EOs) have been used therapeutically for centuries. In recent decades, randomized controlled (clinical) trials have supported efficacy in specific therapeutic indications for a few of them. Some EOs, their components or derivatives thereof have been approved as drugs. Nevertheless, they are still considered products that are mainly used in complementary and alternative medicine. EO components occupy a special niche in chemical space, that offers unique opportunities based on their unusual physicochemical properties, because they are typically volatile and hydrophobic. Here we evaluate selected physicochemical parameters, used in conventional drug discovery, of EO components present in a range of commercially available EOs. We show that, contrary to generally held belief, most EO components meet current-day requirements of medicinal chemistry for good drug candidates. Moreover, they also offer attractive opportunities for lead optimization or even fragment-based drug discovery. Because their therapeutic potential is still under-scrutinized, we propose that this be explored more vigorously with present-day methods.

Fragment-to-Lead Medicinal Chemistry Publications in 2018.

This Perspective, the fourth in an annual series, summarizes fragment-to-lead (F2L) success stories published during 2018. Topics such as target class, screening methods, physicochemical properties, and ligand efficiency are discussed for the 2018 examples as well as for the combined 111 F2L examples covering 2015-2018. While the overall properties of fragments and leads have remained constant, a number of new trends are noted, for example, broadening of target class coverage and application of FBDD to covalent inhibitors. Moreover, several studies make use of fragment hits that were previously described in the literature, illustrating that fragments are versatile starting points that can be optimized to structurally diverse leads. By focusing on success stories, the hope is that this Perspective will identify and inform best practices in fragment-based drug discovery.

Are We Opening the Door to a New Era of Medicinal Chemistry or Being Collapsed to a Chemical Singularity?

The paradigm of "drug-like-ness" dramatically altered the behavior of the medicinal chemistry community for a long time. In recent years, scientists have empirically found a significant increase in key properties of drugs that have moved structures closer to the periphery or the outside of the rule-of-five "cage". Herein, we show that for the past decade, the number of molecules claimed in patent records by major pharmaceutical companies has dramatically decreased, which may lead to a "chemical singularity". New compounds containing fragments with increased 3D complexity are generally larger, slightly more lipophilic, and more polar. A core difference between this study and recently published papers is that we consider the nature and quality of sp3-rich frameworks rather than sp3 count. We introduce the original descriptor MCE-18, which stands for medicinal chemistry evolution, 2018, and this measure can effectively score molecules by novelty in terms of their cumulative sp3 complexity.

Analytical methods and biological activities of Panax notoginseng saponins: Recent trends.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng (Burk.) F. H. Chen, also called Sanqi, is a widely used traditional Chinese medicine, which has long history used as herbal medicines. It is currently an important medicinal material in China, holding the first place in the sale volume of the whole patent medicines market in China, and the market size of the single species has exceeded 10 billion yuan. In addition, P. notoginseng is an important constituent part of many famous Chinese patent medicines, such as Compound Danshen Dripping Pills and Yunnan Baiyao. P. notoginseng saponins (PNSs), which are the major active components of P. notoginseng, are a kind of chemical mixture containing different dammarane-type saponins. Many studies show that PNSs have been extensively used in medical research or applications, such as atherosclerosis, diabetes, acute lung injury, cancer, and cardiovascular diseases. In addition, various PNS preparations, such as injections and capsules, have been made commercially available and are widely applied in clinical practice. AIM OF THE REVIEW: Since the safety and efficacy of compounds are related to their qualitative and quantitative analyses, this review briefly summarizes the analytic approaches for PNSs and their biological effects developed in the last decade. METHODOLOGY: This review conducted a systematic search in electronic databases, such as Pubmed, Google Scholar, SciFinder, ISI Web of Science, and CNKI, since 2009. The information provided in this review is based on peer-reviewed papers and patents in either English or Chinese. RESULTS: At present, the chromatographic technique remains the most extensively used approach for the identification or quantitation of PNSs, coupled with different detectors, among which the difference mainly lies in their sensitivity and specificity for analyzing various compounds. It is well-known that PNSs have traditionally strong activity on cardiovascular diseases, such as atherosclerosis, intracerebral hemorrhage, or brain injury. The recent studies showed that PNSs also responded to osteoporosis, cancers, diabetes, and drug toxicity. However, some other studies also showed that some PNSs injections and special PNS components might lead to some biological toxicity under certain dosages. CONCLUSION: This review may be used as a basis for further research in the field of quantitative and qualitative analyses, and is expected to provide updated and valuable insights into the potential medicinal applications of PNSs.

