79999-46-5

Upstream product

• 55628-54-1 3,4,6-tri-O-benzyl-D-glucal 
• 120818-50-0 (4R,5S,6R)-4,5-Bis-benzyloxy-6-benzyloxymethyl-2-[(3S,8R,9S,10S,13R,14S,17R)-17-((R)-1,5-dimethyl-hexyl)-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-3-yloxy]-tetrahydro-pyran-2-carboxylic acid 
• 134502-27-5 (2R,3R,4R)-1,3,4-Tris-benzyloxy-6,6,6-tris-methylsulfanyl-hexan-2-ol 
• 160549-11-1 3,4,6-tri-O-benzyl-2-deoxy-D-glucopyranose 
• 889665-25-2 1,2-dideoxy-3,4,5-tri-O-benzyl-1,1-dithianyl-D-arabino-hexopyranosee 
• 80040-79-5 3,4,6-tri-O-benzyl-D-galactal 
• 60933-68-8 3,4,6-tri-O-benzyl-β-D-arabinofuranoside 
• 25878-60-8 D-galactose pentaacetate 
• 100-39-0 benzyl bromide 
• 21193-75-9 D-galactal 
• 6386-24-9 2,3,4,6-tetra-O-benzyl-D-galactopyranose 
• 4098-06-0 triacetyl-D-galactal 
• 2873-29-2 D-glucal triacetate 
• 13265-84-4 D-glucal 

Downstream Products

• 162284-48-2 tri-O-benzyl-2-azido-2-deoxy-D-mannono-1,5-lactone 
• 211934-99-5 2,6-anhydro-4,5,7-tri-O-benzyl-1-(propane-1,3-diyl-dithioacetal)-1,3-dideoxy-D-arabino-hept-1-enitol 
• 475630-58-1 methyl (3R,4R,5R)-3,4,6-tris(benzyloxy)-5-hydroxyhexanoate 
• 130912-27-5 (2R,3S,4R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-6-phenyl-3,4-dihydro-2H-pyran 
• 475630-60-5 (3R,4S,5R)-3,4,6-Tris-benzyloxy-5-methanesulfonyloxy-hexanoic acid methyl ester 
• 1312437-71-0 2,6-anhydro-1,3-dideoxy-4,5,7-tri-O-benzyl-D-glucohept-1-enitol 
• 1312437-72-1 3-deoxy-4,5,7-tri-O-benzyl-α-D-glycero-D-xylo-hept-2-ulopyranose 
• 1247813-78-0 1-(2-phenyl-ethynyl)-3,4,6-tris-O-benzyl-D-glucal 
• 160701-84-8 (3R,4R,5R,6R)-3-azido-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-one 
• 475630-59-2 (3R,4S,5R)-3,4,6-Tris-benzyloxy-5-hydroxy-hexanoic acid methyl ester 
• 1355241-44-9 p-methoxyphenyl-tri-O-benzyl-2-azido-2-deoxy-D-galactopyranoside 

Relevant academic research and scientific papers

TARGETED BIFUNCTIONAL DEGRADERS

The present invention provides, in one aspect, bifunctional compounds that can be used to promote or enhance degradation of certain circulating proteins. In another aspect, the present invention provides bifunctional compounds that can be used to promote or enhance degradation of certain autoantibodies. In certain embodiments, treatment or management of a disease and/or disorder requires degradation, removal, or reduction in concentration of the circulating protein or the autoantibody in the subject. Thus, in certain embodiments, administration of a compound of the invention to the subject removes or reduces the circulation concentration of the circulating protein or the autoantibody, thus treating, ameliorating, or preventing the disease and/or disorder. In certain embodiments, the circulating protein is TNF.

ENGINEERED ANTIBODIES AS MOLECULAR DEGRADERS THROUGH CELLULAR RECEPTORS

The present disclosure provides, in one aspect, bifunctional compounds that can be used to promote or enhance degradation of certain circulating proteins. In certain embodiments, the circulating protein mediates a disease and/or disorder in a subject, and treatment or management of the disease and/or disorder requires degradation, removal, or reduction in concentration of the circulating protein in the subject. Thus, in certain embodiments, administration of a compound of the disclosure to the subject removes or reduces the circulation concentration of the circulating protein, thus treating, ameliorating, or preventing the disease and/or disorder.

BIFUNCTIONAL SMALL MOLECULES TO TARGET THE SELECTIVE DEGRADATION OF CIRCULATING PROTEINS

The present invention is directed to bifunctional small molecules which contain a circulating protein binding moiety (CPBM) linked through a linker group to a cellular receptor binding moiety (CRBM) which is a membrane receptor of degrading cell such as a hepatocyte or other degrading cell. In embodiments, the (CRBM) is a moiety which binds to asialoglycoprotein receptor (an asialoglycoprotein receptor binding moiety, or ASGPRBM) of a hepatocyte. In additional embodiments, the (CRBM) is a moiety which binds to a receptor of other cells which can degrade proteins, such as a LRP1, LDLR, FcyRI, FcRN, Transferrin or Macrophage Scavenger receptor. Pharmaceutical compositions based upon these bifunctional small molecules represent an additional aspect of the present invention. These compounds and/or compositions may be used to treat disease states and conditions by removing circulating proteins through degradation in the hepatocytes or macrophages of a patient or subject in need of therapy. Methods of treating disease states and/or conditions in which circulating proteins are associated with the disease state and/or condition are also described herein.

