Review
Pharmacology & Pharmacy
Bingyao Xu, Lan Bai, Lu Chen, Rongsheng Tong, Yibin Feng, Jianyou Shi
Summary: This review provides an overview of recent research on a range of terpenoid natural products associated with the PI3K/Akt pathway. It discusses their chemical structures, mechanisms of action, associated diseases, and experimental methods. The review highlights 16 natural terpenoids and their structure-activity relationships (SAR), suggesting their potential as natural neuroprotective agents.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Heather J. Lacey, Peter J. Rutledge
Summary: The Streptomyces genus has been a valuable source of bioactive compounds for decades. Recent studies have revealed that the genus is capable of producing far more compounds than previously thought. Researchers are actively exploring this potential through various approaches, resulting in the discovery of numerous novel secondary metabolites.
Article
Chemistry, Multidisciplinary
Lukas Anton Wein, Klaus Wurst, Thomas Magauer
Summary: The study presented the construction of seven novel ent-trachylobane diterpenoids using a bioinspired synthetic strategy. Enantioselective and scalable access to five ent-trachylobanes was achieved in the first phase, with one compound produced on a 300 mg scale. Chemical C-H oxidation methods were then used in the second phase to selectively convert two higher functionalized ent-trachylobanes, revealing the potential and limitations of established protocols for complex molecule synthesis.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Multidisciplinary
Julian M. Feilner, Immanuel Plangger, Klaus Wurst, Thomas Magauer
Summary: This study utilized highly functionalized bifunctional alkenes to achieve a polyene tetracyclization, leading to the total synthesis of the tricyclic diterpenoid pimara-15-en-3 alpha-8 alpha-diol. The versatile route also allowed for the preparation of a diverse library of cyclization precursors for the total synthesis of the tetracyclic nor-diterpenoid norflickinflimiod C, providing insights into complex pentacyclic products.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Review
Biochemistry & Molecular Biology
Ali Amiri Naeini, Alexandre A. Ziegelmeier, William J. Chain
Summary: Icetexane diterpenoids are a diverse family of natural products sourced from terrestrial plants, exhibiting a broad array of biological activities. This review summarizes icetexane natural products isolated since 2009, provides an overview of new synthetic approaches and proposes a novel classification based on unique structures.
CHEMISTRY & BIODIVERSITY
(2022)
Article
Chemistry, Multidisciplinary
Juan Xiong, Peng-Jun Zhou, Hao-Wen Jiang, Ting Huang, Yu-Hang He, Ze-Yu Zhao, Yi Zang, Yeun-Mun Choo, Xiaojuan Wang, Amar G. Chittiboyina, Pankaj Pandey, Mark T. Hamann, Jia Li, Jin-Feng Hu
Summary: Forrestiacids A and B are novel [4+2] pentaterpenoids derived from Pseudotsuga forrestii, exhibiting potent inhibitory activities against ATP-citrate lyase and potential for treating glycolipid metabolic disorders. Compound 1 also effectively attenuated de novo lipogenesis, providing a new chemical class for developing therapeutic agents for ACL-related diseases.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Multidisciplinary
Binbin Gu, Bernd Goldfuss, Jeroen S. S. Dickschat
Summary: The second sesterterpene synthase from bacteria was identified in this study, which is the sesterviolene synthase from Streptomyces violens. Isotopic labelling experiments and DFT calculations were used to gain insights into its complex cyclisation mechanism. Through enzyme engineering via site-directed mutagenesis, a high-yielding enzyme variant was obtained that produced six additional minor products and the main product in sufficient quantities for chemistry studies.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Physical
T. Rehka, Deepti Sharma, Fu Lin, Yeu Khai Choong, Chinchin Lim, Chacko Jobichen, Congqiang Zhang
Summary: The crystal structure of Agrocybe pediades linalool synthase (Ap.LS) was determined, revealing that its specificity is determined by the region of 60-69aa and Tyr299. Mutants of Ap.LS Y299 produced long-chain products. It was also found that microbial terpene synthases with asparagine at a specific position mainly produce cyclized products, while those with a bulky tyrosine produce linear products.