Fragment-to-Lead Medicinal Chemistry Publications in 2017.

This Miniperspective is the third in a series reviewing fragment-to-lead publications from a given year. Following our reviews for 2015 and 2016, this Miniperspective provides tabulated summaries of relevant articles published in 2017 along with some general observations. In addition, we discuss insights obtained from analysis of the combined data set of 85 examples from all three years of publications.

[The present situation and countermeasures of Uighur medicine compound].

Uighur medicine compound, which created and used by Uighur nationality, is under the guidance of the Uighur medical theory system of herbal formula and dialectical use of minority nationality conventional medicines. In recent years, Uighur medicine attracted more and more attention of people which have used and were using it. Combining the history of Uighur medicine, this article summarizes the Uighur resources, medicinal materials, drugs preparation, ancient documents, and the establishment of the clinical evaluation system and so on, and then analyzes the status quo and the existing problems in Uighur medicine compound research and industry. On this basis, we put forward countermeasures and suggestions for the development of Uighur medicine.

Computer-Aided Drug Discovery from Marine Compounds: Identification of the Three-Dimensional Structural Features Responsible for Antimalarial Activity.

An integrated computational approach, based on molecular dynamics/mechanics, semi-empirical, and DFT calculations as well as dynamic docking studies, has been employed to gain insight into the mechanism of action of new antimalarial agents characterized by the scaffold of the marine compounds plakortin and aplidinone. The results of this approach show that these molecules, after interaction with Fe(II), likely coming from the heme molecule, give rise to the formation of radical species, that should represent the toxic intermediates responsible for subsequent reactions leading to plasmodium death. The three-dimensional structural requirements necessary for the activity of these new classes of antimalarial agents have been identified and discussed throughout the chapter.

Bluegenics: Bioactive Natural Products of Medicinal Relevance and Approaches to Their Diversification.

Nature provides a valuable resource of medicinally relevant compounds, with many antimicrobial and antitumor agents entering clinical trials being derived from natural products. The generation of analogues of these bioactive natural products is important in order to gain a greater understanding of structure activity relationships; probing the mechanism of action, as well as to optimise the natural product's bioactivity and bioavailability. This chapter critically examines different approaches to generating natural products and their analogues, exploring the way in which synthetic and biosynthetic approaches may be blended together to enable expeditious access to new designer natural products.

Discovery and Development of Novel Drugs.

Drug discovery and development process is nowadays conducted in relatively standardised sequence of phases, starting with Discovery and being followed by Preclinical, Clinical and Non-Clinical Development. Discovery phase is divided in Hit Finding, Lead generation, Lead Optimisation and Candidate Identification Phase. Main drivers of the whole process are regulatory requirements and the aim to eliminate the unnecessary spending by early elimination of unlikely drug candidates. Marine products, once purified, isolated and produced in required quantities, follow the same route as any other synthetic drug.

Nutraceuticals, A New Challenge for Medicinal Chemistry.

