Elucidation of Biosynthetic Pathways of Natural Products

During the last decade, we have revealed biosynthetic pathways responsible for the formation of important and chemically complex natural products isolated from various organisms through genetic manipulation. Detailed in vivo and in vitro characterizations enabled elucidation of unexpected mechanisms of secondary metabolite biosynthesis. This personal account focuses on our recent efforts in identifying the genes responsible for the biosynthesis of spirotryprostatin, aspoquinolone, Sch 210972, pyranonigrin, fumagillin and pseurotin. We exploit heterologous reconstitution of biosynthetic pathways of interest in our study. In particular, extensive involvement of oxidation reactions is discussed. Heterologous hosts employed here are Saccharomyces cerevisiae, Aspergillus nidulans and A. niger that can also be used to prepare biosynthetic intermediates and product analogs by engineering the biosynthetic pathways using the knowledge obtained by detailed characterizations of the enzymes. (998 char.)     

亚胺的杂Diels-Alder反应在天然产物合成中的应用

综述了近年来用亚胺杂Diels-AJder反应合成天然产物的研究进展．     

Current Progress in the Chemoenzymatic Synthesis of Natural Products

Natural products, with their array of structural complexity, diversity, and biological activity, have inspired generations of chemists and driven the advancement of techniques in their total syntheses. The field of natural product synthesis continuously evolves through the development of methodologies to improve stereoselectivity, yield, scalability, substrate scope, late-stage functionalization, and/or enable novel reactions. One of the more interesting and unique techniques to emerge in the last thirty years is the use of chemoenzymatic reactions in the synthesis of natural products. This review highlights some of the recent examples and progress in the chemoenzymatic synthesis of natural products from 2019–2022.     

苯乙烯内酯类天然产物的全合成进展

结合本研究小组的相关课题工作，综述了苯乙烯内酯类天然产物全合成方法的 研究进展。主要包括以呋喃甲醇类化合物的氧化重排反应、烯烃复分解环化反应（ RCM）和酸催化的酯化关环等作为关键反应的方法。     

Therapeutic Intervention of COVID-19 by Natural Products: A Population-Specific Survey Directed Approach

To date very few promising leads from natural products (NP) secondary metabolites with antiviral and immunomodulatory properties have been identified for promising/potential intervention for COVID-19. Using in-silico docking studies and genome based various molecular targets, and their in vitro anti-SARS CoV-2 activities against whole cell and/or selected protein targets, we select a few compounds of interest, which can be used as potential leads to counteract effects of uncontrolled innate immune responses, in particular those related to the cytokine storm. A critical factor for prevention and treatment of SARS-CoV-2 infection relates to factors independent of viral infection or host response. They include population-related variables such as concurrent comorbidities and genetic factors critically relevant to COVID-19 health disparities. We discuss population risk factors related to SARS-CoV-2. In addition, we focus on virulence related to glucose-6-phosphate dehydrogenase deficiency (G6PDd), the most common human enzymopathy. Review of data on the response of individuals and communities with high prevalence of G6PDd to NP, prompts us to propose the rationale for a population-specific management approach to rationalize design of therapeutic interventions of SARS-CoV-2 infection, based on use of NP. This strategy may lead to personalized approaches and improve disease-related outcomes.     

Ugi反应在环肽生物碱和小肽衍生物抗生素及细胞毒素类等天然产物合成中的应用

Ugi反应是由1分子醛或酮、1分子胺、1分子异腈和1分子羧酸4个组分通过缩聚反应生成α- 酰氨基酰胺类化合物的反应。 具有反应条件温和、产率高和原子经济性好等特点。 该反应还可与Suzuki、Heck和Smiles等经典反应偶联,使得其在天然产物合成方面得到越来越多的关注。 本文概括总结了近几十年来Ugi反应在一些天然产物合成中的应用。     

New Approach to the Synthesis of the Natural Product Aripuanin

Abstract

Aripuanin is a megastigmane that exists in the leaves of Ficus aripuanensis C.C. Berg (Moraceae). The present study describes a new approach to the total synthesis of this natural product starting from the readily available β-ionone. The proposed synthetic route provided racemic aripuanin in moderate yields (~31%). This route can be applied to the synthesis of other natural products bearing the megastigmane moiety, as well as to the enantioselective synthesis of aripuanin derivatives.     

