Biosynthesis-based artificial evolution of microbial natural products

Natural products are often secondary metabolites in living organisms with a wide variety of biological activities. The diversification of their structures, aiming to the search for biologically active small molecules by expanding chemical and functional spaces, is a major area of current interest in synthetic chemistry. However, developing synthetic accessibility and efficiency often faces challenges associated with structural complexity. Synthetic biology has recently emerged and is promising to accomplish complex molecules; by contrast, the application to structural diversification of natural products relies on the understanding, development and utilization of compatible biosynthetic machinery. Here, we review the strategies primarily concerning the artificial evolution of microbial natural products whose biosynthesis features template enzymology, including ribosomally synthesized and post-translationally modified peptides as well as the assembly line-resultant polyketides, non-ribosomal peptides and hybrids. The establishment of these approaches largely facilitates the expansion of the molecular diversity and utility through bioengineering at different stages/levels of biosynthetic pathways.     

Combinatorial chemistry toward understanding the function(s) of carbohydrates and carbohydrate conjugates

Combinatorial chemistry has contributed significantly to understanding the structure-function relationships of biologically important molecules such as proteins and nucleic acids. However, carbohydrates and carbohydrate conjugates, which have been identified as key modulators of several biological functions have not enjoyed the same measure of success. The complexity and synthetic challenges of carbohydrate conjugates have resulted in a number of conceptual approaches to rapidly access sufficient quantities of these biomolecules. This article summarizes these combinatorial approaches and also highlights fully automated library synthesis of artificial glycopeptides with the goals of understanding their biological roles.     

Total Synthesis of Lactacystin and Salinosporamide A

Lactacystin and salinosporamide A are fascinating molecules with regard to both their chemical structures and biological activities. These naturally occurring compounds are potent and selective proteasome inhibitors. The molecular structures are characterized by their densely functionalized γ‐lactam cores. The structure and biological properties of these two compounds are attracting the attention of many chemists as challenging synthetic targets. We discuss their synthetic strategies in this review.     

Multi-Step Continuous-Flow Organic Synthesis: Opportunities and Challenges

Continuous-flow multi-step synthesis takes the advantages of microchannel flow chemistry and may transform the conventional multi-step organic synthesis by using integrated synthetic systems. To realize the goal, however, innovative chemical methods and techniques are urgently required to meet the significant remaining challenges. In the past few years, by using green reactions, telescoped chemical design, and/or novel in-line separation techniques, major and rapid advancement has been made in this direction. This minireview summarizes the most recent reports (2017–2020) on continuous-flow synthesis of functional molecules. Notably, several complex active pharmaceutical ingredients (APIs) have been prepared by the continuous-flow approach. Key technologies to the successes and remaining challenges are discussed. These results exemplified the feasibility of using modern continuous-flow chemistry for complex synthetic targets, and bode well for the future development of integrated, automated artificial synthetic systems.     

Sliding on DNA: From Peptides to Small Molecules

Many DNA binding proteins utilize one‐dimensional (1D) diffusion along DNA to accelerate their DNA target recognition. Although 1D diffusion of proteins along DNA has been studied for decades, a quantitative understanding is only beginning to emerge and few chemical tools are available to apply 1D diffusion as a design principle. Recently, we discovered that peptides can bind and slide along DNA—even transporting cargo along DNA. Such molecules are known as molecular sleds. Here, to advance our understanding of structure–function relationships governing sequence nonspecific DNA interaction of natural molecular sleds and to explore the potential for controlling sliding activity, we test the DNA binding and sliding activities of chemically modified peptides and analogs, and show that synthetic small molecules can slide on DNA. We found new ways to control molecular sled activity, novel small‐molecule synthetic sleds, and molecular sled activity in N‐methylpyrrole/N‐methylimidazole polyamides that helps explain how these molecules locate rare target sites.     

Evolutionary chemistry approach toward finding novel inhibitors of the type 2 diabetes target glucose-6-phosphate translocase

A genetic algorithm (GA), driven by experimentally determined biological activities as a feedback fitness function, was used to propose novel small molecules as inhibitors of glucose-6-phosphate translocase (G6PT) in iterative rounds of evolutionary optimization. A straightforward polymer-supported synthetic sequence was implemented to synthesize molecules proposed by the GA, and the biological activities of the compounds were determined by a microsomal assay. Additional compound design strategies were integrated, such as Tanimoto similarity-based selection of starting materials and transfer of favored structure elements into a new chemical scaffold to identify more active and selective inhibitors.     

Emerging supramolecular chemistry of gases

Molecular recognition of gases is an emerging area of chemistry. Supramolecular chemistry helps us to understand how gases interact with biological molecules and offers delicate insights into the mechanisms of their physiological activity. Principles of molecular recognition have been used for gas sensing, and have provided fundamental knowledge about the structure and dynamics of receptor-analyte complexes, and novel materials for gas sensing and storage have been developed. Supramolecular chemistry is also enabling us to learn how to transform gases into synthetically useful reagents. The rational design of novel catalysts for gas conversion and, more recently, encapsulation complexes with gases open novel directions in preparative synthetic chemistry.     

