Water-soluble thioester and selenoester compounds and methods for making and using the same

• US 8,034,900 B2
• Filed: 12/30/2003
• Issued: 10/11/2011
• Est. Priority Date: 12/30/2002
• Status: Expired due to Fees

• Current Assignee: Astrazeneca Pharmaceuticals LP (Astrazeneca PLC)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Kent, Stephen B. H., Miranda, Leslie Philip
• Primary Examiner(s): Tsang; Cecilia J
• Assistant Examiner(s): HEARD, THOMAS SWEENEY
• Application Number:
  US10/541,078
• Publication Number:
  US 20060173159A1
• Time in Patent Office: 2,842 Days
• Field of Search: None
• US Class Current: 530/333
• CPC Class Codes: C07C 327/32 having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 391/00 Compounds containing selenium
• CPC Class Codes: C07K 1/04 on carriers C07K1/003, C07K1/006 take precedence
• CPC Class Codes: C07K 1/086 containing sulfur
• CPC Class Codes: C07K 1/088 containing other elements, e.g. B, Si, As
• CPC Class Codes: C07K 1/10 using coupling agents C07K1/006 takes precedence
• CPC Class Codes: C07K 14/001 by chemical synthesis

Abstract

Water-soluble thioester and selenoester compounds, their generators, as well as methods for making and using the same, are provided. The subject thioester and selenoester compounds are characterized by including an amino acid synthon having a C-terminal group bonded to a water-soluble polymer through a thioester or selenoester linkage. Solid phase resins and protocols for generating the subject compounds are also provided. The subject water soluble thioester and selenoester compounds and generators find use in a variety of different applications, including thioester or selenoester mediated chemical ligation reactions.

Claims

1. A water-soluble thioester or selenoester compound of the formula:

2. The thioester or selenoester compound according to claim 1 wherein Y is a peptide or polypeptide.

3. The thioester or selenoester compound according to claim 2 wherein said peptide or polypeptide comprises protected amino acids.

4. The thioester or selenoester compound according to claim 2 wherein said Y contains an N-terminal amino acid containing a group that supports chemical ligation.

5. The thioester or selenoester compound according to claim 1 wherein

R₃ comprises a group of the formula —

C(R₇)(R₈)-U-Polymer, where

R₇ and R₈ are each individually selected from the group consisting of;

hydrogen or linear, branched, substituted, or unsubstituted alkyl, aryl, heteroaryl, and benzyl, and

U is selected from the group consisting of alkyl, aryl, heteroalkyl, heteroaryl, alkoxy, of up to 18 carbon atoms, and

Polymer is selected from the group consisting of;

—

[C(O)-φ

-C(O)—

NH-ψ

-NH]n₅ and —

[NH-ψ

-NH—

C(O)-φ

-C(O)]n₅, where n₅ is an integer from 1 to 100, and φ and

ψ

are divalent radicals selected from the group consisting of —

((CH₂)n₆-(CH₂CH₂O)n₇-(CH₂)n₆-)- and —

((CH₂)n₆-(O—

CH₂—

CH₂)n₇-(CH₂)n₆-)-, where n₆ is an integer from 1 to 6 and n₇ is an integer from 2-50.

6. The thioester or selenoester compound of claim 1 wherein Polymer comprises a divalent radical of having the structure:

7. The thioester or selenoester compound of claim 5 wherein

φ

is —

(CH₂—

CH₂)— and

ψ

is —

(CH₂—

(CH₂—

CH₂—

O)₃—

CH₂—

CH₂—

CH₂)—

or —

(CH₂—

CH₂—

CH₂—

(O—

CH₂—

CH₂)₃—

CH₂)—

.

8. The thioester or selenoester compound of claim 1 wherein R is a group of the structure —

C(R₄)(R₅)(R₆),

where R₄, R₅, and R₆ each individually are selected from the group consisting of;

hydrogen, linear, branched, substituted or unsubstituted alkyl, aryl, heteroaryl, and benzyl.

9. The thioester or selenoester compound of claim 5 wherein

Y is a peptide or polypeptide;

X is sulfur;

n₁ and n₂ are 0;

R₇ and R₈ are each individually selected from the group consisting of;

hydrogen, —

CH₃, and —

CH(CH₃)₂.

10. The thioester or selenoester compound of claim 9 wherein:

n₅ is from 2 to 50, n₆ is from 1 to 3, n₇ is from 2 to 5; and

φ

is —

(CH₂—

CH₂)— and

ψ

is —

(CH₂—

(CH₂—

CH₂—

O)₃—

CH₂—

CH₂—

CH₂)—

or —

(CH₂—

CH₂—

CH₂—

(O—

CH₂—

CH)₃—

CH₂)—

.

11. The thioester or selenoester compound of claim 1 wherein Y comprises an N-terminal group that supports chemical ligation.

12. The thioester or selenoester compound of claim 11 wherein the N-terminal group comprises cysteine or selenocysteine.

13. The thioester or selenoester compound of claim 12 wherein the cysteine or selenocysteine is protected.

14. A method of cleaving a thioester or selenoester compound from a solid support, said method comprising:

providing a thioester or selenoester generator having the formula;

15. A thioester or selenoester generator comprising a composition having the formula: