Natural Diels–Alderases that selectively form endo or exo products are increasingly well known but generally form one stereoisomer with limited substrate scope. Here we report the discovery of two homologous groups of flavin-adenine-dinucleotide-dependent enzymes that catalyse intermolecular Diels–Alder reactions on the same substrates with opposite endo/exo selectivity and high enantioselectivity. We show that these enzymes are effective biocatalysts with a wide range of diene and dienophile substrates. The crystal structure of an exo-selective Diels–Alderase was determined at 2.94 Å resolution. Based on the structure and computational investigation of the catalytic mechanism, we designed and prepared mutant enzymes that reverse the stereoselectivity from exo to endo. A combination of structure-based comparison, computational and mutational studies have revealed two different catalytic mechanisms that control the endo/exo selectivity in these enzymatic Diels–Alder reactions.
Guixing Ma, Sanshan Wang , Kebin Wu, Weizhe Zhang, Ashfaq Ahmad, Quan Hao *,Xiaoguang Lei *, Hongmin Zhang *
Bioorganic and Medicinal Chemistry 29.(2021) .115902 β-lactam antibiotics have long been the mainstay for the treatment of bacterial infections. New Delhi metallo- β-lactamase 1 (NDM-1) is able to hydrolyze nearly all β-lactam antibiotics and even clinically used serine- β-lactamase inhibitors. The wide and rapid spreading of NDM-1 gene among pathogenic bacteria has attracted extensive attention, therefore high potency NDM-1 inhibitors are urgently needed. Here we report a series of structure-guided design of D-captopril derivatives that can inhibit the activity of NDM-1 in vitro and at cellular levels. Structural comparison indicates the mechanisms of inhibition enhancement and provides insights for further inhibitor optimization.
Kaiqi Chen, Fan Wu, Xiaoguang Lei* Chinese Journal of Chemistry, 2021, 39(4), pp. 838–854 Natural products and their derivatives have long been used as medicinal agents, and they still make up a significant fraction of clinically approved drugs. Natural product synthesis provides a rich and unparalleled opportunity to develop new synthetic transformations, conceive novel and general strategies to access complex structures, and study the mechanism of action of bioactive targets. The combination of the tools and principles of chemistry, together with the tools of modern biology, allows us to create complex synthetic and natural molecules, comprising processes with novel biological, chemical and physical properties. This account will illustrate the opportunities that lie at this interface between synthetic organic chemistry and chemical biology by describing a series of examples that we are actively working on in our laboratory at Peking University. We take the inspiration from mother nature to develop new synthetic strategies to achieve the efficient synthesis of complex natural products. In addition, we also conduct chemical biology studies for these bioactive natural products to elucidate their cellular targets and mode of action. Moreover, we further use bioactive natural products to explore new biology and develop novel drug candidates for human diseases, such as cancers and infectious diseases
Kaiqi Chen , Haoran Dong, Jin Wang, Xiaoguang Lei , * Tetrahedron, 2021, 87, 132120 A concise total synthesis of the plant indole alkaloid natural product nauclefine (1) was accomplished from the commercially available nicotinic acid and the known compound in 6 steps. The synthesis features a regioselective rhodium(III)-catalyzed oxidative C-H activation for the construction of the key naphthyridinone ring. The intramolecular Mitsunobu-type annulation, allylic oxidation and Fischer indolization were used successively to complete the total synthesis of nauclefine (1).
Daohong Liao, Shaoqiang Yang , Kaiqing Ma, Xiaoming Wang , Xiaoguang Lei *
Received 12 February 2021 Revised 29 April 2021 Accepted 4 May 2021
Tetrahedron Letters, 2021, 153156
An enantioselective route for the efficient synthesis of the key C16–C25 fragment of alchivemycins A and B is described. The route features an Achmatowicz-type rearrangement of furan and a highly enantio- and diastereoselective dihydroxylation as key reactions.
Chapter First Online: 02 April 2021，Progress in the Chemistry of Organic Natural Products 114 pp 313-337
Natural products are a class of chemical compounds that are biosynthesized by living organisms, including humans. Endogenous natural products are produced by human cells as well as by the human microbiome. This contribution describes the current understanding and recent progress made on endogenous natural products that are produced by human cells, including amines, steroids, and fatty acid-derived natural products. The co-metabolism and natural product produced by the human microbiome will also be described, including the involvement of tryptophan, bile acids, choline, and cysteine. New strategies and technologies have been introduced that can be applied to identify and characterize those natural products produced by the human microbiome in terms of their composition and physiological function.
