scholarly journals Neoglycosylation and neoglycorandomization: enabling tools for the discovery of novel glycosylated bioactive probes and early stage leads

MedChemComm ◽  
2014 ◽  
Vol 5 (8) ◽  
pp. 1036-1047 ◽  
Author(s):  
Randal D. Goff ◽  
Jon. S. Thorson
Keyword(s):  
Natural Products ◽  
Small Molecules ◽  
Early Stage

Alkoxyamine-based strategies for the rapid chemoselective conjugation of sugars to drugs, natural products and bioactive small molecules.

Investigating the influence of aromatic moieties on the formulation of hydrophobic natural products and drugs in poly(2-oxazoline) based amphiphiles

2018 ◽  
Author(s):  
Robert Luxenhofer ◽  
Michael M Lübtow ◽  
Lukas Hahn ◽  
Thomas Lorson ◽  
Rainer Schobert
Keyword(s):  
Natural Products ◽  
Small Molecules ◽  
Water Solubility ◽  
Drug Loading ◽  
High Drug ◽  
Long Term Stability ◽  
Aromatic Content ◽  
Important Interaction ◽  
Amorphous Structures ◽  
High Drug Loading

Many natural compounds with interesting biomedical properties share one physicochemical property, namely a low water solubility. Polymer micelles are, among others, a popular means to solubilize hydrophobic compounds. The specific molecular interactions between the polymers and the hydrophobic drugs are diverse and recently it has been discussed that macromolecular engineering can be used to optimize drug loaded micelles. Specifically, π-π stacking between small molecules and polymers has been discussed as an important interaction that can be employed to increase drug loading and formulation stability. Here, we test this hypothesis using four different polymer amphiphiles with varying aromatic content and various natural products that also contain different relative amounts of aromatic moieties. While in the case of paclitaxel, having the lowest relative content of aromatic moieties, the drug loading decreases with increasing relative aromatic amount in the polymer, the drug loading of curcumin, having a much higher relative aromatic content, is increased. Interestingly, the loading using schizandrin A, a dibenzo[a,c]cyclooctadiene lignan with intermediate relative aromatic content is not influenced significantly by the aromatic content of the polymers employed. The very high drug loading, long term stability, the ability to form stable highly loaded binary coformulations in different drug combinations, small sized formulations and amorphous structures in all cases, corroborate earlier reports that poly(2-oxazoline) based micelles exhibit an extraordinarily high drug loading and are promising candidates for further biomedical applications. The presented results underline that the interaction between the polymers and the incorporated small molecules are complex and must be investigated in every specific case.<br>

Harnessing methylation and AdoMet-utilising enzymes for selective modification in cascade reactions

2021 ◽  
Author(s):  
Freideriki Michailidou ◽  
Andrea Rentmeister
Keyword(s):  
Natural Products ◽  
Small Molecules ◽  
Cascade Reactions ◽  
Fine Tuning ◽  
Wide Range

Enzyme-mediated methylation is a very important reaction in nature, yielding a wide range of modified natural products, diversifying small molecules and fine-tuning the activity of biomacromolecules. The field has attracted...

scholarly journals The Pharmaceutical Industry in 2019. An Analysis of FDA Drug Approvals from the Perspective of Molecules

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 745 ◽  
Author(s):  
Beatriz G. de la Torre ◽  
Fernando Albericio
Keyword(s):  
Natural Products ◽  
Pharmaceutical Industry ◽  
Small Molecules ◽  
Chemical Structure ◽  
New Drugs ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
The Us ◽  
New Chemical Entities ◽  
Antibody Drug

During 2019, the US Food and Drug Administration (FDA) approved 48 new drugs (38 New Chemical Entities and 10 Biologics). Although this figure is slightly lower than that registered in 2018 (59 divided between 42 New Chemical Entities and 17 Biologics), a year that broke a record with respect to new drugs approved by this agency, it builds on the trend initiated in 2017, when 46 drugs were approved. Of note, three antibody drug conjugates, three peptides, and two oligonucleotides were approved in 2019. This report analyzes the 48 new drugs of the class of 2019 from a strictly chemical perspective. The classification, which was carried out on the basis of chemical structure, includes the following: Biologics (antibody drug conjugates, antibodies, and proteins); TIDES (peptide and oligonucleotides); drug combinations; natural products; and small molecules.

