Multifunctionalized solid support resins for synthesis of combinatorial libraries and method for using the same

• US 6,600,016 B1
• Filed: 08/24/1999
• Issued: 07/29/2003
• Est. Priority Date: 08/24/1999
• Status: Expired due to Fees

• Current Assignee: Boliang Lou
• Original Assignee: Advanced Syntech LLC
• Inventors: Zhang, Jinfang, Lu, Boliang, Campian, Eugene
• Primary Examiner(s): Low, Christopher S. F.
• Assistant Examiner(s): Lukton, David
• Application Number:
  US09/379,848
• Time in Patent Office: 1,435 Days
• Field of Search: 530/333, 530/334, 530/335-337
• US Class Current: 506/40
• CPC Class Codes: C07K 1/042 characterised by the nature of the carrier
• CPC Class Codes: C07K 1/047 Simultaneous synthesis of different peptide species; Peptide libraries

Abstract

Multifunctionalized support resin for the solid phase synthesis of combinatorial libraries is disclosed. The support resin comprises a resin backbone to which is attached a template containing at least two more attachment points which carry mutiple functionalized benzyl-type linkers. Each linker displays differing chemical stability under cleavage conditions so that products can be selectively and sequentially cleaved and separated from the reaction vessel. The linkers are independently different benzyl-type moieties, and each product synthesized on the linkers may have a different chemical structure. The support resin may further comprise an additional linker which is directly attached to the resin backbone. This linker can benzyl-type linkers or other traditional cleavable-linkers. The invention is further directed to a method for the production of mutiple combinatorial libraries in a simultaneous fashion utilizing the above described support resin. The products are selectively cleaved under conditions where only one linker site is cleaved so that the product is individually separated from the reaction vessel.

Claims

1. A multifunctionalized solid support for the solid support synthesis of at least two different compounds, said solid support having the structure:

wherein P is a resin backbone, T is a diamino acid moiety template having at least three attachment points, X is a covalent bonding entity for attachment of T to P and L₁ and L₂ are independently different benzyl linker moieties having the formula;

wherein Z is selected from the group consisting of a covalent bond, O, —

C(O)—

, C1-6 alkylene, C5-10 aryl, carbonylC1-6alkylene, carbonylC1-6alkyleneoxy, carbonyl C5-10 aryl and carbonyl C5-10 heteroaryl, said alkylene, aryl and heteroaryl groups being substituted with H or C1-3 alkyl;

R₁ and R₂ are independently selected from the group consisting of H, nitro, halo and C1-6alkoxy;

R₃ and R₄ are independently selected from the group consisting of H, C1-6 alkyl, C5-10 aryl and C5-10 heteroaryl, said alkyl, aryl and heteroaryl groups being substituted with H, C1-3 alkyl or C1-3 alkoxy; and

W is selected from the group consisting of OH, NH₂ and NHpg where pg is a protecting group.

2. The multifunctionalized solid support of claim 1 wherein said benzyl linker moieties have different fuctionalities and are selectively cleavable.

3. The multifunctionalized solid support resin of claim 1 wherein said benzyl linker moieties independently comprise 4-(hydroxymethyl)-phenoxyacetic acid (HMPA) and 4-hydroxymethylbenzoic acid (HMBA).

4. The multifunctionalized solid support resin of claim 3 having the structure:

5. The multifunctionalized solid support resin of claim 1 wherein T is lysine and said benzyl linker moieties independently comprise 4-hydroxymethylbenzoic acid (HMBA) and 4-(hydroxymethyl)-phenoxyacetic acid (HMPA).

6. The multifimctionalized solid support resin of claim 5 having the structure:

7. The multifunctionalized solid support resin of claim 1 wherein T is lysine and said benzyl linker moieties independently comprise 4-hydroxymethylbenzoic acid (HMBA) Knorr linker.

8. The multi-functionalized solid support resin of claim 7 having the structure:

11. The multifunctionalized solid support resin of claim 3 having the structure:

13. A method for preparing the multiftnctionalized support resin of claim 1, comprising:

a) coupling a diamino carboxylic acid template to a resin backbone, wherein each of the two amino groups of the diamino acid template are protected;

b) deprotecting one of the two protected amino groups of the template to generate a first deprotected amino group;

c) reacting the first deprotected amino group with a first benzyl linker moiety under conditions effective to covalently bond the benzyl linker moiety to the first deprotected amino group;

d) deprotecting the remaining protected amino group of the diamine carboxylic acid template to generate a second deprotected amino group;

e) reacting the second deprotected amino group with a second benzyl moiety under conditions effective to covalently bond the second benzyl linker moiety to the second deprotected amino group thereby to forming the multifunctionalized resin of claim 1; and

f) recovering the multifunctionalized resin of claim 1.

9. A multifinctionalized solid support resin having the structure

wherein P is a resin backbone, T is a template having at least three attachment points, X is a covalent bonding entity for attachment of T to P and L₁ and L₂ are independently selected from the group consisting of 4-hydroxymethylbenzoic acid (HMBA) and aminosulfonyl benzoic acid and when L₁ is HMBA, L₂ is aminosulfonyl benzoic acid and when L₁ is aminosulfonyl benzoic acid, L₂ is HMBA.

10. The multi-functionalized solid support resin of claim 9 having the structure:

12. A multifunctionalized solid support resin having the structure:

where P is a resin backbone, T is a diamino acid moiety having at least three attachment points, X is a covalent bonding entity for bonding T to P, L₁ and L₂ are structurally different benzyl linker moieties and are independently selected from the group consisting of acid-labile, base-labile, nucleophile-labile, electrophile-labile, photolabile, oxidant-labile and reductant-labile linkers having the formula;

wherein Z is selected from the group consisting of a covalent bond, 0, —

C(O)—

, C1-6 alkylene, C5-10 aryl, carbonylC1-6alkylene, carbonylC1-6alkyleneoxy, carbonyl C5-10 aryl and carbonyl C5-10 heteroaryl, said alkylene, aryl and heteroaryl groups being substituted with H or C1-3 alkyl;

R₁ and R₂ are independently selected from the group consisting of H, nitro, halo and C1-6alkoxy;

R₃ and R₄ are independently selected from the group consisting of H, C1-6 alkyl, C5-10 aryl and C5-10 heteroaryl, said alkyl, aryl and heteroaryl groups being substituted; and

W is selected from the group consisting of OH, NH₂ and NHpg where pg is a protecting group.