Stereocontrolled Synthesis of 2-Fluorinated C-Glycosides

A systematic study of the addition of C-based nucleophiles to fluorinated lactones based on 2-deoxy-2-fluoro-d-pyranoses is disclosed. This high yielding, α-selective process was found to be independent on the nature or configuration [(R)-C(sp3)–F, (S)-C(sp3)–F] of the substituent at C2. Representative, fluorinated analogues of Trehalose, Carminic acid, and the spirocyclic cores of Tofogliflozin and Papulacandin D are also reported. These glycomimics constitute a valuable series of 19F NMR active probes for application in structural biology.

Fluorine-Directed Glycosylation Enables the Stereocontrolled Synthesis of Selective SGLT2 Inhibitors for Type II Diabetes

Inhibition of the sodium-glucose co-transporters (SGLT1 and SGLT2) is a validated strategy to address the increasing prevalence of type II diabetes mellitus. However, achieving selective inhibition of human SGLT1 or SGLT2 remains challenging. Orally available small molecule drugs based on the d-glucose core of the natural product Gliflozin have proven to be clinically effective in this regard, effectively impeding glucose reabsorption. Herein, we disclose the influence of molecular editing with fluorine at the C2 position of the pyranose ring of Phlorizin analogues Remogliflozin Etabonate and Dapagliflozin (Farxiga) to concurrently direct β-selective glycosylation, as is required for biological efficacy, and enhance aspects of the physicochemical profile. Given the abundance of glycosylated pharmaceuticals in diabetes therapy that contain a β-configured d-glucose nucleus, it is envisaged that this strategy may prove to be expansive.

A concise synthesis of N-substituted fagomine derivatives and the systematic exploration of their α-glycosidase inhibition

A novel and concise scheme has been developed successfully for the syntheses of N-substituted fagomine derivatives. The transformation of lactone (2) to 1,5-diol (3) was carried on with high yield (93-95%). The cyclization of 4 to 5 is a high stereoselect

Synthesis of C-spiro-glycoconjugates from sugar lactones via zinc mediated Barbier reaction

Anomeric gem-diallylation, mono-β-crotylation and mono-β- propargylation of sugar 1,5 and 1,4 lactones have been achieved under Barbier reaction conditions using Zn powder and a catalytic amount of TMSCl as an activator. Ring closing olefin metathesis of the synthesized gem-diallyl derivatives furnished C-spiro cyclopentene glycosides. Finally, the cyclopentene rings were converted into carbohydrate based tricyclic morpholine fused triazole glycoconjugates as potential SGLT2 inhibitors.

A substrate-based approach to skeletal diversity from dicobalt hexacarbonyl (C1)-alkynyl glycals by exploiting its combined ferrier-nicholas reactivity

Novel substrates that combine dicobalt hexacarbonyl propargyl (Nicholas) and pyranose-derived allylic (Ferrier) cations have been generated by treatment of hexacarbonyldicobalt (C-1)-alkynyl glycals with BF3 .Et2O. The study of these cations has resulted in the discovery of novel reaction pathways that have shown to be associated to the nature of O-6 substituent in the starting alkynyl glycals. Accordingly, compounds resulting from ring expansion (oxepanes), ring contraction (tetrahydrofurans), or branched pyranoses, by incorporation of nucleophiles, can be obtained from 6-O-benzyl, 6-hydroxy, or 6-O-silyl derivatives, respectively. The use of a 6-O-allyl alkynyl glycal led to a suitable funtionalized oxepane able to experience an intramolecular Pauson-Khand cyclization leading to a single tricyclic derivative.

Stereoselective total synthesis of (-)-batzellasides a, b, and c

Total synthesis of (-)-L-batzellasides A, B, and C has been achieved in 13 steps from known lactone 2 in 12.6, 13.2, and 13.8 % overall yields, respectively. The key steps in this synthesis were the stereoselective introduction of an allyl group at the C1

Glycomimetic ligands for the human asialoglycoprotein receptor

The asialoglycoprotein receptor (ASGPR) is a high-capacity galactose-binding receptor expressed on hepatocytes that binds its native substrates with low affinity. More potent ligands are of interest for hepatic delivery of therapeutic agents. We report several classes of galactosyl analogues with varied substitution at the anomeric, C2-, C5-, and C6-positions. Significant increases in binding affinity were noted for several trifluoromethylacetamide derivatives without covalent attachment to the protein. A variety of new ligands were obtained with affinity for ASGPR as good as or better than that of the parent N-acetylgalactosamine, showing that modification on either side of the key C3,C4-diol moiety is well tolerated, consistent with previous models of a shallow binding pocket. The galactosyl pyranose motif therefore offers many opportunities for the attachment of other functional units or payloads while retaining low-micromolar or better affinity for the ASGPR.