Plant metabolites play important roles in both plant physiology and drug discovery. Taking advantage of new emerging technologies such as next generation sequencing (NGS), whole genome assembly, bioinformatics, omics-based strategies have been demonstrated as popular and powerful ways to elucidate complex metabolic pathways in plants. In this viewpoint, biosynthetic intermediates probes have been proposed as the potentinal tools to study the plant natural product biosynthesis via chemical proteomics appoaches or transcriptome analysis.
Jinyi Bai , Fusheng Guo , Mengyao Li , Yulong Li * and Xiaoguang Lei* Received 6th January 2021 , Accepted 18th March 2021 First published on 20th March 2021
We here describe a fluorescent signal amplification method termed “Click-based amplification” that can be well integrated with various click-labelling modes, including chemical labelling, genetic incorporation and covalent inhibitor probe mediated target labelling. Picolyl azide (pAz) was used as a functional group of a streptavidin-based amplifier to enhance the efficiency of click chemistry. Click-based amplification provided 3.0–12.7 fold amplification on fixed HeLa cells with different click-labelling modes. Click-based amplification has proven to be superior to tyramide signal amplification (TSA) in view of its low nonspecific amplification and high signal-to-noise ratio. Moreover, in terms of the challenging signal amplification of tissue specimens, Click-based amplification successfully achieved remarkable fluorescence enhancement on intestinal tissue slices of afatinib-N3 treated mice, which provided direct evidence of the presence of afatinib-N3 in the intestinal tissues and helped in revealing the off-target toxicity of afatinib. Collectively, these results illustrate that Click-based amplification could serve as a promising method for bioimaging studies
Polycyclic natural products are an inexhaustible source of medicinal agents, and their complex molecular architecture renders challenging synthetic targets where innovative and effective approaches for their rapid construction are urgently required. The total synthesis of polycyclic natural products has witnessed exponential progression along with the emergence of new synthetic strategies and concepts, such as sequential C−H functionalizations, radical-based transformations, and functional group pairing strategies. Our group exerts continued interest in the construction of bioactive and structurally complex natural products as well as evaluation of the mode of action of these molecules. In this Account, we will showcase how these new synthetic strategies are employed and guide our total synthesis endeavors. During the last two decades, a series of remarkable advances in C−H functionalization have led to the emergence of many new approaches to directly functionalize C−H bonds into useful functional groups. These selective transformations have provided a great opportunity for the step- and atom-economical construction of key fragments in complex molecule synthesis. We recently furnished the total syntheses for polycyclic natural products: incarviatone A, chrysomycin A, polycarcin V, and gilvocarcin V by employing a multiple C−H bond functionalization strategy. The polysubstituted benzene or naphthalene skeleton was constructed through sequential and site-selective C−H functionalizations from readily available simple starting materials, which reduced the number of steps and streamlined synthesis.
The rise of resistance against all known antibiotics is a global crisis. There is an urgent need to develop rapid and sensitive diagnostic methods to detect pathogenic bacteria in clinical samples. Pseudopaline, a metallophore produced by the human pathogen Pseudomonas aeruginosa, transports divalent metal ions via a dedicated active transport system, making it an ideal carrier for a second functional moiety. In this work, we have developed a fluorescein-labeled pseudopaline probe (P-FL), which could specifically detect P. aeruginosa in samples (in vitro) with many other bacterial species, mammalian cells, or mouse stomach tissue sections. By replacing the fluorescein with the near-infrared fluorophore Cy-7 (P-Cy7), we showed that P. aeruginosa infections could also be specifically detected in a mouse model (in vivo). The remarkable selectivity of these pseudopaline fluorescent probes is because the pseudopaline-mediated metal transport system is specific to P. aeruginosa only. Therefore, our results show that pseudopaline based probes may provide a new way to develop fast and effective diagnostics of P. aeruginosa infections.
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Enzymatic control of endo- and exo-stereoselective Diels–Alder reactions with broad substrate scope
Lei Gao, Yike Zou, Xiaojing Liu, Jun Yang, Xiaoxia Du, Jin Wang, Xinshui Yu, Junping Fan,
Mingxuan Jiang , Yuli Li, K. N. Houk* and Xiaoguang Lei*
Nature Catalysis volume 4, pages1059–1069 (2021) https://doi.org/10.1038/s41929-021-00717-8
Natural Diels–Alderases that selectively form endo or exo products are increasingly well known but generally form one stereoisomer with limited substrate scope. Here we report the discovery of two homologous groups of flavin-adenine-dinucleotide-dependent enzymes that catalyse intermolecular Diels–Alder reactions on the same substrates with opposite endo/exo selectivity and high enantioselectivity. We show that these enzymes are effective biocatalysts with a wide range of diene and dienophile substrates. The crystal structure of an exo-selective Diels–Alderase was determined at 2.94 Å resolution. Based on the structure and computational investigation of the catalytic mechanism, we designed and prepared mutant enzymes that reverse the stereoselectivity from exo to endo. A combination of structure-based comparison, computational and mutational studies have revealed two different catalytic mechanisms that control the endo/exo selectivity in these enzymatic Diels–Alder reactions.
