Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies.

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.

Cyclization Reactions of Oxyallyl Cation. A Method for Cyclopentane Ring Formation.

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.

Enantioselective Synthesis of the Platensimycin Core by Silver(I)-Promoted Cyclization of Δ6 -α-Iodoketone.

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.

Gold(I)-Catalyzed Domino Cyclizations of Diynes for the Synthesis of Functionalized Cyclohexenone Derivatives. Total Synthesis of (-)-Gabosine H and (-)-6-epi-Gabosine H.

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.

Substrate stereocontrol in the intramolecular organocatalyzed Tsuji-Trost reaction: enantioselective synthesis of allokainates.

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.

Total synthesis and biological evaluation of (-)-atrop-abyssomicin C.

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.

A novel C,D-spirolactone analogue of paclitaxel: autophagy instead of apoptosis as a previously unknown mechanism of cytotoxic action for taxoids.

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.

An aldol approach to the enantioselective synthesis of (-)-oseltamivir phosphate.

A formal asymmetric synthesis of the antiviral agent (-)-oseltamivir phosphate is achieved using two aldol reactions as key steps.

A useful synthetic equivalent of a hydroxyacetone enolate.

Indium promoted allylation of carbonyl compounds with 4-(bromomethyl)-1,3-dioxol-2-one diastereoselectively affords anti-α,ß-dihydroxyketones, protected as enol carbonates. These initial products can be deprotected to free dihydroxyketones or transformed under mild conditions into the corresponding cyclic carbonates, which constitutes a useful approach to hydroxyacetone aldols.

Organocatalyzed cyclizations of pi-allylpalladium complexes: a new method for the construction of five- and six-membered rings.

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.

Ring closing metathesis/fragmentation route to (Z)-configured medium ring cycloalkenes. Total synthesis of (+/-)-periplanone C.

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.

Ring-closing metathesis/fragmentation route to geometrically defined medium-ring cycloalkenes: total synthesis of (+/-)-periplanone C.

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]