Browse
Submit Data
Databases
API
Help

Dataset Information

12 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A Photochemical Route to Optically Active Hexahydro-4H-furopyranol, a High-Affinity P2 Ligand for HIV-1 Protease Inhibitors.

ABSTRACT: We describe here the syntheses of optically pure (3aS,4S,7aR)-hexahydro-4H-furo[2,3-b]pyran-4-ol and (3aR,4R,7aS)-hexahydro-4H-furo[2,3-b]pyran-4-ol. These stereochemically defined heterocycles are important high-affinity P2 ligands for a variety of highly potent HIV-1 protease inhibitors. The key steps involve an efficient Paternò-Büchi [2 + 2] photocycloaddition, catalytic hydrogenation, acid-catalyzed cyclization to form the racemic ligand alcohol, and an enzymatic resolution with immobilized Amano Lipase PS-30. Optically active ligands (-)-6 and (+)-6 were obtained with high enantiomeric purity. Enantiomer (-)-6 has been converted to potent HIV-1 protease inhibitor 3.

SUBMITTER: Ghosh AK

PROVIDER: S-EPMC7048240 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

A Photochemical Route to Optically Active Hexahydro-4H-furopyranol, a High-Affinity P2 Ligand for HIV-1 Protease Inhibitors.

Ghosh Arun K AK Robinson William L WL

The Journal of organic chemistry 20190716 15

We describe here the syntheses of optically pure (3aS,4S,7aR)-hexahydro-4H-furo[2,3-b]pyran-4-ol and (3aR,4R,7aS)-hexahydro-4H-furo[2,3-b]pyran-4-ol. These stereochemically defined heterocycles are important high-affinity P2 ligands for a variety of highly potent HIV-1 protease inhibitors. The key steps involve an efficient Paternò-Büchi [2 + 2] photocycloaddition, catalytic hydrogenation, acid-catalyzed cyclization to form th ...[more]

PMID: 31310117

Similar Datasets

An enantioselective enzymatic desymmetrization route to hexahydro-4H-furopyranol, a high-affinity ligand for HIV-1 protease inhibitors.

Project description:An enantioselective synthesis of (3aS,4S,7aR)-hexahydro-4H-furo[2,3-b]pyran-4-ol, a high-affinity nonpeptide ligand for a variety of potent HIV-1 protease inhibitors is described. The key steps involved a highly enantioselective enzymatic desymmetrization of meso-diacetate, an efficient transacetalization, and a highly diastereoselective reduction of a ketone. This route is amenable to large-scale synthesis using readily available starting materials.

| S-EPMC5708567 | biostudies-literature

En Route Towards the Control of Luminescent, Optically-Active 3D Architectures.

Project description:?-Extended systems are key components for the development of future organic electronic technologies. While conceiving molecules with improved properties is fundamental for the evolution of materials science, keeping control over the 3D arrangement of molecules represents an ever-expanding challenge. Herein, a synthetic protocol to replace carbon atoms of ?-systems by dissymmetric phosphorus atoms is reported; in particular, it allowed for conceiving new fused phosphapyrene derivatives with improved properties. The presence of dissymmetric phosphorus atoms precluded the formation of excimers. X-ray diffraction revealed that, meanwhile, strong intermolecular interactions are taking place in the solid state. The phosphapyrenes photoluminesce in the visible region with high quantum yields; importantly, they are CD-active. In addition, the unique non-planar features of phosphorus atoms allowed for the control of the 3D arrangement of molecules, rendering lemniscate-like structures. Based on our discoveries, we envisage the possibility to construct higher-order, chiral 3D architectures from larger phosphorus-containing ?-systems.

| S-EPMC7820950 | biostudies-literature

Synthesis and biological evaluation of novel allophenylnorstatine-based HIV-1 protease inhibitors incorporating high affinity P2-ligands.

Project description:A series of stereochemically defined cyclic ethers as P2-ligands were incorporated in an allophenylnorstatine-based isostere to provide a new series of HIV-1 protease inhibitors. Inhibitors 3b and 3c, containing conformationally constrained cyclic ethers, displayed impressive enzymatic and antiviral properties and represent promising lead compounds for further optimization.

| S-EPMC3179850 | biostudies-literature

Mechanistically Inspired Route toward Hexahydro-2H-chromenes via Consecutive [4 + 2] Cycloadditions.

Project description:Utilizing two robust C-C bond-forming reactions, the Baylis-Hillman reaction and the Diels-Alder reaction, we report a highly enantio-, regio-, and diastereoselective synthesis of hexahydro-2H-chromenes via two sequential [4 + 2] cycloadditions. These tandem and formal cycloadditions have also been performed as a "one-pot" sequence to access the corresponding heterocycles constituting up to five contiguous stereocenters in excellent yields and stereoselectivity.

| S-EPMC5342895 | biostudies-literature

Configurational Molecular Glue: One Optically Active Polymer Attracts Two Oppositely Configured Optically Active Polymers.

