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
Unsaturated oxyallyl cations with a suitably positioned alkene bond undergo 5-exo-cyclization with the formation of vinylcyclopentane derivatives. Alkyne analogues provide allenes. The reaction proceeds with a moderate to excellent level of stereoselectivity and allows for asymmetric induction in the reaction with chiral substrate.
ABSTRACT
1,6-Diynes with a t-butylcarbonate group in the propargylic position undergo gold(I)-catalyzed domino-cyclization which affords α-hydroxycyclohexenones. The described sequence can be applied on functionalized, highly oxygenated substrates, as examplified in the synthesis of (-)-gabosine H and its epimer.
ABSTRACT
Organocatalyzed Tsuji-Trost cyclization of 3b proceeds with asymmetric induction and allows for stereoselective synthesis of (+)-allokainic acid. The stereochemical outcome of the cyclization was predicted by calculations.
ABSTRACT
Enantioselective synthesis of a marine antibiotic (-)-atrop-abyssomicin C was accomplished in 21 steps, in 1.8% overall yield (4%, based on the recovered starting material). The key steps of the synthesis are the formation of the functionalized cyclohexane core by an organocatalyzed Tsuji-Trost reaction, the formation of a tricyclic spirotetronate unit by a gold-catalyzed reaction sequence and the highly efficient eleven-membered ring closure by a Nozaki-Hiyama-Kishi reaction. Biological tests showed all abyssomicin derivatives to possess strong antibacterial activity against methicillin resistant S. aureus strains; however, they also proved to be cytotoxic, both to malignant and to normal somatic cells.
Subject(s)
Bacteria/drug effects , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/toxicity , Catalysis , Cell Survival/drug effects , Gold/chemistry , HeLa Cells , Humans , Leukocytes, Mononuclear/drug effects , Microbial Sensitivity Tests , Molecular Structure , 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
Synergic combination of organotransition metal catalysis and organocatalysis allows, for the first time, the Tsuji-Trost cyclization of aldehydes. A catalytic asymmetric variant of the reaction is also possible.
Subject(s)
Aldehydes/chemical synthesis , Organometallic Compounds/chemistry , Organometallic Compounds/chemical synthesis , Palladium/chemistry , Pyrrolidines/chemistry , Aldehydes/chemistry , Catalysis , Combinatorial Chemistry Techniques , Cyclization , Molecular Structure , StereoisomerismABSTRACT
The combination of ring closing metathesis and beta-fragmentation offers an efficient entry into (Z)-configured medium ring cycloalkenes. The fragmentation step can be effected under anionic or radical conditions. The versatility of this method is demonstrated by the total synthesis of (+/-)-periplanone C-a macrocyclic pheromone of Periplaneta americana.
Subject(s)
Alkenes/chemistry , Cycloparaffins/chemical synthesis , Cyclization , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray Ionization , StereoisomerismABSTRACT
The combination of alkene metathesis and beta-fragmentation offers an efficient entry into (Z)-configured medium-ring cycloalkenes. The versatility of this method is demonstrated by the total synthesis of Periplanone C, a semiochemical of Periplaneta americana. [reaction: see text]