Article
Microbiology
Polpass Arul Jose, Anjisha Maharshi, Bhavanath Jha
Summary: Actinobacteria are recognized as important biosynthetic factories that produce a wide range of secondary metabolites. Recent genomic insights have impacted the exploitation and discovery of new compounds from these metabolically active bacteria, leading to significant progress in the field of drug discovery.
MICROBIOLOGICAL RESEARCH
(2021)
Review
Biochemistry & Molecular Biology
Shaheera Tabassum, Ameer Fawad Zahoor, Sajjad Ahmad, Razia Noreen, Samreen Gul Khan, Hamad Ahmad
Summary: Cross-coupling reactions are powerful tools for synthesizing natural products, with Suzuki, Negishi, Heck, Sonogashira, and Stille reactions being commonly used in total synthesis. This review highlights the significance of these reactions in organic synthesis and provides examples of incorporating multiple types of cross-coupling reactions in the synthesis of natural products.
MOLECULAR DIVERSITY
(2022)
Review
Biochemistry & Molecular Biology
Didi Nurhadi Illian, Ihsanul Hafiz, Okpri Meila, Ahmad Rusdan Handoyo Utomo, Arif Nuryawan, Gontar Alamsyah Siregar, Mohammad Basyuni
Summary: In 2020, there were an estimated 19.3 million new cancer cases and nearly 10 million cancer deaths worldwide, with colorectal cancer ranking third. Various treatments have been attempted against cancer, with many people opting for natural products. In Indonesia, natural products with potential activity against colorectal cancer are mainly composed of terpenoids, phytosterols, phenolics, alkaloids, and polyisoprenoids.
Review
Biochemistry & Molecular Biology
Branislav Sojic, Sanja Milosevic, Danica Savanovic, Zoran Zekovic, Vladimir Tomovic, Branimir Pavlic
Summary: Using food additives is a common method for preserving the quality of meat and meat products. However, the negative health implications of these additives have led scientists to explore alternatives. Terpenoid-rich extracts, such as essential oils, have gained recognition for their safety and acceptance by consumers. This review aims to summarize the characteristics of different procedures for extracting terpenoid-rich extracts and their effects on the environment. It also highlights the antioxidant and antimicrobial potential of these extracts and essential oils in meat and various meat products.
Review
Biochemistry & Molecular Biology
Ignacio Moratilla-Rivera, Marta Sanchez, Jose Antonio Valdes-Gonzalez, Maria Pilar Gomez-Serranillos
Summary: Neurodegenerative diseases (NDs) are common diseases affecting the West due to increased life expectancy. Cells accumulate oxidative damage, triggering neurodegeneration. The transcription factor Nrf2 regulates endogenous antioxidant systems and induces the transcription of genes containing ARE in response to prooxidant conditions. Natural products such as quercetin, curcumin, and terpenoids can positively modulate Nrf2, reducing oxidative damage to the nervous system. This review aims to update knowledge on the potential treatments for NDs by activating the Nrf2 pathway with secondary metabolites of health interest.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Chemistry, Medicinal
Yue Liu, Liangyu Yang, Hong Wang, Yongai Xiong
Summary: Triterpenoids, important secondary plant metabolites, have diverse structures and wide-ranging bioactivities, including antiviral, antioxidant, anticancer, and anti-inflammatory properties. This review focuses on the antiviral activities of different triterpenoids, particularly tetracyclic and pentacyclic triterpenoids, and their potential as antiviral agents against human immunodeficiency virus, influenza virus, and hepatitis virus.
