CN113121634A - Synthesis method of novel biomacromolecule for preparing ADC (azodicarbonamide) medicine - Google Patents
Synthesis method of novel biomacromolecule for preparing ADC (azodicarbonamide) medicine Download PDFInfo
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- CN113121634A CN113121634A CN202110330067.1A CN202110330067A CN113121634A CN 113121634 A CN113121634 A CN 113121634A CN 202110330067 A CN202110330067 A CN 202110330067A CN 113121634 A CN113121634 A CN 113121634A
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- 239000003814 drug Substances 0.000 title claims abstract description 16
- 238000001308 synthesis method Methods 0.000 title claims description 4
- 239000004156 Azodicarbonamide Substances 0.000 title description 3
- XOZUGNYVDXMRKW-AATRIKPKSA-N azodicarbonamide Chemical compound NC(=O)\N=N\C(N)=O XOZUGNYVDXMRKW-AATRIKPKSA-N 0.000 title description 3
- 235000019399 azodicarbonamide Nutrition 0.000 title description 3
- 229940079593 drug Drugs 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 239000000126 substance Substances 0.000 claims abstract description 12
- 239000007853 buffer solution Substances 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- 229920002521 macromolecule Polymers 0.000 claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 8
- 239000000243 solution Substances 0.000 claims abstract description 7
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 6
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000000872 buffer Substances 0.000 claims description 3
- VBKNTGMWIPUCRF-UHFFFAOYSA-M potassium;fluoride;hydrofluoride Chemical group F.[F-].[K+] VBKNTGMWIPUCRF-UHFFFAOYSA-M 0.000 claims description 3
- BFXAWOHHDUIALU-UHFFFAOYSA-M sodium;hydron;difluoride Chemical compound F.[F-].[Na+] BFXAWOHHDUIALU-UHFFFAOYSA-M 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims 1
- 235000019000 fluorine Nutrition 0.000 abstract description 6
- 238000009509 drug development Methods 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 4
- 229920001184 polypeptide Polymers 0.000 abstract description 4
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 4
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052731 fluorine Inorganic materials 0.000 abstract description 3
- 239000011737 fluorine Substances 0.000 abstract description 3
- 125000001153 fluoro group Chemical group F* 0.000 abstract description 3
- 125000000524 functional group Chemical group 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 3
- 229940126062 Compound A Drugs 0.000 abstract 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 abstract 1
- 239000000611 antibody drug conjugate Substances 0.000 description 11
- 229940049595 antibody-drug conjugate Drugs 0.000 description 11
- 150000003384 small molecules Chemical class 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 3
- 229930010555 Inosine Natural products 0.000 description 2
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 2
- 239000000562 conjugate Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229960003786 inosine Drugs 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- UJMWVICAENGCRF-UHFFFAOYSA-N oxygen difluoride Chemical compound FOF UJMWVICAENGCRF-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 101710112752 Cytotoxin Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- -1 small molecule compounds Chemical class 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
- C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
- C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
A method for synthesizing a novel biomacromolecule useful for the preparation of ADC drugs, comprising the steps of: dissolving the compounds shown in the formula A and the formula B in a solution; adding a catalyst, adjusting the pH value of the buffer solution to 4-11, and directly generating the compound shown in the formula 1 by using the compound A and the compound B in the buffer solution, wherein R1 is a biological macromolecule, and R2 and R3 are chemical micromolecules. Based on the bioorthogonal connection technology of the imidazofuroxydifluoride as the core linker, the two fluorines of the difluoride can be selectively combined with the amino and the phenolic hydroxyl. Therefore, after one fluorine is combined with the phenolic hydroxyl, the obtained B can be efficiently connected with protein macromolecules under the condition of biocompatibility, and meanwhile, the functional group has good compatibility and certain stability; meanwhile, the polypeptide can be selectively dissociated under specific conditions, and is a very important linker candidate in ADC drug development.
Description
Technical Field
The invention relates to the technical field of chemical biology, in particular to a method for synthesizing novel biomacromolecules for preparing ADC medicines.
Background
Antibody-drug Conjugate (ADC) is a drug bridged by an Antibody, a cytotoxic drug and a Conjugate. Wherein the antibody specifically recognizes and directs the drug to the lesion, and the conjugate is cleaved at the PH of the lesion site to release the therapeutic cytotoxin. The chemotherapy drug with strong cytotoxicity is formed by coupling the linker and the monoclonal antibody, has strong lethality of small molecule drugs and high targeting property of the pure monoclonal antibody, can improve the selectivity of tumor treatment, and can better deal with the drug resistance problem of the targeted monoclonal antibody, thereby becoming a research and development hotspot of tumor targeted treatment.