scholarly journals Simultaneous Assessment of the Efficacy and Toxicity of Marine Mollusc–Derived Brominated Indoles in an In Vivo Model for Early Stage Colon Cancer

2017 ◽  
Vol 17 (2) ◽  
pp. 248-262 ◽  
Author(s):  
Babak Esmaeelian ◽  
Kirsten Benkendorff ◽  
Richard K. Le Leu ◽  
Catherine A. Abbott
Keyword(s):  
Colon Cancer ◽  
Natural Products ◽  
Liver Toxicity ◽  
Early Stage ◽  
Blood Biochemistry ◽  
In Vivo Model ◽  
Liver Histopathology ◽  
Genotoxic Carcinogens ◽  
Early Stage Colon Cancer

The acute apoptotic response to genotoxic carcinogens animal model has been extensively used to assess the ability of drugs and natural products like dietary components to promote apoptosis in the colon and protect against colorectal cancer (CRC). This work aimed to use this model to identify the main chemopreventative agent in extracts from an Australian mollusc Dicathais orbita, while simultaneously providing information on their potential in vivo toxicity. After 2 weeks of daily oral gavage with bioactive extracts and purified brominated indoles, mice were injected with the chemical carcinogen azoxymethane (AOM; 10 mg/kg) and then killed 6 hours later. Efficacy was evaluated using immunohistochemical and hematoxylin staining, and toxicity was assessed via hematology, blood biochemistry, and liver histopathology. Comparison of saline- and AOM-injected controls revealed that potential toxic side effects can be interpreted from blood biochemistry and hematology using this short-term model, although AOM negatively affected the ability to detect histopathological effects in the liver. Purified 6-bromoisatin was identified as the main cancer preventive agent in the Muricidae extract, significantly enhancing apoptosis and reducing cell proliferation in the colonic crypts at 0.05 mg/g. There was no evidence of liver toxicity associated with 6-bromoisatin, whereas 0.1 mg/g of the brominated indole tyrindoleninone led to elevated aspartate aminotransferase levels and a reduction in red blood cells. As tyrindoleninone is converted to 6-bromoisatin by oxidation, this information will assist in the optimization and quality control of a chemopreventative nutraceutical from Muricidae. In conclusion, preliminary data on in vivo safety can be simultaneously collected when testing the efficacy of new natural products, such as 6-bromoisatin from Muricidae molluscs for early stage prevention of colon cancer.

Alkynyl Prins and Alkynyl Aza-Prins Annulations: Scope and Synthetic Applications

Synthesis ◽  
2020 ◽  
Vol 52 (14) ◽  
pp. 1991-2007 ◽  
Author(s):  
Alison J. Frontier ◽  
Shukree Abdul-Rashed ◽  
Connor Holt
Keyword(s):  
Natural Products ◽  
Small Molecules ◽  
Natural Product ◽  
Natural Product Synthesis ◽  
Pericyclic Reactions ◽  
Prins Reaction ◽  
Prins Cyclization ◽  
Synthetic Utility ◽  
Cascade Processes ◽  
Saturated Heterocycles

This review focuses on alkynyl Prins and alkynyl aza-Prins cyclization­ processes, which involve intramolecular coupling of an alkyne with either an oxocarbenium or iminium electrophile. The oxocarbenium or iminium species can be generated through condensation- or elimination-type processes, to achieve an overall bimolecular annulation that enables the synthesis of both oxygen- and nitrogen-containing­ saturated heterocycles with different ring sizes and substitution patterns. Also discussed are cascade processes in which alkynyl Prins heterocyclic adducts react to trigger subsequent pericyclic reactions, including [4+2] cycloadditions and Nazarov electrocyclizations, to rapidly construct complex small molecules. Finally, examples of the use of alkynyl Prins and alkynyl aza-Prins reactions in the synthesis of natural products are described. The review covers the literature through the end of 2019.1 Introduction1.1 Alkyne-Carbonyl Coupling Pathways1.2 Coupling/Cyclization Cascades Using the Alkynyl Prins Reaction2 Alkynyl Prins Annulation (Oxocarbenium Electrophiles)2.1 Early Work2.2 Halide as Terminal Nucleophile2.3 Oxygen as Terminal Nucleophile2.4 Arene as Terminal Nucleophile (Intermolecular)2.5 Arene Terminal Nucleophile (Intramolecular)2.6 Cyclizations Terminated by Elimination3 Synthetic Utility of Alkynyl Prins Annulation3.1 Alkynyl Prins-Mediated Synthesis of Dienes for a [4+2] Cyclo­- addition­-Oxidation Sequence3.2 Alkynyl Prins Cyclization Adducts as Nazarov Cyclization Precursors3.3 Alkynyl Prins Cyclization in Natural Product Synthesis4 Alkynyl Aza-Prins Annulation4.1 Iminium Electrophiles4.2 Activated Iminium Electrophiles5 Alkynyl Aza-Prins Cyclizations in Natural Product Synthesis6 Summary and Outlook

scholarly journals Molecular architecture of zinc chelating small molecules that inhibit spliceosome assembly at an early stage

