160701-84-8

Upstream product

• 72605-77-7 (2R,3R,4R)-3,4-bis-benzyloxy-2-benzyloxymethyltetrahydropyran-5-one 
• 80040-79-5 3,4,6-tri-O-benzyl-D-galactal 
• 100-39-0 benzyl bromide 
• 21193-75-9 D-galactal 
• 4098-06-0 triacetyl-D-galactal 
• 25878-60-8 D-galactose pentaacetate 
• 79781-69-4 2-azido-3,4,6-tri-O-benzyl-2-deoxy-D-galactopyranose 

Downstream Products

• 160701-97-3 1-O-Acetyl-2-azido-3,4,6-tri-O-benzyl-2-deoxy-1-(2-thiazolyl)-β-D-galactopyranose 
• 160701-78-0 2-Azido-3,4,6-tri-O-benzyl-2-deoxy-1-(2-thiazolyl)-α-D-galactopyranose 
• 79781-69-4 2-azido-3,4,6-tri-O-benzyl-2-deoxy-D-galactopyranose 
• 175981-95-0 (3R,4R,5R,6R)-3-Azido-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-tetrahydro-pyran-2-ol 
• 176169-12-3 2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-D-galactono-1,5-lactone 
• 271243-81-3 3-azido-4,5,7-tri-O-benzyl-1,3-dideoxy-1-dimethoxyphosphoryl-α-D-galacto-2-heptulopyranose 
• 443915-89-7 3,7-anhydro-4-azido-5,6,8-tri-O-benzyl-1,2,4-trideoxy-D-glycero-L-manno-oct-1-ynitol 
• 443915-87-5 3,7-anhydro-4-azido-5,6,8-tri-O-benzyl-1,2,4-trideoxy-1-C-(trimethylsilyl)-D-glycero-L-manno-oct-1-ynitol 
• 271243-83-5 2,6-anhydro-3-azido-4,5,7-tri-O-benzyl-1,3-dideoxy-1-dimethoxyphosphoryl-D-glycero-L-manno-heptitol 
• 271243-86-8 3-acetamido-2,6-anhydro-4,5,7-tri-O-benzyl-1,3-dideoxy-1-dimethoxyphosphoryl-D-glycero-L-manno-heptitol 
• 176198-89-3 N-((2S,3R,4R,5R,6R)-4,5-Dihydroxy-6-hydroxymethyl-2-phenyl-tetrahydro-pyran-3-yl)-acetamide 

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.

One-Step TEMPO-Catalyzed and Water-Mediated Stereoselective Conversion of Glycals into 2-Azido-2-deoxysugars with a PIFA-Trimethylsilyl Azide Reagent System

An unprecedented water-mediated and TEMPO-catalyzed, one-step, highly regiospecific and stereoselective functionalization of glycals to 2-azido-2-deoxysugars has been developed using a PIFA-Me3SiN3 reagent system in the presence of B

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.

Synthesis of α- and β-glycosyl asparagine ethylene isosteres (C-glycosyl asparagines) via sugar acetylenes and Garner aldehyde coupling

A convergent approach has been developed for the synthesis of C-glycosyl amino acids in which the glycinyl moiety CH(NH2)CO2H is connected to the anomeric center of the sugar residue by a three carbon atom tether. Essentially, these compounds are isosteres of N-glycosyl asparagines in which the amide group has been replaced by an ethylene bridge. Following the coupling of α- or β-D-linked lithium C-glycoside acetylides with N-Boc D-serinal acetonide (Garner aldehyde), the resulting adducts were transformed into the final N-Boc-C-glycosyl-α-aminopentanoic acids via reduction of the triple bond, deoxygenation, and oxidative cleavage of the oxazolidine ring. By this protocol, 12 C-glycosyl asparagines, six pairs of α- and β-anomers, have been prepared incorporating the gluco, galacto, manno, and the corresponding 2-acetamido-2-deoxy residues.

Convenient preparation of perbenzylated 2-Azido and 2-N-acetylamino-2-deoxy-D-hexono-1,5-lactones by oxidation of the corresponding lactols

2-Azido-3,4,6-tri-O-benzyl-2-deoxy-D-galacto, gluco and mannopyranoses (1, 2, 3) were oxidized with DMSO in the presence of acetic anhydride. From 1 and 2 the corresponding lactone derivatives were obtained in good yield (89-92%), whereas from 3, glucono-1,5-lactone was obtained (92%) after complete epimerization at C-2. 2-N-Acetylamino-3,4,6-tri-O-benzyl-2-deoxy-D-galacto, gluco and mannopyranoses (7, 8, 9) were obtained from the corresponding 2-azido phenylselenoglycopyranosides (13, 14, 15) by reduction, N-acetylation and hydrolysis catalyzed by mercury trifluoroacetate. Oxidation of 7 and 8 by tetra-n-propylammonium tetra-oxoruthenate (VII) in the presence of 4-methylmorpholine-N-oxide afforded the corresponding lactones in good yield (90%) and high purity. Epimerization at C-2 occurred during oxidation of 9 and perbenzylated D-glucono-1,5-lactone (11) was obtained (90%).

Electrophilic Azidation of 2-Deoxy-aldono-1,5-lactones: an Alternative Route to 2-Azido-2-deoxy-aldopyranoses

Electrophilic azidation of tri-O-benzyl-2-deoxy-D-galactono-1,5-lactone 3 with triisopropylphenylsulfonyl azide, followed by selective reduction with diisobutylaluminium hydride, yielded tri-O-benzyl-2-azido-2-deoxy-D-galactopyranose 5 as the sole product

Thiazole-based synthesis of formyl C-glycosides

A method for the installation of the formyl group at the anomeric position of pyranoses and furanoses starting from the corresponding lactones has been developed. The strategy involves the addition of 2-lithiothiazole to the sugar lactone, followed by the silane reduction of the acetylated resultant ketol and the unmasking of the formyl group from the thiazole ring. All steps have been studied in some details to improve chemical efficiency and stereochemical control. Hence, reversed α:β ratios of ketols were found in kinetic and thermodynamic mixtures, the former being consistent with a steric effect control of the substituents and the latter by the electronic effect of the ring oxygen. Seven sugar aldehydes with different D-pyranosidic (2,3,4,6-tetra-O-benzyl-gluco, -galacto, and -manno, 2-azido-3,4,6-tri-O-benzyl-2-deoxy-galacto) and D-furanosidic moieties (5-O-benzyl-2,3-isopropylidene-ribo; 2,3,5-tri-O-benzyl-ribo; 2,3:5,6-di-O-isopropylidene-manno) were prepared in 52-65% isolated overall yield from the corresponding lactone.