ABSTRACT
The development of new therapies to treat methicillin-resistant Staphylococcus aureus (MRSA) is needed to counteract the significant threat that MRSA presents to human health. Novel inhibitors of DNA gyrase and topoisomerase IV (TopoIV) constitute one highly promising approach, but continued optimization is required to realize the full potential of this class of antibiotics. Herein, we report further studies on a series of dioxane-linked derivatives, demonstrating improved antistaphylococcal activity and reduced hERG inhibition. A subseries of analogues also possesses enhanced inhibition of the secondary target, TopoIV.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , DNA Gyrase/metabolism , Dioxanes/chemistry , Methicillin-Resistant Staphylococcus aureus/enzymology , Topoisomerase Inhibitors/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Binding Sites , DNA Gyrase/chemistry , DNA Topoisomerase IV/antagonists & inhibitors , DNA Topoisomerase IV/chemistry , DNA Topoisomerase IV/metabolism , Down-Regulation , ERG1 Potassium Channel/metabolism , Humans , K562 Cells , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Protein Binding , Structure-Activity Relationship , Topoisomerase Inhibitors/chemistry , Topoisomerase Inhibitors/pharmacologyABSTRACT
Azaspiracid-34 (AZA34) is a recently described structurally unique member of the azaspiracid class of marine neurotoxins. Its novel structure, tentatively assigned on the basis of MS and 1H NMR spectroscopy, is accompanied by a 5.5-fold higher level of toxicity against Jurkat T lymphocytes than AZA1. To completely assign the structure of AZA34 and provide material for in-depth biological evaluation and detection, synthetic access to AZA34 was targeted. This began with the convergent and stereoselective assembly of the C1-C19 domain of AZA34 designed to dovetail with the recent total synthesis approach to AZA3.
Subject(s)
Jurkat Cells/cytology , Marine Toxins/toxicity , Neurotoxins/toxicity , Spiro Compounds/chemical synthesis , Humans , Jurkat Cells/chemistry , Magnetic Resonance Spectroscopy , Marine Toxins/chemical synthesis , Marine Toxins/chemistry , Molecular Structure , Spiro Compounds/chemistryABSTRACT
The previously accepted structure of the marine toxin azaspiracid-3 is revised based upon an original convergent and stereoselective total synthesis of the natural product. The development of a structural revision hypothesis, its testing, and corroboration are reported. Synthetic (6R,10R,13R,14R,16R,17R,19S,20S,21R,24S,25S,28S,30S,32R, 33R,34R,36S,37S,39R)-azaspiracid-3 chromatographically and spectroscopically matched naturally occurring azaspiracid-3, whereas the previously assigned 20R epimer did not.
Subject(s)
Biological Products/chemistry , Biological Products/chemical synthesis , Furans/chemistry , Furans/chemical synthesis , Pyrans/chemistry , Pyrans/chemical synthesis , Carbon-13 Magnetic Resonance Spectroscopy , Chromatography, Liquid , Mass Spectrometry , Molecular Structure , Oxidation-Reduction , Proton Magnetic Resonance Spectroscopy , StereoisomerismABSTRACT
A convergent and stereoselective total synthesis of the previously assigned structure of azaspiracid-3 has been achieved by a late-stage Nozaki-Hiyama-Kishi coupling to form the C21-C22 bond with the C20 configuration unambiguously established from l-(+)-tartaric acid. Postcoupling steps involved oxidation to an ynone, modified Stryker reduction of the alkyne, global deprotection, and oxidation of the resulting C1 primary alcohol to the carboxylic acid. The synthetic product matched naturally occurring azaspiracid-3 by mass spectrometry, but differed both chromatographically and spectroscopically.