An efficient method for the construction of functionalized DNA bearing amino acid groups through cross-coupling reactions of nucleoside triphosphates followed by primer extension or PCR

Single-step aqueous cross-coupling reactions of nucleobase-halogenated 2'-deoxynucleosides (8-bromo-2'-deoxyadenosine, 7-iodo-7-deaza-2'-deoxyadenosine, or 5-iodo-2'-deoxy-uridine) or their 5'-triphosphates with 4-boronophenylalanine or 4-ethynylphenylalanine have been developed and used for efficient synthesis of modified 2'-deoxynucleoside triphosphates (dNTPs) bearing amino acid groups. These dNTPs were then tested as substrates for DNA polymerases for construction of functionalized DNA through primer extension and PCR. While 8-substituted adenosine triphosphates were poor substrates for DNA polymerases, the corresponding 7-substituted 7-deazaadenine and 5-substituted uracil nucleotides were efficiently incorporated in place of dATP or dTTP, respectively, by Pwo (Pyrococcus woesei) DNA polymerase. Nucleotides bearing the amino acid connected through the less bulky acetylene linker were incorporated more efficiently than those directly linked through a more bulky phenylene group. In addition, combinations of modified dATPs and dTTPs were incorporated by Pwo polymerase. Novel functionalized DNA duplexes bearing amino acid moieties were prepared by this two-step approach. PCR can be used for amplification of duplexes bearing large number of modifications, while primer extension is suitable for introduction of just one or several modifications in a single DNA strand.     

Natural Products in Mitigation of Bisphenol A Toxicity: Future Therapeutic Use

Bisphenol A (BPA) is a ubiquitous environmental toxin with deleterious endocrine-disrupting effects. It is widely used in producing epoxy resins, polycarbonate plastics, and polyvinyl chloride plastics. Human beings are regularly exposed to BPA through inhalation, ingestion, and topical absorption routes. The prevalence of BPA exposure has considerably increased over the past decades. Previous research studies have found a plethora of evidence of BPA’s harmful effects. Interestingly, even at a lower concentration, this industrial product was found to be harmful at cellular and tissue levels, affecting various body functions. A noble and possible treatment could be made plausible by using natural products (NPs). In this review, we highlight existing experimental evidence of NPs against BPA exposure-induced adverse effects, which involve the body’s reproductive, neurological, hepatic, renal, cardiovascular, and endocrine systems. The review also focuses on the targeted signaling pathways of NPs involved in BPA-induced toxicity. Although potential molecular mechanisms underlying BPA-induced toxicity have been investigated, there is currently no specific targeted treatment for BPA-induced toxicity. Hence, natural products could be considered for future therapeutic use against adverse and harmful effects of BPA exposure.     

Discovery of Novel c-Jun N-Terminal Kinase 1 Inhibitors from Natural Products: Integrating Artificial Intelligence with Structure-Based Virtual Screening and Biological Evaluation

c-Jun N-terminal kinase 1 (JNK1) is currently considered a critical therapeutic target for type-2 diabetes. In recent years, there has been a great interest in naturopathic molecules, and the discovery of active ingredients from natural products for specific targets has received increasing attention. Based on the above background, this research aims to combine emerging Artificial Intelligence technologies with traditional Computer-Aided Drug Design methods to find natural products with JNK1 inhibitory activity. First, we constructed three machine learning models (Support Vector Machine, Random Forest, and Artificial Neural Network) and performed model fusion based on Voting and Stacking strategies. The integrated models with better performance (AUC of 0.906 and 0.908, respectively) were then employed for the virtual screening of 4112 natural products in the ZINC database. After further drug-likeness filtering, we calculated the binding free energy of 22 screened compounds using molecular docking and performed a consensus analysis of the two methodologies. Subsequently, we identified the three most promising candidates (Lariciresinol, Tricin, and 4′-Demethylepipodophyllotoxin) according to the obtained probability values and relevant reports, while their binding characteristics were preliminarily explored by molecular dynamics simulations. Finally, we performed in vitro biological validation of these three compounds, and the results showed that Tricin exhibited an acceptable inhibitory activity against JNK1 (IC₅₀ = 17.68 μM). This natural product can be used as a template molecule for the design of novel JNK1 inhibitors.     

