Lecture 4: Natural Products, Prof. Trader, Winter 2025 PDF

Lecture 4: Natural Products Prof. Trader Winter 2025 External References Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019 J. Nat. Prod. 2020, 83, 770−803 Natural Products in drug discovery: advances and opportunities...

Lecture 4: Natural Products Prof. Trader Winter 2025 External References Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019 J. Nat. Prod. 2020, 83, 770−803 Natural Products in drug discovery: advances and opportunities Nature Reviews Drug Discovery 200 | March 2021 | Volume 20 Natural product drug discovery in the artificial intelligence era Chem. Sci., 2022, 13, 1526 For fun: A Historical Overview of Natural Products in Drug Discovery Metabolites 2012, 2, 303-336; doi:10.3390/metabo2020303 What is a natural product (NP)? Comes from something alive Plants Bacteria Coral Animals Etc. Can have wild ring structures and typically has many stereocenters, make them very unique. But can NPs really be drugs? 1981-2019 = 1881 Drugs Nephrol Dial Transplant, 2024, Vol. 39, No. 3 Natural Products are a great source of NCEs Steps required for Drug Development from Natural Sources Need A LOT of the source of the NP (grow it? Harvest it?) Evaluating biological activity Crude extract? Semi-purify it? What assay is best? Identify from the ”soup” the one molecule you want that is active Synthetically optimize the hit Bioactivity- Guided Isolation Fractionationà Chromatography HPLCà High Performance Liquid Chromatography  HPLC Reverse-Phase Column “catches” hydrophobic molecules  Standard Silica Gel Chromatography Hydrophilic molecules stick to silica gel, and require strong solvents to elute the molecule off the silica gel Example OH OH O O O HO OH O 1 2 3 4 Genome Mining Discovery- General Genome Mining Example Hit to Lead of NPs TB Drug Example What to modify? So why don’t we all just screen natural products? AI Can Help Lots of information from just looking at structure Tanimoto Index (Score) Antibiotic SAR- Case Study Enzyme Inhibition “Mycobacterium tuberculosis and certain yeasts do not have a well-organized riboflavin uptake system, therefore they predominantly depend on the endogenous production of riboflavin for their survival”  Riboflavin Synthase Inhibitor Hunanamycin A Natural Product Screen for Antibiotic Properties Marine bacterium SNA-048 was isolated from a sediment sample collected from a mangrove swamp in the Bahamas and isolated on an acidified Gauze media. Analysis of the strain by 16S rRNA revealed a 98% identity to Bacillus hunanensis. (8) A large-scale fermentation (120 L) by shake fermentation was carried out to obtain sufficient material for full chemical and biological analysis of the new compounds. Org. Lett. 2013, 15, 2, 390–393 SAR of Hunanamycin Synthesis Synthesis Cont.  SAR of Hunanamycin Synthesized 87+ derivatives!