Tandem reactions,cascade sequences,and biomimetic strategies in total synthesis

Cascade reactions and biomimetic strategies are being increasingly applied to the construction of natural and designed molecules. Such processes, in which ideally a single event triggers the conversion of a starting material to a product which then becomes a substrate for the next reaction until termination leads to a stable final product, are highly desirable not only due to their elegance, but also because of their efficiency and economy in terms of reagent consumption and purification. Often, these multistep, one-pot procedures are accompanied by dramatic increases in molecular complexity and impressive selectivity. The discovery of new molecular diversity from Nature and the demand for more efficient and environmentally benign chemical processes dictates and invites the further development of such synthetic strategies and tactics as we move into a new age of chemical synthesis. Within this article, a number of instructive examples of such synthetic strategies from the principal author's laboratories are discussed.     

Aminoboronic acids and esters: from synthetic challenges to the discovery of unique classes of enzyme inhibitors

Although boronic acids have attracted considerable interest as versatile intermediates in organic synthesis, their contributions in chemical biology and drug discovery programs have long been underestimated. This situation is changing since the beginning of the 2000s, mainly due to significant advances in modern organoborane chemistry and the recent FDA approval of Velcade?, a boropeptide used for multiple myeloma treatment. There is now a significant renewed interest in the design and synthesis of new boron-containing compounds. Due to their close analogy to their carbon counterparts, aminoboronic acids, alone or incorporated at the C-terminal position of a peptide, represent one of the major classes of organoboranes evaluated as potential drug candidates. This critical review aims to provide an overview of the current state of the art in their synthesis and their most relevant biological properties (156 references).     

Combinatorial chemistry: libraries from libraries, the art of the diversity-oriented transformation of resin-bound peptides and chiral polyamides to low molecular weight acyclic and heterocyclic compounds

Combinatorial chemistry has deeply impacted the drug discovery process by accelerating the synthesis and screening of large numbers of compounds having therapeutic and/or diagnostic potential. These techniques offer unique enhancement in the potential identification of new and/or therapeutic candidates. Our efforts over the past 10 years in the design and diversity-oriented synthesis of low molecular weight acyclic and heterocyclic combinatorial libraries derived from amino acids, peptides, and/or peptidomimetics are described. Employing a "toolbox" of various chemical transformations, including alkylation, oxidation, reduction, acylation, and the use of a variety of multifunctional reagents, the "libraries from libraries" concept has enabled the continued development of an ever-expanding, structurally varied series of organic chemical libraries.     

Non-peptidic natural products as ubiquitin-proteasome inhibitors

Approval of bortezomib has validated ubiquitin-proteasome pathway as an important target for treatment of haematological malignancies. However, clinical shortcomings of bortezomib, a covalent peptide proteasome inhibitor, has prompted a paradigm shift in anti-proteasome drug discovery towards development of non-peptidic inhibitors and targeting of upstream ubiquitin system which has drawn traction for interdisciplinary forays. It is being widely recognized that natural products provide valuable leads in the discovery of potent, chemically diverse, non-peptidic inhibitors of 20S proteasome and of key enzymes involved in ubiquitination machinery. As a result, total synthesis of natural, non-peptidic inhibitors of ubiquitin-proteasome pathway has emerged as a critical interlink between organic synthesis, medicinal chemistry, biochemical profiling and drug discovery. An up-to-date account of contextual synthetic challenges, strategies and accomplishments as well as mapping of the chemical diversity space around the natural scaffolds has been captured in this review.     