五引物单管聚合酶链反应(PCR)扩增法快速测定人CYP2D6*10等位基因的类型

以人CYP2D6*10等位基因位点为研究对象,建立了一种由5条引物同时PCR扩增在单管中进行等位基因快速检测的新方法。该方法在等位基因特异性扩增法的基础上,在内引物3′端引入了一个人工错配碱基并在5′端附加一段“尾巴”作为引物的锚定部分,使扩增反应的特异性得到了提高。本实验所建立的方法可在单管中同时完成SNP3种可能等位基因类型的快速检测。实测了47份样品的CYP2D6*10等位基因的类型,并随机对其中20份样品的测定结果用RFLP法进行了验证,结果完全一致。结果表明本法简便、快速,结果准确。     

Synthesis of Two Bioactive Natural Products: FR252921 and Pseudotrienic Acid B

Jackpot: Two for one! Concise and highly convergent syntheses of the immunosuppressive agent FR252921 and the related antimicrobial natural product pseudotrienic acid B were achieved from one common intermediate by using optically active titanium complexes to control the configuration of the stereogenic centers, a highly stereo‐ and regioselective cross‐metathesis to generate the triene moieties, and a Stille cross‐coupling to install the dienic units.

     

Recent Advances in Discovery of Lead Structures from Microbial Natural Products: Genomics- and Metabolomics-Guided Acceleration

Natural products (NPs) are evolutionarily optimized as drug-like molecules and remain the most consistently successful source of drugs and drug leads. They offer major opportunities for finding novel lead structures that are active against a broad spectrum of assay targets, particularly those from secondary metabolites of microbial origin. Due to traditional discovery approaches’ limitations relying on untargeted screening methods, there is a growing trend to employ unconventional secondary metabolomics techniques. Aided by the more in-depth understanding of different biosynthetic pathways and the technological advancement in analytical instrumentation, the development of new methodologies provides an alternative that can accelerate discoveries of new lead-structures of natural origin. This present mini-review briefly discusses selected examples regarding advancements in bioinformatics and genomics (focusing on genome mining and metagenomics approaches), as well as bioanalytics (mass-spectrometry) towards the microbial NPs-based drug discovery and development. The selected recent discoveries from 2015 to 2020 are featured herein.     

天然产物Combretastatin A-1和Combretastatin B-1的合成

基于Perkin反应策略合成了具有强效抗肿瘤、抗血管活性的天然产物Combretastatin A-1(CA1)和Combretastatin B-1(CB1).以2,3,4-三羟基苯甲醛(1)为起始物, 经单甲基化反应得到2,3-二羟基-4-甲氧基苯甲醛(2), 再经酚羟基保护得到2,3-二异丙基-4-甲氧基苯甲醛(3), 该化合物与3,4,5-三甲氧基苯乙酸(4)发生Perkin反应分离得到E-2-(3,4,5-三甲氧基苯基)-3-(2',3'-二异丙氧基-4'-甲氧基)丙烯酸(E-5), 经脱羧反应得到Z-3,4,4',5-四甲氧基-2',3'-二异丙氧基二苯乙烯(6), 最后经脱保护反应得到CA1.另外, 将E-2-(3,4,5-三甲氧基苯基)-3-(2',3'-二异丙氧基-4'-甲氧基)丙烯酸(E-5)脱去保护基得到E-2-(3,4,5-三甲氧基苯基)-3-(2',3'-二羟基-4'-甲氧基)丙烯酸(7), 该化合物经脱羧-异构化反应得到E-3,4,4',5-四甲氧基-2',3'-二羟基二苯乙烯(E-CA1), 最后经催化氢化得到CB1.     

有机膦催化环化及环加成反应在天然产物全合成中的应用研究进展*

有机膦小分子催化是一种反应条件温和、环境友好的有机合成方法,已广泛应用于有机合成领域。其中亲核有机膦催化的环化及环加成反应已经逐渐发展成为构建碳环和杂环化合物以及天然产物的重要工具之一。通过介绍近年来发展的有机膦催化环化及环加成反应的方法学,综述了近年来有机膦催化的环化及环加成反应在天然产物全合成中的应用研究进展。     

硝酮在天然化合物全合成中的应用

通过硝酮与烯烃化合物的1, 32偶极环加成反应合成了许多天然产物, 如生物碱、B2内酰胺、生物素、氨基糖等。该综述介绍了这一国际前沿研究领域的进展。