Project description:D-configured poly(D-lactic acid) (D-PLA) and poly(D-2-hydroxy-3-methylbutanoic acid) (D-P2H3MB) crystallized separately into their homo-crystallites when crystallized by precipitation or solvent evaporation, whereas incorporation of L-configured poly(L-2-hydroxybutanoic acid) (L-P2HB) in D-configured D-PLA and D-P2H3MB induced co-crystallization or ternary stereocomplex formation between D-configured D-PLA and D-P2H3MB and L-configured L-P2HB. However, incorporation of D-configured poly(D-2-hydroxybutanoic acid) (D-P2HB) in D-configured D-PLA and D-P2H3MB did not cause co-crystallization between D-configured D-PLA and D-P2H3MB and D-configured D-P2HB but separate crystallization of each polymer occurred. These findings strongly suggest that an optically active polymer (L-configured or D-configured polymer) like unsubstituted or substituted optically active poly(lactic acid)s can act as "a configurational or helical molecular glue" for two oppositely configured optically active polymers (two D-configured polymers or two L-configured polymers) to allow their co-crystallization. The increased degree of freedom in polymer combination is expected to assist to pave the way for designing polymeric composites having a wide variety of physical properties, biodegradation rate and behavior in the case of biodegradable polymers.

| S-EPMC5364539 | biostudies-literature

Focused peptide library screening as a route to a superior affinity ligand for antibody purification.

Project description:Affinity chromatography is the linchpin of antibody downstream processing and typically relies on bacterial immunoglobulin (Ig)-binding proteins, epitomized by staphylococcal protein A-based ligands. However, such affinity ligands are fairly costly and suffer from chemical instability, leading to ligand denaturation and leaching from chromatographic support. Innovations in this area are aimed at developing robust and highly selective antibody ligands capable of withstanding harsh column sanitization conditions. We report the development and first-stage characterization of a selective short linear peptide ligand of the IgG Fc region capable of capturing all four IgG subclasses. The ligand was discovered through in vitro directed evolution. A focused phage-display library based on a previously identified peptide lead was subjected to a single-round screen against a pool of human IgG. The hits were identified with next-generation sequencing and ranked according to the enrichment ratio relative to their frequency in the pre-screened library. The top enriched peptide GSYWYNVWF displaying highest affinity for IgG was coupled to bromohydrin-activated agarose beads via a branched linker. The resulting affinity matrix was characterized with a dynamic binding capacity of approx. 43 mg/mL, on par with commercially employed protein A-based resin.

| S-EPMC8173005 | biostudies-literature

A convenient route to optically pure ?-alkyl-?-(sec-amino)alanines.

Project description:The cyclization of N-Boc-?-alkylserines to corresponding ?-lactones under Mitsunobu reaction conditions and the ring opening with heterocyclic amines (pyrrolidine, piperidine, morpholine and thiomorpholine) produced N-Boc-?-alkyl-?-(sec-amino)alanines. The removal of the Boc group gives di-hydrochlorides of non-protein amino acids.

| S-EPMC3351611 | biostudies-literature

Novel HIV-1 Protease Inhibitors with Morpholine as the P2 Ligand to Enhance Activity against DRV-Resistant Variants.

Project description:Flexible heterocyclic moieties as the P2 ligands of HIV-1 protease inhibitors may be adapted to the minimally distorted active site of mutations easily and enhance activity against DRV-resistant HIV-1 variants. Herein, the design, synthesis, and biological evaluation of a new series of inhibitors containing morpholine derivatives as the P2 ligands were described, among which, carbamate inhibitor 23a and carbamido inhibitor 27a exhibited almost 4- and 2-fold superior activity with enzyme Ki of 0.092 nM and 0.21 nM, as well as antiviral IC50 values of 0.41 nM and 0.95 nM, respectively, compared to DRV. Besides, they exhibited excellent activity with inhibition of 94% and 91%, respectively. Furthermore, they also showed appreciable antiviral activity against DRV-resistant HIV-1 variants.

| S-EPMC7294734 | biostudies-literature

Ligand-bound structures of the dengue virus protease reveal the active conformation.

Project description:Dengue is a mosquito-borne viral hemorrhagic disease that is a major threat to human health in tropical and subtropical regions. Here we report crystal structures of a peptide covalently bound to dengue virus serotype 3 (DENV-3) protease as well as the serine-protease inhibitor aprotinin bound to the same enzyme. These structures reveal, for the first time, a catalytically active, closed conformation of the DENV protease. In the presence of the peptide, the DENV-3 protease forms the closed conformation in which the hydrophilic ?-hairpin region of NS2B wraps around the NS3 protease core, in a manner analogous to the structure of West Nile virus (WNV) protease. Our results confirm that flavivirus proteases form the closed conformation during proteolysis, as previously proposed for WNV. The current DENV-3 protease structures reveal the detailed interactions at the P4' to P3 sites of the substrate. The new structural information explains the sequence preference, particularly for long basic residues in the nonprime side, as well as the difference in substrate specificity between the WNV and DENV proteases at the prime side. Structural analysis of the DENV-3 protease-peptide complex revealed a pocket that is formed by residues from NS2B and NS3; this pocket also exists in the WNV NS2B/NS3 protease structure and could be targeted for potential antivirus development. The structural information presented in the current study is invaluable for the design of specific inhibitors of DENV protease.

| S-EPMC3255909 | biostudies-literature

Highly potent HIV-1 protease inhibitors with novel tricyclic P2 ligands: design, synthesis, and protein-ligand X-ray studies.

Project description:The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor's potent antiviral activity and excellent resistance profiles.

| S-EPMC3800042 | biostudies-literature