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AssigneeGryphon Therapeutics, Inc.
InventorsPaolo Botti, James A. Bradburne, Stephen B.H. Kent
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The invention is directed to nucleophile-stable thioester generating compounds comprising an orthothioloester or a carboxyester thiol, methods of production and use. The compounds and methods have wide applicability in organic synthesis, including the generation of peptide-, polypeptide- and other polymer-thioesters. The invention is particularly useful for generating activated-thioesters from precursors that are made under conditions in which strong nucleophiles are employed, such as peptides or polypeptides made using Fmoc SPPS, as well as multi-step ligation or conjugation schemes that require (or benefit from the use of) compatible selective approaches for directing a specific ligation or conjugation reaction of interest.
A nucleophile-stable orthothioloester of the formula X—C(OR′)2-S—R, where X is a target molecule of interest optionally comprising one or more nucleophile-labile protecting groups removable under nucleophilic cleavage conditions, R′ is a nucleophile-stable protecting group removable under non-nucleophilic cleavage conditions, and R is any group compatible with the orthothiolo moiety —C(OR′)2-S—.
A nucleophile-stable thioester-generating resin comprising an orthothioloester.
A nucleophile-stable carboxyester thiol of the formula X—C(O)—O—CH(R″)—CH2n-S—R ″, where X is a target molecule of interest comprising one or more nucleophile-labile protecting groups, R″ is hydrogen or a non-nucleophile stable group, n is 1 or 2, and R′″ is hydrogen, a protecting group or an acid, reductive, or light labile linker attached to a resin or protecting group that is removable under non-nucleophilic conditions.
The nucleophile-stable carboxyester thiol of claim 12, wherein X comprises an amine protected with a nucleophile-labile protecting group.
The nucleophile-stable carboxyester thiol of claim 13, wherein said amine is present on a moiety selected from the group consisting of an amino acid, peptide and polypeptide.
A nucleophile-stable thioester-generating resin comprising a carboxyester thiol.
A polymer comprising a thioester-reactive nucleophilic group and a nucleophile-stable group selected from a non-cyclic orthothioloester, a cyclic orthothioloester, a carboxyester aryl thiol, carboxyester benzyl thiol, and a carboxyester alkyl thiol.
A polymer comprising a protected thioester-reactive nucleophilic group and a nucleophile-stable group selected from a non-cyclic orthothioloester, a cyclic orthothioloester, a carboxyester aryl thiol, carboxyester benzyl thiol, and a carboxyester alkyl thiol.
A method for chemical ligation of polymers, said method comprising step:
A method for synthesizing a nucleophile-stable thioester-generating composition that comprises a molecule of interest, said method comprising steps:
A method for synthesizing a nucleophile-stable thioester-generating composition that comprises a molecule of interest, said method comprising steps:
The method of claim 36, which further comprises:
The method of claim 36, wherein said carboxyester thiol is covalently attached to a resin through a linker, and wherein said linker is stable under nucleophilic cleavage conditions.
The method of claim 36, wherein said carboxyester thiol is covalently attached to a resin through a linker, and wherein said linker is cleavable under non-nucleophilic cleavage conditions.
Dependencies are inferred from the claim text.