Molecular Design in Practice: A Review of Selected Projects in a French Research Institute That Illustrates the Link between Chemical Biology and Medicinal Chemistry

Chemical biology and drug discovery are two scientific activities that pursue different goals but complement each other. The former is an interventional science that aims at understanding living systems through the modulation of its molecular components with compounds designed for this purpose. The latter is the art of designing drug candidates, i.e., molecules that act on selected molecular components of human beings and display, as a candidate treatment, the best reachable risk benefit ratio. In chemical biology, the compound is the means to understand biology, whereas in drug discovery, the compound is the goal. The toolbox they share includes biological and chemical analytic technologies, cell and whole-body imaging, and exploring the chemical space through state-of-the-art design and synthesis tools. In this article, we examine several tools shared by drug discovery and chemical biology through selected examples taken from research projects conducted in our institute in the last decade. These examples illustrate the design of chemical probes and tools to identify and validate new targets, to quantify target engagement in vitro and in vivo, to discover hits and to optimize pharmacokinetic properties with the control of compound concentration both spatially and temporally in the various biophases of a biological system.     

A New Heterocyclic Multicomponent Reaction For the Combinatorial Synthesis of Fused 3-Aminoimidazoles

When general and reliable , multicomponent reactions are among the most powerful tools in modern drug discovery. The principle of chemical ligation of reactive partners (see reaction scheme) has been employed to find a new, highly efficient synthesis of fused 3-aminoimidazoles.     

多组分反应在合成含肽类药物开发中的应用

多组分反应可以快速大量的合成结构复杂的药物分子,因此现代药物开发与多组分反应的发展密切相关。本文总结了近年来国内外有关多组分反应研究的发展概况及其在含肽链类新药物开发中的应用研究进展。     

Recent Advances in the Chemistry and Biology of Naturally Occurring Antibiotics

Ever since the world‐shaping discovery of penicillin, nature's molecular diversity has been extensively screened for new medications and lead compounds in drug discovery. The search for agents intended to combat infectious diseases has been of particular interest and has enjoyed a high degree of success. Indeed, the history of antibiotics is marked with impressive discoveries and drug‐development stories, the overwhelming majority of which have their origin in natural products. Chemistry, and in particular chemical synthesis, has played a major role in bringing naturally occurring antibiotics and their derivatives to the clinic, and no doubt these disciplines will continue to be key enabling technologies. In this review article, we highlight a number of recent discoveries and advances in the chemistry, biology, and medicine of naturally occurring antibiotics, with particular emphasis on total synthesis, analogue design, and biological evaluation of molecules with novel mechanisms of action.     

Virtual darwinian drug design: QSAR inverse problem, virtual combinatorial chemistry, and computational screening

The generation of diversity and its further selection by an external system is a common mechanism for the evolution of the living species and for the current drug design methods. This assumption allows us to label the methods based on generation and selection of molecular diversity as "Darwinian" ones, and to distinguish them from the structure-based, structure-modulation approaches. An example of a Darwinian method is the inverse QSAR. It consists of the computational generation of candidate chemical structures and their selection according to a previously established QSAR model. New trends in the field of combinatorial chemical syntheses comprise the concepts of virtual combinatorial synthesis and virtual or computational screening. Virtual combinatorial synthesis, closely related to inverse QSAR, can be defined as the computational simulation of the generation of new chemical structures by using a combinatorial strategy to generate a virtual library. Virtual screening is the selection of chemical structures having potential desirable properties from a database or virtual library in order to be synthesized and assayed. This review is mainly focused on graph theoretical drug design approaches, but a survey with key references is provided that covers other simulation methods.     

Modern drug discovery technologies: opportunities and challenges in lead discovery

The identification of promising hits and the generation of high quality leads are crucial steps in the early stages of drug discovery projects. The definition and assessment of both chemical and biological space have revitalized the screening process model and emphasized the importance of exploring the intrinsic complementary nature of classical and modern methods in drug research. In this context, the widespread use of combinatorial chemistry and sophisticated screening methods for the discovery of lead compounds has created a large demand for small organic molecules that act on specific drug targets. Modern drug discovery involves the employment of a wide variety of technologies and expertise in multidisciplinary research teams. The synergistic effects between experimental and computational approaches on the selection and optimization of bioactive compounds emphasize the importance of the integration of advanced technologies in drug discovery programs. These technologies (VS, HTS, SBDD, LBDD, QSAR, and so on) are complementary in the sense that they have mutual goals, thereby the combination of both empirical and in silico efforts is feasible at many different levels of lead optimization and new chemical entity (NCE) discovery. This paper provides a brief perspective on the evolution and use of key drug design technologies, highlighting opportunities and challenges.     