Structure-guided optimization of D-captopril for discovery of potent NDM-1 inhibitors
Guixing Ma, Sanshan Wang , Kebin Wu, Weizhe Zhang, Ashfaq Ahmad, Quan Hao *,Xiaoguang Lei *, Hongmin Zhang *
Bioorganic and Medicinal Chemistry 29.(2021) .115902
β-lactam antibiotics have long been the mainstay for the treatment of bacterial infections. New Delhi metallo-
β-lactamase 1 (NDM-1) is able to hydrolyze nearly all β-lactam antibiotics and even clinically used serine-
β-lactamase inhibitors. The wide and rapid spreading of NDM-1 gene among pathogenic bacteria has attracted
extensive attention, therefore high potency NDM-1 inhibitors are urgently needed. Here we report a series of
structure-guided design of D-captopril derivatives that can inhibit the activity of NDM-1 in vitro and at cellular
levels. Structural comparison indicates the mechanisms of inhibition enhancement and provides insights for
further inhibitor optimization.
Function-Oriented Natural Product Synthesis
Kaiqi Chen, Fan Wu, Xiaoguang Lei*
Chinese Journal of Chemistry, 2021, 39(4), pp. 838–854
Natural products and their derivatives have long been used as medicinal agents, and they still make up a significant fraction of clinically approved drugs. Natural product synthesis provides a rich and unparalleled opportunity to develop new synthetic transformations, conceive novel and general strategies to access complex structures, and study the mechanism of action of bioactive targets. The combination of the tools and principles of chemistry, together with the tools of modern biology, allows us to create complex synthetic and natural molecules, comprising processes with novel biological, chemical and physical properties. This account will illustrate the opportunities that lie at this interface between synthetic organic chemistry and chemical biology by describing a series of examples that we are actively working on in our laboratory at Peking University. We take the inspiration from mother nature to develop new synthetic strategies to achieve the efficient synthesis of complex natural products. In addition, we also conduct chemical biology studies for these bioactive natural products to elucidate their cellular targets and mode of action. Moreover, we further use bioactive natural products to explore new biology and develop novel drug candidates for human diseases, such as cancers and infectious diseases
Concise total synthesis of nauclefine: A regioselective Rhodium(III)-catalyzed oxidative C-H activation approach
Kaiqi Chen , Haoran Dong, Jin Wang, Xiaoguang Lei , *
Tetrahedron, 2021, 87, 132120
A concise total synthesis of the plant indole alkaloid natural product nauclefine (1) was accomplished from the commercially available nicotinic acid and the known compound in 6 steps. The synthesis features a regioselective rhodium(III)-catalyzed oxidative C-H activation for the construction of the key naphthyridinone ring. The intramolecular Mitsunobu-type annulation, allylic oxidation and Fischer indolization were used successively to complete the total synthesis of nauclefine (1).
Stereoselective synthesis of the C16–C25 fragment of alchivemycins A and B
Daohong Liao, Shaoqiang Yang , Kaiqing Ma, Xiaoming Wang , Xiaoguang Lei *
Received 12 February 2021
Revised 29 April 2021
Accepted 4 May 2021
Tetrahedron Letters, 2021, 153156
An enantioselective route for the efficient synthesis of the key C16–C25 fragment of alchivemycins A and B is described. The route features an Achmatowicz-type rearrangement of furan and a highly enantio- and diastereoselective dihydroxylation as key reactions.
Human Endogenous Natural Products
Yingjie BaiLiyun ZhangXiaoguang Lei*
Chapter
First Online: 02 April 2021，Progress in the Chemistry of Organic Natural Products 114 pp 313-337
Natural products are a class of chemical compounds that are biosynthesized by living organisms, including humans. Endogenous natural products are produced by human cells as well as by the human microbiome. This contribution describes the current understanding and recent progress made on endogenous natural products that are produced by human cells, including amines, steroids, and fatty acid-derived natural products. The co-metabolism and natural product produced by the human microbiome will also be described, including the involvement of tryptophan, bile acids, choline, and cysteine. New strategies and technologies have been introduced that can be applied to identify and characterize those natural products produced by the human microbiome in terms of their composition and physiological function.