Chemical methods for degradation of target proteins using designed light-activatable organic molecules

Molecular design, chemical synthesis, and biological evaluation of several designed organic molecules, which target-selectively degrade proteins upon photo-irradiation, are introduced. The designed molecules for protein photo-degradation include 2-phenylquinoline-steroid hormone hybrids and porphyrin derivatives, both of which selectively photo-degrade estrogen receptor-α, and fullerene-sugar and -sulfonic acid hybrids, which selectively photo-degrade HIV-1 protease and amyloid β, respectively. The information will provide a novel and effective way to control specific functions of proteins, and contribute to the molecular design of novel protein photo-degrading agents, which should find wide application in chemistry, biology, and medicine.     

Molecules with Large Cavities in Supramolecular Chemistry

Supramolecular chemistry is a new area of research that has rapidly developed from pure synthetic chemistry, and its novelty has led to interdisciplinary cooperation between organic and inorganic chemistry, biochemistry, physical and theoretical chemistry, and physics. Whereas molecular chemistry essentially deals with the covalent bonding of atoms, Supramolecular chemistry is predominantly involved in the study of the weaker intermolecular interactions resulting in the association and self-organization of several components to form larger aggregates (supramolecules). The first crown ether discovered by the subsequent Nobel prizewinner Pedersen was more the fortuitous reaction product of an impurity, but nowadays, some twenty-five years later, chemists are able to tailor host molecules to special requirements. Host compounds having a cyclophane skeleton make an important contribution, since their aromatic structural units ensure the necessary rigidity of the molecular structures and thereby improve the preorganization of the coordination sites for the cooperative binding of the guests. During the course of the rapid development of Supramolecular chemistry such a large number of synthetic hosts has been developed and their interaction with guests studied in such depth that we must restrict ourselves here to a discussion of a particular group of host compounds, namely cavity-supporting macrobicyclic and macrooligocyclic phanesu, which bear a similar relation to open-chain and monocyclic hosts as the metal-complexing cryptands to the podands and crown ethers. The molecular architecture of these three-dimensionally bridged macrooligocycles is a challenge for synthetic chemistry. (Not only the size and shape of the intramolecular cavity, but also the provision of the latter with suitable coordination centers have to be included in the synthesis strategy.) The capacity for the envelopment of guests from all sides and the expedient endo functionalization often also produce a particularly strong binding of host and guest, outstanding selectivities with regards to molecular recognition, and special properties of the Supramolecular complexes.     

New Advances in the Synthesis of Emerging Cyclic Amidrazones to Foster Bioisosterism of Azaheterocycles

The pace and the scope of new molecules design is often constrained by limitations in synthetic chemistry. The azaheterocyclic amidrazones are of particular interest for bioisosteric considerations in drug discovery. However, the lack of efficient synthetic access has undoubtedly hampered their occurrence in the drug chemical space. Our current results describe a robust synthetic access relying on cyclization of aminohydrazine in presence of various orthoesters by either metal free- or metal-catalyzed condensations. This optimized synthetic access to cyclic amidrazones as original scaffold should inspire the chemist community and further drive innovation in the design of molecular structure for many applications (for example, drugs, materials, dyes).     

The most common chemical replacements in drug-like compounds

We have written a method that extracts one-to-one replacements of chemical groups in pairs of drug-like molecules with the same biological activity and counts the frequency of the replacements in a large collection of such molecules. There are two variations on the method that differ in their treatment of replacements in rings. This method is one possible approach to systematically identify candidate bioisosteres. Here we look at the MDDR database because it has a large diversity of drug-like compounds in a large number of therapeutic areas. The most frequent replacements in MDDR seem generally consistent with medicinal chemistry intuition about what chemical groups are equivalent or with groups that are easily converted by synthetic or metabolic pathways. This method can be applied to any set of molecules wherein the molecules can be paired by similar biological activity.     

化学生物学-新兴的交叉前沿学科领域

化学生物学正在成为一个重要的新兴交叉学科, 它是化学与生物学和医学等学科领域相互交叉、相互渗透的产物。化学的工具和方法, 包括合成的、结构的和分析的, 被用于研究生物和医学问题; 分子生物学的手段也被用来解决化学问题。其主要策略是采用天然的或人工设计合成的小分子作为探针, 改变生物分子的功能, 探讨各种生理和病理过程中分子识别和信号通路的分子机制。这些研究得到的知识不仅有助于阐明细胞过程的细节和调节机制、增进在分子水平上对生命的认识, 而且对于创制和发展新颖药物都具有重要意义。     

新型有机小分子DNA切割试剂的合成

根据活性基团的协同催化原理,设计合成了有机小分子核酸切割剂1-(N-胍乙基)-4-(N-羟乙基)哌嗪盐酸盐(4),并通过核磁共振和液相色谱-质谱联用技术对其结构进行了表征.利用琼糖凝胶电泳研究了pH值对其切割pUC 19 DNA效率的影响,通过自由基猝灭实验研究其切割DNA的反应类型.运用密度泛函理论,利用Gaussian软件进行了理论计算,研究其裂解DNA的反应方式.研究结果表明,在pH=7.2时化合物4的裂解效率最高,且能通过非氧化还原反应以磷酯转移的方式裂解DNA的磷酸二酯键.     