Quality, not quantity: the role of natural products and chemical proteomics in modern drug discovery

Chemical genetics and reverse chemical genetics parallel classical genetics but target genes at the protein level and have proven useful in recent years for screening combinatorial libraries for compounds of biological interest. However, the performance of combinatorial chemistry in filling pharmaceutical pipelines has been lower than anticipated and the tide may be turning back to Nature in the search for new drug candidates. Even though diversity oriented synthesis is now producing molecules that are natural product-like in terms of size and complexity, these molecules have not evolved to interact with biomolecules. Natural products, on the other hand, have evolved to interact with biomolecules, which is why so many can be found in pharmacopoeias. However, the cellular targets and modes of action of these fascinating compounds are seldom known, hindering the drug development process. This review focuses on the emergence of chemical proteomics and reverse chemical proteomics as tools for the discovery of cellular receptors for natural products, thereby generating protein/ligand pairs that will prove useful in identifying new drug targets and new biologically active small molecule scaffolds. Such a system-wide approach to identifying new drugable targets and their small molecule ligands will help unblock the pharmaceutical product pipelines by speeding the process of target and lead identification.     

Construction of a Meroterpenoid-Like Compounds Library Based on Diversity-Enhanced Extracts

The structural diversity of natural products and their derivatives have long contributed to the development of new drugs. However, the difficulty in obtaining compounds bearing skeletally novel structures has recently led to a decline of pharmaceutical research into natural products. This paper reports the construction of a meroterpenoid-like library containing 25 compounds with diverse molecular scaffolds obtained from diversity-enhanced extracts. This method constitutes an approach for increasing the chemical diversity of natural-product-like compounds by combining natural product chemistry and diversity-oriented synthesis. Extensive pharmacological screening of the library revealed promising compounds for anti-osteoporotic and anti-lymphoma/leukemia drugs. This result indicates that the use of diversity-enhanced extracts is an effective methodology for producing chemical libraries for the purpose of drug discovery.     

A green protocol for efficient discovery of novel natural compounds: Characterization of new ginsenosides from the stems and leaves of Panax ginseng as a case study

Exploration of new natural compounds is of vital significance for drug discovery and development. The conventional approaches by systematic phytochemical isolation are low-efficiency and consume masses of organic solvent. This study presents an integrated strategy that combines offline comprehensive two-dimensional liquid chromatography, hybrid linear ion-trap/Orbitrap mass spectrometry, and NMR analysis (2D LC/LTQ-Orbitrap-MS/NMR), aimed to establish a green protocol for the efficient discovery of new natural molecules. A comprehensive chemical analysis of the total ginsenosides of stems and leaves of Panax ginseng (SLP), a cardiovascular disease medicine, was performed following this strategy. An offline 2D LC system was constructed with an orthogonality of 0.79 and a practical peak capacity of 11,000. The much greener UHPLC separation and LTQ-Orbitrap-MS detection by data-dependent high-energy C-trap dissociation (HCD)/dynamic exclusion were employed for separation and characterization of ginsenosides from thirteen fractionated SLP samples. Consequently, a total of 646 ginsenosides were characterized, and 427 have not been isolated from the genus of Panax L. The ginsenosides identified from SLP exhibited distinct sapogenin diversity and molecular isomerism. NMR analysis was finally employed to verify and offer complementary structural information to MS-oriented characterization. The established 2D LC/LTQ-Orbitrap-MS/NMR approach outperforms the conventional approaches in respect of significantly improved efficiency, much less use of drug materials and organic solvent. The integrated strategy enables a deep investigation on the therapeutic basis of an herbal medicine, and facilitates new compounds discovery in an efficient and environmentally friendly manner as well.     