"Nutraceuticals" are food-derived products largely used for their presumed healthpromoting or disease-preventing effects. In the recent years, many efforts have been aimed at assessing nutraceutical efficacy and safety, but these factors are difficult to address because of the complex chemical compositions and multiple mode of actions. Thus, the study of nutraceutical ingredients poses several challenges for the medicinal chemistry field, some of which are related to extraction and chemical characterization, some to in vitro and in vivo bioactivity evaluation, and some to the bioavailability and interaction of these natural mixtures with organs and microbiota. Furthermore, because of their nature as medicinal and food products, these nutraceuticals can also be considered as a valuable source of new "lead compounds", creating the opportunity to discover new classes of therapeutic agents. This review provides information on these themes, showing the new challenges that comprehensive medicinal chemistry research is called to answer in the field of nutraceuticals.

[Development and innovation of traditional Chinese medicine processing discipline and Chinese herbal pieces industry].

To elucidate the key issues in the development and innovation of traditional Chinese medicine processing discipline and Chinese herbal pieces industry Chinese herbal pieces industry. According to the author's accumulated experience over years and demand of the development of the Chinese herbal pieces industry, the key issues in the development and innovation on the Chinese herbal pieces industry were summarized. According to the author, the traditional Chinese medicine processing discipline shall focus on a application basis research. The development of this discipline should be closely related to the development of Chinese herbal pieces. The traditional Chinese medicine processing discipline can be improved and its results can be transformed only if this discipline were correlated with the Chinese herbal pieces industry, matched with the development of the Chinese herbal pieces industry, and solved the problems in the development on the Chinese herbal pieces industry. The development of traditional Chinese medicine processing discipline and the Chinese herbal pieces industry also requires scientific researchers to make constant innovations, realize the specialty of the researches, and innovate based on inheritance.

[Scalability and extensionality of innovative Chinese medicine preparation under guidance of component structure theory].

Chinese medicine preparation is a science to study how to make raw material into suitable dosage forms to be used in clinical operations. Its study scope is significantly different from traditional chemical drugs. As is known, the ingredients of Chinese medicine are complex and various, as a result, the composition of the ingredients is not clear and the property is not unified. The pre-treatment process is the key factor to affect the druggability, safety and efficacy of the Chinese medicine. The connotation of Chinese medicine is a huge systematic project, not only including the traditional dosage form design process but also including the components structure optimization process on material basis, components extraction, separation and purification process, components characterization process as well as the pharmacological and toxicological study processes which aim to select suitable dosage form to exert the maximum drug efficacy and evaluate the properties of preparations. Therefore, according to the requirement of modern innovative preparations and based on the integrity and systematicness of Chinese medicine, in this paper we will explore the scalability and extensionality of modern Chinese medicine, including the material basis of Chinese medicine based on component structure theory; separation, refining and purification of components; component structure optimization and network pharmacology and regulation, as well as biopharmaceutics properties of representative components, and we will construct the multi-unit drug delivery system and Chinese medicine multi-dimensional dynamic quality control system. This paper elaborates the scientific connotation and systematicness of modern Chinese preparation, and provides ideas and methods for the development of modern innovative Chinese preparations.

Comparison of three development approaches for Stationary Phase Optimised Selectivity Liquid Chromatography based screening methods Part I: A heterogeneous group of molecules (slimming agents in food supplements).

Three approaches for the development of a screening method to detect adulterated dietary supplement, based on Stationary Phase Optimised Selectivity Liquid Chromatography were compared for their easiness/speed of development and the performance of the optimal method obtained. This comparison was performed for a heterogeneous group of molecules, i.e. slimming agents (Part I) and a group of structural analogues, i.e. PDE-5 inhibitors (Part II). The first approach makes use of primary runs at one isocratic level, the second of primary runs in gradient mode and the third of primary runs at three isocratic levels to calculate the optimal combination of segments of stationary phases. In each approach the selection of the stationary phase was followed by a gradient optimisation. For the slimming agents, the heterogeneous group of molecules, the method obtained with the first approach was selected as optimal, based on the speed of development and the performance of the method. The method shows a good separation of the compounds, allowing the screening to be performed with diode array detection, and is fully compatible with mass spectrometry. The method was validated for its selectivity following the guidelines as described for the screening of pesticide residues and residues of veterinary medicines in food.