Article
Chemistry, Multidisciplinary
Yusuke Imamura, Kyohei Takaoka, Yuma Komori, Masanori Nagatomo, Masayuki Inoue
Summary: This study presents a 34-step synthesis of Taxol, involving inter- and intramolecular radical reactions to connect the A- and C-ring fragments and cyclize the B-ring. The A- and C-ring functional groups were then efficiently modified using newly developed selective reactions. The construction of the D-ring and its conjugation with the beta-amino acid led to the successful synthesis of Taxol. This synthesis provides useful insights for the design of multistep syntheses of diverse bioactive natural products.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Carsten E. Seyfert, Christoph Porten, Biao Yuan, Selina Deckarm, Fabian Panter, Chantal D. Bader, Janetta Coetzee, Felix Deschner, Kamaleddin H. M. E. Tehrani, Paul G. Higgins, Harald Seifert, Thomas C. Marlovits, Jennifer Herrmann, Rolf Mueller
Summary: In recent decades, the pipeline for antibiotics targeting Gram-negative bacteria has become depleted due to the insufficiency in potency, pharmacokinetic properties, and toxicity of most discovered candidates. A new class of promising drug candidates called darobactins has been developed, which bind to a novel antibiotic target called BamA, an outer membrane protein. This study presents the cryo-EM structures of the Bam complex with darobactin 9 (D9) and the biotechnological generation of twenty new darobactins, including halogenated analogs, using an optimized purification method. The newly engineered darobactin 22 binds more effectively to BamA and exhibits 32-fold improved activity against clinically relevant pathogens such as carbapenem-resistant Acinetobacter baumannii, without any observed toxic effects.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Lena Keller, Emilia Oueis, Amninder Kaur, Nasim Safaei, Susanne H. Kirsch, Antonia P. Gunesch, Sibylle Haid, Ulfert Rand, Luka Cicin-Sain, Chengzhang Fu, Joachim Wink, Thomas Pietschmann, Rolf Mueller
Summary: A new strain of actinobacteria, Kibdelosporangium persicum sp. nov., collected from a hot desert in Iran, yielded a novel family of sesquarterpenoids (persicamidines A-E) with remarkable antiviral activity. Extensive NMR analysis revealed a hexacyclic terpenoid molecule with a modified sugar moiety on one side and a unique isourea moiety fused to the terpenoid structure. Persicamidines A-E exhibited potent activity against hCoV-229E and SARS-CoV-2 viruses in the nanomolar range, along with excellent selectivity indices, showing promise as potential drug candidates.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Biochemistry & Molecular Biology
Joscha Meiers, Jan Dastbaz, Sebastian Adam, Sari Rasheed, Susanne H. Kirsch, Peter Meiser, Peter Gross, Rolf Mueller, Alexander Titz
Summary: The highly glycosylated spike protein of SARS-CoV-2 is crucial for infection and is a target for antiviral agents and vaccines. A pineapple-derived lectin AcmJRL has been found to bind mannosides and is present in the medication bromelain. This study showed that AcmJRL binds to the spike protein of SARS-CoV-2 with a low-micromolar K-D in a carbohydrate-dependent manner.
Editorial Material
Biochemistry & Molecular Biology
Julian D. Hegemann, Joy Birkelbach, Sebastian Walesch, Rolf Mueller
Review
Biochemistry & Molecular Biology
Sebastian Walesch, Joy Birkelbach, Gwenaelle Jezequel, F. P. Jake Haeckl, Julian D. Hegemann, Thomas Hesterkamp, Anna K. H. Hirsch, Peter Hammann, Rolf Mueller
Summary: Antibacterial resistance is a significant threat to human health, and the development of new therapeutics has slowed down since the first antibiotics were approved in the 20(th) century. Most of the current drug leads are modifications of existing antibacterials, many of which come from natural products. This review highlights the challenges, advancements, and current status of the clinical and preclinical antibacterial research pipeline, and advocates for renewed investment and enthusiasm in the antibacterial discovery process.