Past and future perspectives of synthetic peptide libraries

Combinatorial preparation and HTS of arrays of compounds have increased the speed of drug discovery. A strong impulse in this field has come by the introduction of the solid phase synthesis method that, through automation and miniaturization, has paved the way to the preparation of large collections of compounds in compact and trackable formats. Due to the well established synthetic procedures, peptides have been largely used to develop the basic concepts of combinatorial chemistry and peptide libraries are still successfully employed in screening programs. However, peptides generally do not fulfil the requirements of low conformational flexibility, stability and bioavailability needed for good drug candidates and peptide leads with high potency and selectivity are often made "druggable" by conversion to more stable structures with improved pharmacological profiles. Such an approach makes the screening of peptide libraries still a valuable tool for drug discovery. We propose here a panoramic review of the most common methods for the preparation and screening of peptide libraries and the most interesting findings of the last decade. We also report on a new approach we follow in our laboratory that is based on the use of "simplified" libraries composed by a minimum number of non-redundant amino acids for the assembly of short peptides. The choice of amino acids is dictated by diversity in lipophilicity, MW, charge and polarity. Newly identified active sequences are then modified by preparing new variants containing analogous amino acids, so that the chemical space occupied by the excluded residues can be explored. This approach offers the advantage of simplifying the synthesis and deconvolution of libraries and provides new active compounds with a molecular size similar to that of small molecules, to which they can be easily converted.     

Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery

Fragment-based drug discovery (FBDD) is a powerful strategy for the identification of new bioactive molecules. FBDD relies on fragment libraries, generally of modest size, but of high chemical diversity. Although good chemical diversity in FBDD libraries has been achieved in many respects, achieving shape diversity – particularly fragments with three-dimensional (3D) structures – has remained challenging. A recent analysis revealed that >75% of all conventional, organic fragments are predominantly 1D or 2D in shape. However, 3D fragments are desired because molecular shape is one of the most important factors in molecular recognition by a biomolecule. To address this challenge, the use of inert metal complexes, so-called ‘metallofragments’ (mFs), to construct a 3D fragment library is introduced. A modest library of 71 compounds has been prepared with rich shape diversity as gauged by normalized principle moment of inertia (PMI) analysis. PMI analysis shows that these metallofragments occupy an area of fragment space that is unique and highly underrepresented when compared to conventional organic fragment libraries that are comprised of orders of magnitude more molecules. The potential value of this metallofragment library is demonstrated by screening against several different types of proteins, including an antiviral, an antibacterial, and an anticancer target. The suitability of the metallofragments for future hit-to-lead development was validated through the determination of IC₅₀ and thermal shift values for select fragments against several proteins. These findings demonstrate the utility of metallofragment libraries as a means of accessing underutilized 3D fragment space for FBDD against a variety of protein targets.

Fragment-based drug discovery (FBDD) using 3-dimensional metallofragments is a new strategy for the identification of bioactive molecules.     

Construction of N-Heterocycles through Cyclization of Tertiary Amines

N-Heterocycles have been found in a large number of natural products, drug molecules, and bioactive compounds, and they thereby play a vital role in diverse research disciplines including drug discovery, organic synthesis, chemical biology, and material science. To this end, the development of new methods and strategies for the construction of N-heterocyclic frameworks is arguably one of the most dynamic and significant research areas in organic synthesis. One of these powerful approaches to the synthesis of N-heterocycles is to establish cyclization reactions based on the transformation of tertiary amines, which has emerged as an attractive research topic. In this Minireview, the significant achievements in the construction of N-heterocycles through cyclization of tertiary amines are highlighted and a comprehensive overview of the rational design, development, and application of these synthetic methods is presented.     