Biosynthetic Intermediate Probes for Visualizing and Identifying the Biosynthetic Enzymes of Plant Metabolites
Lei Gao*and Xiaoguang Lei*
ChemBioChem, 2021, 22(6), pp. 982–984
Plant metabolites play important roles in both plant physiology and drug discovery. Taking advantage of new emerging technologies such as next generation sequencing (NGS), whole genome assembly, bioinformatics, omics-based strategies have been demonstrated as popular and powerful ways to elucidate complex metabolic pathways in plants. In this viewpoint, biosynthetic intermediates probes have been proposed as the potentinal tools to study the plant natural product biosynthesis via chemical proteomics appoaches or transcriptome analysis.
Click-based amplification: designed to facilitate various target labelling with ultralow background
Jinyi Bai , Fusheng Guo , Mengyao Li , Yulong Li * and Xiaoguang Lei*
Received 6th January 2021 , Accepted 18th March 2021
First published on 20th March 2021
We here describe a fluorescent signal amplification method termed “Click-based amplification” that can be well integrated with various click-labelling modes, including chemical labelling, genetic incorporation and covalent inhibitor probe mediated target labelling. Picolyl azide (pAz) was used as a functional group of a streptavidin-based amplifier to enhance the efficiency of click chemistry. Click-based amplification provided 3.0–12.7 fold amplification on fixed HeLa cells with different click-labelling modes. Click-based amplification has proven to be superior to tyramide signal amplification (TSA) in view of its low nonspecific amplification and high signal-to-noise ratio. Moreover, in terms of the challenging signal amplification of tissue specimens, Click-based amplification successfully achieved remarkable fluorescence enhancement on intestinal tissue slices of afatinib-N3 treated mice, which provided direct evidence of the presence of afatinib-N3 in the intestinal tissues and helped in revealing the off-target toxicity of afatinib. Collectively, these results illustrate that Click-based amplification could serve as a promising method for bioimaging studies
New Strategies in the Efficient Total Syntheses of Polycyclic Natural Products
Polycyclic natural products are an inexhaustible source of medicinal agents, and their complex molecular architecture renders challenging synthetic targets where innovative and effective approaches for their rapid construction are urgently required. The total synthesis of polycyclic natural products has witnessed exponential progression along with the emergence of new synthetic strategies and concepts, such as sequential C−H functionalizations, radical-based transformations, and functional group pairing strategies. Our group exerts continued interest in the construction of bioactive and structurally complex natural products as well as evaluation of the mode of action of these molecules. In this Account, we will showcase how these new synthetic strategies are employed and guide our total synthesis endeavors. During the last two decades, a series of remarkable advances in C−H functionalization have led to the emergence of many new approaches to directly functionalize C−H bonds into useful functional groups. These selective transformations have provided a great opportunity for the step- and atom-economical construction of key fragments in complex molecule synthesis. We recently furnished the total syntheses for polycyclic natural products: incarviatone A, chrysomycin A, polycarcin V, and gilvocarcin V by employing a multiple C−H bond functionalization strategy. The polysubstituted benzene or naphthalene skeleton was constructed through sequential and site-selective C−H functionalizations from readily available simple starting materials, which reduced the number of steps and streamlined synthesis.
A pseudopaline fluorescent probe for the selective detection of Pseudomonas aeruginosa
The rise of resistance against all known antibiotics is a global crisis. There is an urgent need to develop rapid and sensitive diagnostic methods to detect pathogenic bacteria in clinical samples. Pseudopaline, a metallophore produced by the human pathogen Pseudomonas aeruginosa, transports divalent metal ions via a dedicated active transport system, making it an ideal carrier for a second functional moiety. In this work, we have developed a fluorescein-labeled pseudopaline probe (P-FL), which could specifically detect P. aeruginosa in samples (in vitro) with many other bacterial species, mammalian cells, or mouse stomach tissue sections. By replacing the fluorescein with the near-infrared fluorophore Cy-7 (P-Cy7), we showed that P. aeruginosa infections could also be specifically detected in a mouse model (in vivo). The remarkable selectivity of these pseudopaline fluorescent probes is because the pseudopaline-mediated metal transport system is specific to P. aeruginosa only. Therefore, our results show that pseudopaline based probes may provide a new way to develop fast and effective diagnostics of P. aeruginosa infections.