Novel therapeutic strategy in the management of COPD: a systems medicine approach.

Respiratory diseases including chronic-obstructive-pulmonary-disease (COPD) are globally increasing, with COPD predicted to become the third leading cause of global mortality by 2020. COPD is a heterogeneous disease with COPD-patients displaying different phenotypes as a result of a complex interaction between various genetic, environmental and life-style factors. In recent years, several investigations have been performed to better define such interactions, but the identification of the resulting phenotypes is still somewhat difficult, and may lead to inadequate assessment and management of COPD (usually based solely on the severity of airflow limitation parameter FEV1). In this new scenario, the management of COPD has been driven towards an integrative and holistic approach. The degree of complexity requires analyses based on large datasets (also including advanced functional genomic assays) and novel computational biology approaches (essential to extract information relevant for the clinical decision process and for the development of new drugs). Therefore, according to the emerging "systems/network medicine", COPD should be re.-evaluated considering multiple network(s) perturbations such as genetic and environmental changes. Systems Medicine (SM) platforms, in which patients are extensively characterized, offer a basis for a more targeted clinical approach, which is predictive, preventive, personalized and participatory ("P4-medicine"). It clearly emerges that in the next future, new opportunities will become available for clinical research on rare COPD patterns and for the identification of new biomarkers of comorbidity, severity, and progression. Herein, we overview the literature discussing the opportunity coming from the adoption of SMapproaches in COPD management, focusing on proteomics and metabolomics, and emphasizing the identification of disease sub-clusters, to improve the development of more effective therapies.

[Research status and prospect of primary processing of traditional Chinese medicinal materials].

The primary processing is important links and closely related to the quality of traditional Chinese medicinal materials, and is not only cleaning of remove the non-officinal parts, drying for termination the physiological status of organisms, but also retaining the most active substances, decreasing the toxic components, and promoting the transformation among chemical ingredients through primary processing. So the traditional primary processing endows with characters, quality, specifications and properties of traditional Chinese medicine, and embodies some important science truth. The traditional primary processing method and technology systems are derived from the long-term practices and experiences, which are distinctive, colorful, diverse, and scientific, which are helpful to development and utilization of traditional Chinese medicine resources. This paper systemically expounds the research status of the Chinese medicine processing method, summarizes the problems in the primary processing of traditional Chinese medicinal materials research, and prospects its bright future.

Phytocannabinoids for Cancer Therapeutics: Recent Updates and Future Prospects.

Phytocannabinoids (pCBs) are lipid-soluble phytochemicals present in the plant, Cannabis sativa L. and non-cannabis plants which have a long history in recreation and traditional medicine. The plant and the constituents isolated were central in the discovery of the endocannabinoid system (ECS), the most new target for drug discovery. The ECS includes two G-protein-coupled receptors; the cannabinoid receptors-1 and -2 (CB1 and CB2) for marijuana's psychoactive principle Δ(9)-tetrahydrocannabinol (Δ(9)-THC), their endogenous small lipid ligands; namely anandamide (AEA) and 2-arachidonoylglycerol (2-AG), also known as endocannabinoids and the enzymes for endocannabinoid biosynthesis and degradation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The ECS has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during pathological conditions including cancer. Targeting the CB1 receptors becomes a concern because of adverse psychotropic reactions. Hence, targeting the CB2 receptors or the endocannabinoid metabolizing enzymes by pCBs obtained from plants lacking psychotropic adverse reactions has garnered interest in drug discovery. These pCBs derived from plants appear safe and effective with a wider access and availability. In the recent years, several pCBs derived other than non-cannabinoid plants have been reported to bind to and functionally interact with cannabinoid receptors and appear promising candidate for drug development including cancer therapeutics. Several of them also targets the endocannabinoid metabolizing enzymes that control endocannabinoid levels. In this article, we summarize and critically discuss the updates and future prospects of the pCBs as novel and promising candidates for cancer therapeutics.