Adventures in Carbohydrate Chemistry: New Synthetic Technologies, Chemical Synthesis, Molecular Design, and Chemical Biology A list of abbreviations can be found at the end of this article. Telemachos Charalambous was an inspiring teacher at the Pancyprian Gymnasium, Nicosia, Cyprus

The field of carbohydrate chemistry has occupied the minds and hearts of many scientists for over a hundred years and, as we enter the twenty-first century, it continues to be both vigorous and challenging. Among the most exciting aspects of organic chemistry in the last few decades has been the interplay between the specialized subdisciplines of carbohydrate chemistry and total synthesis, each enabling and advancing the other in new directions and towards greater heights. In this review article we highlight our own adventures at the interface of these disciplines, which were driven for the most part by objectives in chemical synthesis and chemical biology. Specifically, we describe our interests and efforts to utilize carbohydrates as starting materials for total synthesis, to invent and develop new synthetic technologies for carbohydrate synthesis, to construct complex oligosaccharides in solution or on solid support, and to utilize carbohydrate templates as scaffolds for peptide mimetics and for molecular diversity construction. Finally, applications of the developed synthetic strategies and enabling technologies towards the solution of biologically significant problems are discussed.     

Insulin—From its Discovery to the Industrial Synthesis of Modern Insulin Analogues

After the discovery of insulin as a drug for diabetes, the pharmaceutical companies were faced with the challenge to meet the demand for insulin with the highest possible degree of purity in the required quantities from animal sources. The observation of an immune reaction of patients to insulin from animal pancreatic extracts made the availability of human insulin of highest priority. Only the enzyme‐catalyzed semisynthesis at the C‐terminus of the insulin B‐chain led to a commercial process, but it depended on porcine insulin and was aggravated by supply concerns. The advent of rDNA technology allowed the commercial preparation of human insulin by biosynthesis in virtually unlimited quantities. An increased chemical diversity was only envisaged through chemical synthesis, which was simplified by advances in solid‐phase peptide synthesis and chemical ligation. Single‐chain insulin precursors are now being synthesized that should enable fast screening of insulin analogues for improved biophysical, biological, and thus promising new therapeutic properties, as well as for the industrial manufacture of insulin analogues not accessible by biosynthesis.     

Modern Approaches in the Discovery and Development of Plant-Based Natural Products and Their Analogues as Potential Therapeutic Agents

Natural products represents an important source of new lead compounds in drug discovery research. Several drugs currently used as therapeutic agents have been developed from natural sources; plant sources are specifically important. In the past few decades, pharmaceutical companies demonstrated insignificant attention towards natural product drug discovery, mainly due to its intrinsic complexity. Recently, technological advancements greatly helped to address the challenges and resulted in the revived scientific interest in drug discovery from natural sources. This review provides a comprehensive overview of various approaches used in the selection, authentication, extraction/isolation, biological screening, and analogue development through the application of modern drug-development principles of plant-based natural products. Main focus is given to the bioactivity-guided fractionation approach along with associated challenges and major advancements. A brief outline of historical development in natural product drug discovery and a snapshot of the prominent natural drugs developed in the last few decades are also presented. The researcher’s opinions indicated that an integrated interdisciplinary approach utilizing technological advances is necessary for the successful development of natural products. These involve the application of efficient selection method, well-designed extraction/isolation procedure, advanced structure elucidation techniques, and bioassays with a high-throughput capacity to establish druggability and patentability of phyto-compounds. A number of modern approaches including molecular modeling, virtual screening, natural product library, and database mining are being used for improving natural product drug discovery research. Renewed scientific interest and recent research trends in natural product drug discovery clearly indicated that natural products will play important role in the future development of new therapeutic drugs and it is also anticipated that efficient application of new approaches will further improve the drug discovery campaign.     

Chemical and biological integrity in natural products screening

Due to pressure from combinatorial chemistry and the streamlining of the drug discovery process through automated high-throughput screening technologies, pharmaceutically based natural products programs are under increasing scrutiny. However by taking advantages of technologies originally developed for high-throughput screening and combinatorial chemistry and applying them to processes considered as bottlenecks in classical natural products chemistry (purification, structure elucidation, sample availability) it is our opinion that natural products can still contribute to the effective discovery of novel bioactive and pharmaceutically relevant metabolites. We describe here several such strategies that if universally implemented, will demonstrate i) whether chemical diversity is truly being accessed, ii) that novel metabolites can be formatted in a manner appropriate for modern screening paradigms, and iii) that natural products can be rapidly identified not only for novelty and pharmaceutical relevance but to assess their true biological origin.