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US 7,910,661 B2Granted
Thiol-selective water-soluble polymer derivatives
AssigneeNektar Therapeutics
InventorsAntoni Kozlowski, Remy F. Gross, III, Samuel P. McManus
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Abstract
The present invention provides water-soluble, polymer derivatives having a thiol-selective terminus suitable for selective coupling to thiol groups, such as those contained in the cysteine residues of proteins.
Claims41
A method for preparing a thiol-selective derivative of a water-soluble polymer, said method comprising:
- reacting a water-soluble polymer comprising a water-soluble polymer segment (“POLY”) having one terminus activated with an electrophile (“—E”) with a molecule of the structure “NU—Y—S, comprising a nucleophile (“—NU”) and a thiol-selective moiety (“—S”) selected from the group consisting of thiol, protected thiol, symmetrical disulfide, maleimide, and iodoacetamide, and a linear group (“—Y—”) interposed between NU and S, under conditions effective to promote reaction between said electrophile and said nucleophile to form a polymer product comprising a thiol-selective terminus selected from the group consisting of thiol, protected thiol, disulfide, maleimide, and iodoacetamide (“POLY—S”),
- wherein the molecular mass of the water-soluble polymer segment is from 1,000 Daltons to 50,000 Daltons.
A water-soluble polymer having a thiol-selective terminus (POLY-S) produced by a method comprising:
- reacting a water-soluble polymer comprising a water-soluble polymer segment (“POLY”) having one terminus activated with an electrophile (“-E”) with a molecule of the structure “NU-Y—S, comprising a nucleophile (”-NU″) and a thiol-selective moiety (“—S”) selected from the group consisting of thiol, protected thiol, disulfide, maleimide, and iodoacetamide, and a linear group (“—Y—”) interposed between NU and S, under conditions effective to promote reaction between said electrophile and said nucleophile to form a polymer product comprising a thiol-selective terminus selected from the group consisting of thiol, protected thiol, disulfide, maleimide, and iodoacetamide (“POLY-S”),
- wherein the molecular mass of the water-soluble polymer segment is from 1,000 Daltons to 50,000 Daltons.
An activated polymer comprising the structure:
- POLY-L-C(O)G-Y—S—W,
- wherein POLY is a water-soluble polymer segment,
- L is a linker,
- G is a heteroatom selected from the group consisting of O, NH, and S,
- Y is selected from the group consisting of C2-C10 alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene, aryl, and substituted aryl,
- S is a sulfur atom, and
- W is H or a protecting group,
- wherein the molecular mass of the water-soluble polymer segment is from 1,000 Daltons to 50,000 Daltons.
5 more elements
An activated polymer comprising the structure:
- POLY-L-C(O)G-Y-Q,
- wherein POLY is a water-soluble polymer segment,
- L is a linker,
- G is a heteroatom selected from the group consisting of O, NH, and S,
- Y is selected from the group consisting of C2-C10 alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene, aryl, and substituted aryl, and
- Q is selected from the group consisting of thiol, protected thiol, maleimide, and iodoacetamide,
- wherein the molecular mass of the water-soluble polymer segment is from 1,000 Daltons to 50,000 Daltons.
4 more elements
A polymer-conjugate comprising the structure:
- POLY-L-C(O)G-Y—S—S-Drug
- wherein POLY is a water-soluble polymer segment,
- L is a linker,
- G is a heteroatom selected from the group consisting of O, NH, and S, and
- Y is selected from the group consisting of C2-C10 alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene, aryl, and substituted aryl,
- wherein the molecular mass of the water-soluble polymer segment is from 1,000 Daltons to 50,000 Daltons.
3 more elements
Dependencies are inferred from the claim text.