Alkaloids Used as Medicines: Structural Phytochemistry Meets Biodiversity—An Update and Forward Look

Selecting candidates for drug developments using computational design and empirical rules has resulted in a broad discussion about their success. In a previous study, we had shown that a species’ abundance [as expressed by the GBIF (Global Biodiversity Information Facility)] dataset is a core determinant for the development of a natural product into a medicine. Our overarching aim is to understand the unique requirements for natural product-based drug development. Web of Science was queried for research on alkaloids in combination with plant systematics/taxonomy. All alkaloids containing species demonstrated an average increase of 8.66 in GBIF occurrences between 2014 and 2020. Medicinal Species with alkaloids show higher abundance compared to non-medicinal alkaloids, often linked also to cultivation. Alkaloids with high biodiversity are often simple alkaloids found in multiple species with the presence of ’driver species‘ and are more likely to be included in early-stage drug development compared to ‘rare’ alkaloids. Similarly, the success of an alkaloid containing species as a food supplement (‘botanical’) is linked to its abundance. GBIF is a useful tool for assessing the druggability of a compound from a certain source species. The success of any development programme from natural sources must take sustainable sourcing into account right from the start.     

Alkaloid accumulation dynamics in Veratrum lobelianum growing in Georgia and biological activity of Jervine

The alkaloid accumulation dymanics in Veratrum lobelianum were investigated. Jervine was found from 0.02 to 0.11% in the subterranean part at all vegetation stages. The jervine content was greatest in subterranean plant organs, reaching a maximum (0.3%) during natural dying off of aerial organs. Jervine, a natural analog of serotonin, can be used as a specific fibroblast growth factor. __________ Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 57–59, January–February, 2006.     

金丝矮陀陀植物中甾体生物碱的分离与化学结构

最近,我们研究了云南产的金丝矮陀陀植物中的甾体生物碱。对植物样品的乙醇提取物作了系统分离,从中得到22个甾体生物碱,     

Three New Pregnane Alkaloids from Veratrum taliense

Three new alkaloids, 3‐O‐acetylveralkamine ( 1 ), veralkamine 3‐(β‐D ‐glucopyranoside) ( 2 ), and 6,7‐epoxyverdine ( 3 ), together with five known alkaloids, veramitaline, veralkamine ( 4 ), angeloylzygadenine, veratroylzygadenine, and veramiline 3‐(β‐D ‐glucopyranoside), were isolated from the whole plants of Veratrum taliense. Their structures were elucidated on the basis of spectroscopic analysis, and the NMR data of veralkamine ( 4 ) are given for the first time. In addition, the cytotoxic activities of all isolated compounds, except for veramitaline, were tested.     

Two New Steroidal Alkaloids from Veratrum nigrum L.

Phytochemical studies on Veratrum nigrum L., collected in Shanxi, P. R. China, resulted in the isolation of two new steroidal alkaloids, 23‐methoxycyclopamine ( 1 ) and 15‐O‐(2‐methylbutanoyl)‐3‐O‐veratroylprotoverine ( 2 ). The structures of the two new compounds were established by means of extensive NMR spectroscopic studies.     

Chromatography: An important tool for drug discovery

Despite substantial developments of extraction and separation techniques, isolation of natural products from natural sources is still a challenging task. Undoubtedly hybrid methods like liquid chromatography with NMR spectroscopy or liquid chromatography coupled with mass spectrometry made on‐line structure elucidation possible and provided impressive examples of natural product identification without prior isolation, however, in many cases the necessity to get the purified compounds in hand is still a fact. The process begins with the collection of desired plant material which is subjected to the suitable extraction process. The complex crude extracts are then monitored by various chromatographic procedures to separate and quantify the desired compounds. The active plant extracts are then fractionated to isolate the bioactive compounds in their pure form. The fully identified compound is used as a lead for the production of related analogues to modulate the biological activity and to carry out structure‐activity relationship. The major isolated bioactive compound is used for semi‐synthetic modification or total synthesis should be carried out such that it is relatively easy to modify the structure of the lead compound. This is a simple and cost‐effective way to increase the chance to discover lead compounds. The biological activity in vitro and in vivo has to be done after purification.     

Production of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure–Activity Relationships

The bengamides, sponge‐derived natural products that have been characterized as inhibitors of methionine aminopeptidases (MetAPs), have been intensively investigated as anticancer compounds. We embarked on a multidisciplinary project to supply bengamides by fermentation of the terrestrial myxobacterium M. virescens, decipher their biosynthesis, and optimize their properties as drug leads. The characterization of the biosynthetic pathway revealed that bacterial resistance to bengamides is conferred by Leu 154 of the myxobacterial MetAP protein, and enabled transfer of the entire gene cluster into the more suitable production host M. xanthus DK1622. A combination of semisynthesis of microbially derived bengamides and total synthesis resulted in an optimized derivative that combined high cellular potency in the nanomolar range with high metabolic stability, which translated to an improved half‐life in mice and antitumor efficacy in a melanoma mouse model.     

