Diketopiperazine forming dipeptidyl linker

A kind of residue, resin technology, applied in the field of dipeptide linker forming diketopiperazine

Inactive Publication Date: 2013-07-03
LONZA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Another disadvantage is that its cleavage is limited to the use of trifluoroacetic acid (TFA) during the cleavage step, meaning that any tBu, Boc, Trt or acetal-based protecting groups on the amino acid residue side chains of the peptide will be partially or completely removed, Its use is thus limited to the preparation of peptides with unprotected side chains or side chain protecting groups other than tBu, Boc, Trt and acetal

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[1197] Example 1: SPPS (0.1 mmol scale) using T20C linked to resin via a dipeptide linker forming a diketopiperazinyl group

[1198] Manual SPPS.

[1199] Method Fmoc-gr-rem (removal of Fmoc group)

[1200] In the following examples, the Fmoc group was removed by these procedures:

[1201] Use 20% (v / v) piperidine in DMF (1 x 1 min, 2 x 10 min; 3 ml each for Examples 1 to 3 and 7, 150 ml each for Examples 4 to 6) Process the resin, followed by:

[1202] DMF washes (5 x 1 min; 3 ml each) (for Examples 1 to 3 and Example 7),

[1203] Continue with DMF wash (600ml) and Chloranil Test Method D (for Examples 4 to 6).

Embodiment 11

[1204] Example 1.1 Attachment of a dipeptide linker forming a diketopiperazinyl group to a resin

[1205] a) Pretreatment of HMPS resin

[1206] HMPS resin (106.2 mg) was swelled with DCM (5 x 1 min; 3 ml each) and DMF (5 x 1 min; 3 ml each) at room temperature and then filtered.

[1207] b) Incorporation of the first amino acid (D-Pro) of the dipeptide linker forming the diketopiperazinyl group onto the resin

[1208] Fmoc-D-Pro-OH (135 mg, 4 equiv) and DIPCDI (31 μl, 2 equiv) in DCM / DMF (15:1, v / v, 2.5 ml) were added to in the prepared resin. Next, DMAP (4.9 mg, 0.4 equiv) in DCM (0.5 ml) was added and left at room temperature for 2 hours. Fmoc-D-Pro-OH was incorporated again at the end of this procedure. After the previous 2 hour coupling time, the resin was washed with DCM (5 x 1 min; 3 ml each) and with DMF (5 x 1 min; 3 ml each). The resin was then capped with acetic anhydride (47 μL, 5 eq) and DIEA (85 μL, 5 eq) in DMF (2.5 ml) for 30 min at room temperature. Afte...

Embodiment 12

[1214] Example 1.2 Synthesis of T20C by SPPS

[1215] Each amino acid is reacted in a reaction cycle. Follow the reaction cycle description (i) or (ii) to carry out the reaction steps in a reaction cycle to incorporate an amino acid.

[1216] a) Reaction cycle description (i)

[1217] A mixture of Fmoc-Xaa-OH (3 equiv), HCTU (140 mg, 3 equiv) and DIEA (110 μl, 6 equiv) in DMF (2 ml) was shaken for 30 seconds at room temperature, then added to the in the resin prepared in the previous step. The mixture was left standing at room temperature for 1 hour. According to the ninhydrin test (method C), no further coupling is required. The resin was then washed with DMF (5 x 1 min; 3 ml each) and with DCM (5 x 1 min; 3 ml each). The Fmoc group was then removed by the method Fmoc-gr-rem.

[1218] b) Reaction cycle description (ii)

[1219] A mixture of Fmoc-Xaa-OH (3 equiv), HCTU (140 mg, 3 equiv), DIEA (110 μl, 6 equiv) in DMF (2 ml) was shaken for 30 seconds at room temperature,...

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Abstract

The invention relates to a method for homogeneous solution phase peptide synthesis (HSPPS) of a N-terminal peptide fragment PEP-N and a C-terminal peptide fragment C-PEP, with C- PEP carrying a specific diketopiperazine (DKP) comprising C-terminal protecting group, which contains a handle group HG, with HG being connected to the C-terminus of the peptide fragment; thereby this specific DKP comprising C-terminal protecting group can be selectively cleaved from the peptide as a conventionally used C-terminal protecting group. By the use of this DKP and HG comprising C-terminal protecting group, certain process steps in convergent peptide synthesis based on a combination of HSPPS and solid phase peptide synthesis (SPPS) can be avoided. The invention relates further to a method for the preparation of such specifically protected fragment C-PEP by SPPS by using a linker comprising a specific dipeptide and HG for connecting the growing peptide chain to the resin, which linker forms said DKP group, when the peptide fragment C-PEP is cleaved from the supporting resin; and further to the intermediates of the preparation method.

Description

technical field [0001] The present invention relates to a method for the homogeneous solution phase peptide synthesis (HSPPS) of the N-terminal peptide fragment PEP-N and the C-terminal peptide fragment C-PEP, wherein C-PEP contains diketopiperazine (DKP) A specific C-terminal protecting group containing a handle group (handle group) HG, wherein the HG is connected to the C-terminal of the peptide fragment; thus this specific C-terminal protecting group comprising DKP can be obtained from the peptide as the conventionally used C Terminal protecting groups are generally selectively cleaved. By using this C-terminal protecting group comprising DKP and HG, certain method steps in pooled peptide synthesis based on a combination of HSPPS and solid phase peptide synthesis (SPPS) can be avoided. [0002] The present invention further relates to a method for preparing the specifically protected fragment C-PEP by SPPS by using a linker comprising a specific dipeptide and HG to link th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K1/04C07K14/16C07K5/06C07K17/08
CPCC07K1/04C07K5/06086Y02P20/55C07K5/06C07K14/16C07K17/08C07K1/062C07K1/068C08F112/08
Inventor 费尔南多·阿尔贝利西欧米谢勒·克里斯托马蒂厄·吉罗米里亚姆·贡戈拉贝尼特斯茱蒂特·图拉-普赫
Owner LONZA LTD
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