Article
Chemistry, Medicinal
Miriam Girardini, Francesca Ferlenghi, Giannamaria Annunziato, Giulia Degiacomi, Bianca Papotti, Cinzia Marchi, Jose Camilla Sammartino, Sari S. Rasheed, Anna Contini, Maria Rosalia Pasca, Federica Vacondio, Joanna C. Evans, Thomas Dick, Rolf Mueller, Gabriele Costantino, Marco Pieroni
Summary: Tuberculosis is a deadly infectious disease and the increase in drug-resistant strains is concerning. Previous studies have identified compounds with inhibitory activity against Mycobacterium tuberculosis strains. In this study, researchers aimed to determine the metabolic fate of these compounds and explore structural modifications to improve activity and avoid rapid clearance. Novel antitubercular chemotypes were also investigated. The findings led to the design of improved compounds with good activity against drug-susceptible and drug-resistant strains.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Carla I. I. Seegers, Danielle J. Lee, Patricia Zarnovican, Susanne H. Kirsch, Rolf Mueller, Thomas Haselhorst, Francoise H. Routier
Summary: The opportunistic fungus Aspergillus fumigatus causes various diseases and forms a biofilm that protects it from the host's immune defenses and antifungal drugs. This study discovered drugs that inhibit biofilm synthesis and disrupt existing biofilms, including Actinomycin X2, Actinomycin D, Rifaximin, and Imatinib.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Plant Sciences
Sergi H. Akone, Joachim J. Hug, Amninder Kaur, Ronald Garcia, Rolf Mueller
Summary: The study reports the discovery, isolation, structure elucidation, and biological evaluation of two new bacterial sterols, nannosterols A and B, from the terrestrial myxobacterium Nannocystis sp. These nannosterols features unique modifications and chemical features, such as a secondary alcohol group at position C-15 and a terminal vicinal diol side chain at C-24-C-25, which have not been observed in bacterial sterols before. The investigation based on myxobacterial high-resolution secondary metabolome data and genomic in silico investigations revealed that nannosterols are frequently produced sterols within the myxobacterial suborder of Nannocystineae. The discovery of nannosterols provides insights into the biosynthesis and evolution of sterols by prokaryotes.
JOURNAL OF NATURAL PRODUCTS
(2023)
Article
Chemistry, Multidisciplinary
Sebastian Adam, Dazhong Zheng, Andreas Klein, Carsten Volz, William Mullen, Sally L. Shirran, Brian O. Smith, Olga V. Kalinina, Rolf Mueller, Jesko Koehnke
Summary: In this study, we identified three proteins (CgnB, CgnC, and CgnE) responsible for the production of the tetracyclic crocagin core. Crystal structures of two homologues (CgnB and CgnE) provided insights into their functions. We also discovered the roles of CgnD and CgnL in the liberation and modification of the crocagin core, respectively, and proposed a biosynthetic scheme. Bioinformatic analyses further revealed potential pathways for the synthesis of structurally diverse peptide-derived pyrroloindoline alkaloids.
Article
Microbiology
Yunsheng Gao, Joy Birkelbach, Chengzhang Fu, Jennifer Herrmann, Herbert Irschik, Bernd Morgenstern, Kerstin Hirschfelder, Ruijuan Li, Youming Zhang, Rolf Jansen, Rolf Mueller
Summary: Microbial secondary metabolites are abundant sources of bioactive compounds and are privileged scaffolds for the development of new drugs. Therefore, continuous discovery of novel bioactive natural products is crucial for pharmaceutical research. Myxobacteria, particularly Sorangium spp., are known for their underexploited biosynthetic potential and serve as proficient producers of such secondary metabolites. In this study, a family of natural products called disorazole Z was isolated and characterized from Sorangium cellulosum strain So ce1875, showing potent anticancer activity. Furthermore, the biosynthesis and heterologous production of disorazole Z were reported, providing potential for the development of disorazole-based anticancer drugs for clinical studies.
MICROBIOLOGY SPECTRUM
(2023)
Article
Chemistry, Multidisciplinary
Feng Xie, Alexander F. Kiefer, Anna K. H. Hirsch, Olga V. Kalinina, Chengzhang Fu, Rolf Mueller
Summary: This study presents the polyketide synthase (PKS)/non-ribosomal peptide synthetase (NRPS) hybrid biosynthetic gene cluster of icumazoles. It is found that an unusual nonterminal thioesterase domain divides the PKS/NRPS assembly line, and the succeeding PKS modules potentially form a rare precursor 4-methyl-2-hexenoyl-ACP. The characterization of IcuL and its homologs TgaD and Leu10 suggests a stricter substrate specificity of this new family of crotonyl carboxylases/reductases (CCRs) than canonical ones, and TgaD shows unprecedented utilization of both NADPH and NADH as cofactors.
