ABSTRACT
We developed new iminosugar-based glycosidase inhibitors against SARS-CoV-2. Known drugs (miglustat, migalastat, miglitol, and swainsonine) were chosen as lead compounds to develop three classes of glycosidase inhibitors (α-glucosidase, α-galactosidase, and mannosidase). Molecular modelling of the lead compounds, synthesis of the compounds with the highest docking scores, enzyme inhibition tests, and in vitro antiviral assays afforded rationally designed inhibitors. Two highly active α-glucosidase inhibitors were discovered, where one of them is the most potent iminosugar-based anti-SARS-CoV-2 agent to date (EC90 = 1.94 µM in A549-ACE2 cells against Omicron BA.1 strain). However, galactosidase inhibitors did not exhibit antiviral activity, whereas mannosidase inhibitors were both active and cytotoxic. As our iminosugar-based drug candidates act by a host-directed mechanism, they should be more resilient to drug resistance. Moreover, this strategy could be extended to identify potential drug candidates for other viral infections.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Models, Molecular , Mannosidases , Antiviral Agents/pharmacology , Molecular Docking SimulationABSTRACT
An evolution of a synthetic route leading to a successful enantioselective total synthesis of monoterpenoid indole alkaloid (+)-alstonlarsine A is represented. The unique 9-azatricyclo[4.3.1.03,8]decane core was assembled through an efficient domino sequence comprising enamine formation in situ, followed by intramolecular dearomative inverse-electron-demand Diels Alder reaction. The preparation of the tricyclic dihydrocyclohepta[b]indole key intermediate via the intramolecular Horner-Wadsworth-Emmons reaction required a development of a new general method for the introduction of the phosphonoacetate moiety into the indole C-2 position, through copper-carbenoid insertion. The modular nature of the represented synthetic approach makes it suitable for the synthesis of analogues with different substituents' patterns.
ABSTRACT
An enantioselective total synthesis of (+)-alstonlarsine A (1), a monoterpenoid indole alkaloid possessing a unique pentacyclic skeleton as well as a rare biological activity, is achieved. The key step is an efficient domino sequence, comprising enamine formation followed by an inverse-electron-demand intramolecular dearomative Diels-Alder cycloaddition for the construction of 9-azatricyclo[4.3.1.03,8 ]decane core. The key intermediate for this domino sequence was synthesized by a newly developed methodology, relying on indole C(2) -H bond functionalization, combined with intramolecular Horner-Wadsworth-Emmons reaction. This tactical combination offers a new general entry into other (privileged) tricyclic frameworks possessing indole ring fused to 6-, 7- or 8-membered rings.
Subject(s)
Indole Alkaloids , Secologanin Tryptamine Alkaloids , Cycloaddition Reaction , Indole Alkaloids/chemistry , StereoisomerismABSTRACT
A chiral-pool-based synthesis of the platensimycin core was achieved using (S)-lactic acid as an inexpensive starting material. The cyclohexenone ring was closed in a Mukaiyama-Michael domino sequence, while the quaternary stereocenter was created by a highly stereoselective decarboxylative allylation. The spirobicyclic skeleton was constructed by a RCM reaction. A new silver(I)-promoted cyclization reaction of Δ6 - and Δ7 -α-iodoketones was developed and applied for the pivotal carbon-carbon bond formation. The scope and limitations of this methodology are also presented.
ABSTRACT
The first total synthesis of the neuroactive indole alkaloid (±)-alstoscholarisineâ A is reported. The key step of the concise synthesis is an efficient domino sequence that was used to assemble the 2,8-diazabicyclo[3.3.1]nonane core through the formation of two C-N bonds and one C-C bond in a single step.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Indoles/chemical synthesis , StereoisomerismABSTRACT
The design, synthesis and biological evaluation of a novel C,D-spirolactone analogue of paclitaxel is described. This is the first paclitaxel analogue without an oxetane D-ring that shows a significant cytotoxic effect (activity one order of magnitude lower than paclitaxel). More importantly, its cytotoxicity is a result of a different mechanism of action, involving mTOR inhibition-dependent autophagy instead of G(2)/M cell cycle arrest-dependent apoptosis.
Subject(s)
Autophagy/drug effects , Paclitaxel/chemistry , Spironolactone/analogs & derivatives , Cell Line, Tumor , Humans , Molecular Structure , Paclitaxel/pharmacologyABSTRACT
A formal asymmetric synthesis of the antiviral agent (-)-oseltamivir phosphate is achieved using two aldol reactions as key steps.
Subject(s)
Oseltamivir/chemical synthesis , Molecular Structure , StereoisomerismABSTRACT
Xanthates have been readily converted into o-chlorophenyl thioethers using a one-step procedure conducted under radical conditions. In some selected cases, these aryl thioethers were successfully oxidized to the corresponding sulfoxides and sulfenic acid elimination afforded the corresponding vinylsilanes.