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.

Intramolecular Dearomative Inverse-Electron-Demand Diels Alder Strategy for the Total Synthesis of (+)-Alstonlarsine A.

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.

Total Synthesis of (+)-Alstonlarsine A.

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.

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.

Total Synthesis of Crocagin†A.

Crocagin A (1) combines an attractive molecular structure with an unusual biosynthesis and bioactivity. An efficient synthesis of crocagin A is presented that hinges on an early formation of the heterotricyclic core, an electrophilic amination, and the stereoselective hydrogenation of a tetrasubstituted double bond. This synthesis confirms the absolute configuration of crocagin A and provides access to the natural product and derivatives thereof for further biological testing.

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.

Total Synthesis of (±)-Alstoscholarisine†A.

The first total synthesis of the neuroactive indole alkaloid (±)-alstoscholarisine 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.

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.

Novel glycoside of vanillyl alcohol, 4-hydroxy-3-methoxybenzyl-α-D-glucopyranoside: study of enzymatic synthesis, in vitro digestion and antioxidant activity.

Novel glucoside of physiological active vanillyl alcohol was synthesized for the first time using maltase from Saccharomyces cerevisiae as catalyst, and established its structure as 4-hydroxy-3-methoxybenzyl-α-D: -glucopyranoside. The key reaction factors for this transglucosylation reaction were optimized using response surface methodology and the highest yield so far in maltase catalyzed transglucosylation reaction was obtained. It was found out that optimum temperature of reaction was 37 °C, optimal maltose concentration was 60% (w/v), optimal pH was 6.6, and optimal concentration of vanillyl alcohol was 158 mM. Under these conditions, yield of glucoside was 90 mM with no by product formation. It was shown that this compound posses good antioxidant activity as well as stability in gastrointestinal tract. It was demonstrated that it is hydrolyzed on brush border membrane of enterocytes, so it can serve in protecting gastrointestinal system from oxidation, as well as source of anticonvulsive drug after the hydrolysis of glucoside on brush border membrane of small intestine.

One-step, inexpensive high yield strategy for Candida antarctica lipase A isolation using hydroxyapatite.

Lipase A from Candida antarctica (CAL A) was purified to apparent homogeneity in a single step using hydroxyapatite (HAP) chromatography. CAL A bound to HAP was eluted with 10mM Na-phosphate buffer, pH 7.0 containing 0.5% Triton X-100. The protocol resulted in a 3.74-fold purification with 94.7% final recovery and 400.83 U/mg specific activity. Silver staining after SDS-PAGE revealed the presence a single band of 45 kDa. The enzyme exhibited a temperature optimum of 60°C, was unaffected by monovalent metal ions, but was destabilized by divalent metal ions (Zn(2+), Ca(2+), Mg(2+), Cu(2+), Mn(2+)) and stimulated by 50mM Fe(2+). Detergents at 0.1% concentrations did not affect lipase activity. Except for Triton X-100, detergent concentrations of 1% had a destabilizing effect.

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.