CELL REPORTS PHYSICAL SCIENCE
(2023)
Article
Chemistry, Multidisciplinary
Asfandyar Sikandar, Alexander Popoff, Ravindra P. Jumde, Attila Mandi, Amninder Kaur, Walid A. M. Elgaher, Lara Rosenberger, Stephan Huettel, Rolf Jansen, Maja Hunter, Jesko Koehnke, Anna K. H. Hirsch, Tibor Kurtan, Rolf Mueller
Summary: The absolute configuration of amidochelocardin was revised using a combination of XRD, NMR spectroscopy, experimental ECD spectra, and TDDFT-ECD calculations. Based on the biosynthetic engineering of chelocardin and the results of TDDFT-ECD calculations, it is proposed that chelocardin has the same absolute configuration. The evaluation of spectral data of two related analogues further supports this conclusion.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Review
Biotechnology & Applied Microbiology
Michael W. Mullowney, Katherine R. Duncan, Somayah S. Elsayed, Neha Garg, Justin J. J. van der Hooft, Nathaniel I. Martin, David Meijer, Barbara R. Terlouw, Friederike Biermann, Kai Blin, Janani Durairaj, Marina Gorostiola Gonzalez, Eric J. N. Helfrich, Florian Huber, Stefan Leopold-Messer, Kohulan Rajan, Tristan de Rond, Jeffrey A. van Santen, Maria Sorokina, Marcy J. Balunas, Mehdi A. Beniddir, Doris A. van Bergeijk, Laura M. Carroll, Chase M. Clark, Djork-Arne Clevert, Chris A. Dejong, Chao Du, Scarlet Ferrinho, Francesca Grisoni, Albert Hofstetter, Willem Jespers, Olga V. Kalinina, Satria A. Kautsar, Hyunwoo Kim, Tiago F. Leao, Joleen Masschelein, Evan R. Rees, Raphael Reher, Daniel Reker, Philippe Schwaller, Marwin Segler, Michael A. Skinnider, Allison S. Walker, Egon L. Willighagen, Barbara Zdrazil, Nadine Ziemert, Rebecca J. M. Goss, Pierre Guyomard, Andrea Volkamer, William H. Gerwick, Hyun Uk Kim, Rolf Mueller, Gilles P. van Wezel, Gerard J. P. van Westen, Anna K. H. Hirsch, Roger G. Linington, Serina L. Robinson, Marnix H. Medema
Summary: The developments in computational omics technologies in combination with artificial intelligence approaches have opened up new possibilities for drug discovery. However, addressing key challenges such as high-quality datasets and algorithm validation is essential to realize the potential of these synergies.
NATURE REVIEWS DRUG DISCOVERY
(2023)
Article
Infectious Diseases
Mariam Rima, Niels Pfennigwerth, Martina Cremanns, Katarina Cirnski, Saoussen Oueslati, Soeren G. Gatermann, Nicola d'Amelio, Jennifer Herrmann, Rolf Mueller, Thierry Naas
Summary: The development of novel antibiotics is crucial to combat the growing problem of antibiotic resistance. In this study, the activity spectrum of cystobactamids and chelocardins, two promising classes of molecules with different modes of action, was determined. These molecules showed potent activities against clinically relevant Gram-negative and Gram-positive bacteria, including multi-drug resistant strains. The findings suggest that cystobactamid CN-DM-861 and chelocardin CDCHD have interesting antibiotic activities on MDR or XDR bacteria without cross-resistance to clinically relevant antibiotics.
Article
Biotechnology & Applied Microbiology
Haowen Zhao, Yuhao Ren, Feng Xie, Huanqin Dai, Hongwei Liu, Chengzhang Fu, Rolf Mueller
Summary: In this study, a new group of catecholate-hydroxamate siderophores, nobachelins, was discovered from Nocardiopsis baichengensis DSM 44845 by correlating a cryptic biosynthetic gene cluster to chemical molecules. Nobachelins, featuring fatty-acylated hydroxyornithine and a rare chlorinated catecholate group, were found to rescue Caenorhabditis elegans from Pseudomonas aeruginosa-mediated killing.
SYNTHETIC AND SYSTEMS BIOTECHNOLOGY
(2023)