Alkaloids: Therapeutic Potential against Human Coronaviruses

Alkaloids are a class of natural products known to have wide pharmacological activity and have great potential for the development of new drugs to treat a wide array of pathologies. Some alkaloids have antiviral activity and/or have been used as prototypes in the development of synthetic antiviral drugs. In this study, eleven anti-coronavirus alkaloids were identified from the scientific literature and their potential therapeutic value against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is discussed. In this study, in silico studies showed an affinity of the alkaloids for binding to the receptor-binding domain of the SARS-CoV-2 spike protein, putatively preventing it from binding to the host cell. Lastly, several mechanisms for the known anti-coronavirus activity of alkaloids were discussed, showing that the alkaloids are interesting compounds with potential use as bioactive agents against SARS-CoV-2.     

Lost in Transcription—Inhibition of RNA Polymerase

Form and function : The natural product myxopyronin A provides the key to understanding the inhibition of bacterial RNA polymerase and should spark new ideas for the design of new antibiotics against tuberculosis and other infectious diseases.

     

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.     

On the Reach of Chemical Synthesis: Creation of a Mini‐Pipeline from an Academic Laboratory

In this retrospective, we recall some select cases of synergy between very challenging chemical synthesis and the identification of promising new candidates for pharmaceutics development. The progression from targets, often referred to as small molecules, to those of a size commonly associated with biologics (including glycoproteins) is also charted.     

Cyclopamine and Hedgehog Signaling: Chemistry,Biology, Medical Perspectives

When Odysseus left the devastated city of Troy after ten years of siege he could not foresee the perils he still had to face. The encounter with the cyclops, a giant with only one eye placed in the middle of its forehead, was doubtlessly one of the creepiest and most dangerous of his adventures. In the end, Odysseus could only escape with the help of a sheep. Whether Homers cyclops was inspired by the observation of terribly malformed neonates remains speculative. However, when sheep herders in Idaho in the middle of the 20th century faced an increasing number of cyclops‐like sheep in their herds, a unique cascade of chemical, biological, and medicinal discoveries was initiated. This Minireview tells this story and shows its impact on modern biomedical research.     

Total Synthesis and Conformational Study of Callyaerin A: Anti‐Tubercular Cyclic Peptide Bearing a Rare Rigidifying (Z)‐2,3‐ Diaminoacrylamide Moiety

The first synthesis of the anti‐TB cyclic peptide callyaerin A ( 1 ), containing a rare (Z)‐2,3‐diaminoacrylamide bridging motif, is reported. Fmoc‐formylglycine‐diethylacetal was used as a masked equivalent of formylglycine in the synthesis of the linear precursor to 1 . Intramolecular cyclization between the formylglycine residue and the N‐terminal amine in the linear peptide precursor afforded the macrocyclic natural product 1 . Synthetic 1 possessed potent anti‐TB activity (MIC₁₀₀=32 μm ) while its all‐amide congener was inactive. Variable‐temperature NMR studies of both the natural product and its all‐amide analogue revealed the extraordinary rigidity imposed by this diaminoacrylamide unit on peptide conformation. The work reported herein pinpoints the intrinsic role that the (Z)‐2,3‐diaminoacrylamide moiety confers on peptide bioactivity.     

Steroidal Alkaloids from Veratrum maackii Regel with Genotoxicity on Brain‐Cell DNA in Mice

Two new steroidal alkaloids, 23‐methoxycyclopamine 3‐O‐β‐D ‐glucopyranoside ( 1 ) and isoecliptalbine ( 2 ), were isolated from the root and rhizoma of Veratrum maackii Regel , together with five known compounds, i.e., verussurine ( 3 ), verabenzoamine ( 4 ), verazine ( 5 ), isoverazine ( 6 ), and verazinine ( 7 ). Their structures were established by extensive analysis of spectroscopic data, as well as by comparison with literature data. Compounds 1 – 7 could cause DNA damage in the cerebellum and cerebral cortex of mice in a dose‐dependent manner by using single‐cell gel electrophoresis (comet assay).     

Biomimetic Synthesis of Rhytidenone A and Mode of Action of Cytotoxic Rhytidenone F

The rhytidenone family comprises spirobisnaphthalene natural products isolated from the mangrove endophytic fungus Rhytidhysteron rufulum AS21B. The biomimetic synthesis of rhytidenone A was achieved by a Michael reaction/aldol/lactonization cascade in a single step from the proposed biosynthetic precursor rhytidenone F. Moreover, the mode of action of the highly cytotoxic rhytidenone F was investigated. The pulldown assay coupled with mass spectrometry analysis revealed the target protein PA28γ is covalently attached to rhytidenone F at the Cys92 residue. The interactions of rhytidenone F with PA28γ lead to the accumulation of p53, which is an essential tumor suppressor in humans. Consequently, the Fas‐dependent signaling pathway is activated to initiate cellular apoptosis. These studies have identified the first small‐molecule inhibitor targeting PA28γ, suggesting rhytidenone F may serve as a promising natural product lead for future anticancer drug development.