From Prebiotic Chemistry to Supramolecular Biomedical Materials: Exploring the Properties of Self-Assembling Nucleobase-Containing Peptides

Peptides and their synthetic analogs are a class of molecules with enormous relevance as therapeutics for their ability to interact with biomacromolecules like nucleic acids and proteins, potentially interfering with biological pathways often involved in the onset and progression of pathologies of high social impact. Nucleobase-bearing peptides (nucleopeptides) and pseudopeptides (PNAs) offer further interesting possibilities related to their nucleobase-decorated nature for diagnostic and therapeutic applications, thanks to their reported ability to target complementary DNA and RNA strands. In addition, these chimeric compounds are endowed with intriguing self-assembling properties, which are at the heart of their investigation as self-replicating materials in prebiotic chemistry, as well as their application as constituents of innovative drug delivery systems and, more generally, as novel nanomaterials to be employed in biomedicine. Herein we describe the properties of nucleopeptides, PNAs and related supramolecular systems, and summarize some of the most relevant applications of these systems.     

20 years of DNA-encoded chemical libraries

The identification of specific binding molecules is a central problem in chemistry, biology and medicine. Therefore, technologies, which facilitate ligand discovery, may substantially contribute to a better understanding of biological processes and to drug discovery. DNA-encoded chemical libraries represent a new inexpensive tool for the fast and efficient identification of ligands to target proteins of choice. Such libraries consist of collections of organic molecules, covalently linked to a unique DNA tag serving as an amplifiable identification bar code. DNA-encoding enables the in vitro selection of ligands by affinity capture at sub-picomolar concentrations on virtually any target protein of interest, in analogy to established selection methodologies like antibody phage display. Multiple strategies have been investigated by several academic and industrial laboratories for the construction of DNA-encoded chemical libraries comprising up to millions of DNA-encoded compounds. The implementation of next generation high-throughput sequencing enabled the rapid identification of binding molecules from DNA-encoded libraries of unprecedented size. This article reviews the development of DNA-encoded library technology and its evolution into a novel drug discovery tool, commenting on challenges, perspectives and opportunities for the different experimental approaches.     

Recognition of Chiral Carboxylates by Synthetic Receptors

Recognition of anionic species plays a fundamental role in many essential chemical, biological, and environmental processes. Numerous monographs and review papers on molecular recognition of anions by synthetic receptors reflect the continuing and growing interest in this area of supramolecular chemistry. However, despite the enormous progress made over the last 20 years in the design of these molecules, the design of receptors for chiral anions is much less developed. Chiral recognition is one of the most subtle types of selectivity, and it requires very precise spatial organization of the receptor framework. At the same time, this phenomenon commonly occurs in many processes present in nature, often being their fundamental step. For these reasons, research directed toward understanding the chiral anion recognition phenomenon may lead to the identification of structural patterns that enable increasingly efficient receptor design. In this review, we present the recent progress made in the area of synthetic receptors for biologically relevant chiral carboxylates.     

Novel 1,4-benzothiazine derivatives: synthesis,crystal structure,and anti-bacterial properties

In order to develop relatively small molecules as pharmacologically active molecules, novel 1,4-benzothiazine derivatives with triazole and oxazolidinone were synthesized. In this study, a series of 1,2,3-triazolylmethyl-1,4-benzothiazine derivatives were developed by exploiting a click chemistry reaction using a CuI-catalyzed Huisgen [3 + 2] cycloaddition. Starting from 2-(substituted)-3,4-dihydro-2H-1,4-benzothiazi-3-one, a number of 1,4-benzothiazine derivatives were also synthesized using different alkylating agents to give a 4-(substituted)-2-(substituted)-3,4-dihydro-2H-1,4-benzothiazi-3-one in good yields. The crystal and molecular structure of compound oxazolidin-2-one in basic benzothiazine was established by single-crystal X-ray diffraction. The newly synthesized products were subjected to in vitro biological evaluation. The result indicated that the compounds show convincing antibacterial activities against different microorganisms. All structures of the synthesized compounds were elucidated on the basis of spectral analyses and chemical reactions.     

Exploring sets of molecules from patents and relationships to other active compounds in chemical space networks

Patents from medicinal chemistry represent a rich source of novel compounds and activity data that appear only infrequently in the scientific literature. Moreover, patent information provides a primary focal point for drug discovery. Accordingly, text mining and image extraction approaches have become hot topics in patent analysis and repositories of patent data are being established. In this work, we have generated network representations using alternative similarity measures to systematically compare molecules from patents with other bioactive compounds, visualize similarity relationships, explore the chemical neighbourhood of patent molecules, and identify closely related compounds with different activities. The design of network representations that combine patent molecules and other bioactive compounds and view patent information in the context of current bioactive chemical space aids in the analysis of patents and further extends the use of molecular networks to explore structure–activity relationships.