RNA ◽  
2012 ◽  
Vol 18 (9) ◽  
pp. 1605-1611 ◽  
Author(s):  
V. Patil ◽  
J. C. Canzoneri ◽  
T. R. Samatov ◽  
R. Luhrmann ◽  
A. K. Oyelere
Keyword(s):  
Small Molecules ◽  
Early Stage ◽  
Molecular Architecture ◽  
Spliceosome Assembly

scholarly journals Scope of 3D Shape-Based Approaches in Predicting the Macromolecular Targets of Structurally Complex Small Molecules Including Natural Products and Macrocyclic Ligands

2020 ◽  
Author(s):  
Ya Chen ◽  
Neann Mathai ◽  
Johannes Kirchmair
Keyword(s):  
Natural Products ◽  
Small Molecules ◽  
Knowledge Base ◽  
Target Prediction ◽  
Molecular Shape ◽  
Macrocyclic Compounds ◽  
Success Rates ◽  
Complex Molecules ◽  
Complete Failure ◽  
Prediction Approach

A plethora of similarity-based, network-based, machine learning and docking approaches for predicting the macromolecular targets of small molecules are available today and recognized as valuable tools for providing guidance in early drug discovery. With the increasing maturity of target prediction methods, researchers have started to explore ways to expand their scope to more challenging molecules such as structurally complex natural products and macrocyclic small molecules. In this work we systematically explore the capacity of an alignment-based approach to identify the targets of structurally complex small molecules (including large and flexible natural products and macrocyclic compounds) based on the similarity of their 3D molecular shape to non-complex molecules (i.e. more conventional, "drug-like", synthetic compounds). For this analysis, query sets of ten representative, structurally complex molecules were compiled for each of 35 pharmaceutically relevant proteins. Subsequently, ROCS, a leading shape-based screening engine, was utilized to generate rank-ordered lists of the potential targets of the 35x10 queries according to the similarity of their 3D molecular shape with that of compounds from a knowledge base of 272 640 non-complex small molecules active on a total of 3642 different proteins. Four of the scores implemented in ROCS were explored for target ranking, with the TanimotoCombo score consistently outperforming all others. The score successfully recovered the targets of 29% and 40% of the 350 queries among the top-5 and top-20 positions, respectively. For 29 out of the 35 investigated targets (83%), the method correctly assigned the first rank (out of 3642) to the target of interest for at least one of the ten queries. The shape-based target prediction approach showed remarkable robustness, with good success rates obtained even for compounds that are clearly distinct from any of the ligands present in the knowledge base. However, complex natural products and macrocyclic compounds proved to be challenging even with this approach, although cases of complete failure were recorded only for a small number of targets.

scholarly journals Multiplexed screening of thousands of natural products for protein-ligand binding in native mass spectrometry

2021 ◽  
Author(s):  
Giang Nguyen ◽  
Jack Bennett ◽  
Sherrie Liu ◽  
Sarah Hancock ◽  
Daniel Winter ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Natural Products ◽  
Drug Discovery ◽  
Small Molecules ◽  
Natural Product ◽  
Drug Targets ◽  
Structural Diversity ◽  
Native Mass Spectrometry ◽  
Protein Targets ◽  
Rapid Measurement

The structural diversity of natural products offers unique opportunities for drug discovery, but challenges associated with their isolation and screening can hinder the identification of drug-like molecules from complex natural product extracts. Here we introduce a mass spectrometry-based approach that integrates untargeted metabolomics with multistage, high-resolution native mass spectrometry to rapidly identify natural products that bind to therapeutically relevant protein targets. By directly screening crude natural product extracts containing thousands of drug-like small molecules using a single, rapid measurement, novel natural product ligands of human drug targets could be identified without fractionation. This method should significantly increase the efficiency of target-based natural product drug discovery workflows.

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