In the development process of the antibody coupled drug, the connection of the antibody and the small molecule needs to have certain stability, so that the drug cannot be out of target prematurely in the in-vivo transportation process, and the drug is consumed and accidentally injured by other normal cells; but not stable after reaching the target, or else not shed off, which can reduce the killing of the target cancer cells. Therefore, there are high demands on the connection technology. For the development of ADC drugs, a very important ring is to enable specific connection between biomacromolecules such as antibodies and small molecule compounds under physiological conditions with high efficiency and high selectivity. The prior art cannot well take both aspects into consideration.
Disclosure of Invention
In order to solve the above problems, the present invention provides a method for synthesizing a novel biomacromolecule useful for preparing ADC drugs, which has not only a certain stability; meanwhile, the polypeptide can be selectively dissociated under specific conditions, and is a very important linker candidate in ADC drug development.
A method for synthesizing a novel biomacromolecule useful for the preparation of ADC drugs, comprising the steps of:
dissolving the compounds shown in the formula A and the formula B in a solution;
adding a catalyst;
directly generating the compound shown in the formula 1 in a buffer solution with the pH value of 4-11, wherein R1 is a biological macromolecule, and R2 and R3 are chemical micromolecules.
Further, the catalyst is potassium bifluoride or sodium bifluoride.
Further, the buffer solution was PBS buffer, which was mixed with acetonitrile 1: 1 and mixing.
Further, the biological macromolecule refers to a protein molecule.
Further, the reaction equivalent is 1 equivalent of biological macromolecule, 5-1000 equivalents of chemical micromolecule and 1-5 equivalents of catalyst; the solution concentration was 1 umol.
By adopting the technical scheme of the invention, the invention has the following technical effects:
based on the bioorthogonal connection technology of the inosine oxydifluoride as the core linker, the two fluorines of the difluoride can be selectively combined with amino and phenolic hydroxyl. Therefore, after one fluorine is combined with the phenolic hydroxyl, the obtained B can be efficiently connected with protein macromolecules under the condition of biocompatibility, and meanwhile, the functional group has good compatibility and certain stability; meanwhile, the polypeptide can be selectively dissociated under specific conditions, and is a very important linker candidate in ADC drug development.
Drawings
FIG. 1 shows the chemical formula of the synthesis method.
Detailed Description
The present invention will now be described in more detail by way of examples, which are given by way of illustration only and are not intended to limit the scope of the present invention in any way.
Example one
A method for synthesizing a novel biomacromolecule useful for the preparation of ADC drugs, comprising the steps of:
taking formula A (R)1-NH2) And formula B: (
) Dissolving the compound in a solution; adding catalyst potassium bifluoride; a (R)1-NH2) And formula B: (
) In a PBS buffer solution with the pH value of 4 to directly generate the compound shown in the formula 1
The chemical formula of the reaction is shown in figure 1. Wherein R1 is a biological substanceMacromolecules, biomacromolecules refer to protein molecules. R2 and R3 are chemical small molecules. The reaction equivalent is 1 equivalent of biological macromolecule, 500 equivalents of chemical micromolecule, 3 equivalents of catalyst, and the concentration of the solution is 1 umol.
It is understood that the ratio of the chemical small molecule and the catalyst can be properly adjusted by those skilled in the art in practical operation errors, and the reaction equivalent is usually 1 equivalent of the biological macromolecule, 5-1000 equivalents of the small molecule, and 1-5 equivalents of the catalyst.
Example two:
example two differs from example one in that the catalyst is sodium bifluoride, and the buffer solution PBS buffer is mixed with acetonitrile 1: 1 and mixing.
Example three:
the difference between the third embodiment and the first embodiment is that the PBS buffer solution has a pH of 11, and it is understood that the PBS buffer solution may have a pH of 7,5,6,8,9, 10.
Through detection, the method of the invention can generate stably and effectively
A substance. Based on the bioorthogonal connection technology of the inosine oxydifluoride as the core linker, the two fluorines of the difluoride can be selectively combined with amino and phenolic hydroxyl. According to the material structure, after one fluorine is combined with the phenolic hydroxyl, the obtained B can be efficiently connected with protein macromolecules under the condition of biocompatibility, and meanwhile, the functional groups have good compatibility and certain stability; meanwhile, the polypeptide can be selectively dissociated under specific conditions, and is a very important linker candidate in ADC drug development.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (5)
1. A method for synthesizing a novel biomacromolecule for preparing ADC medicines is characterized by comprising the following steps:
dissolving the compounds shown in the formula A and the formula B in a solution;
adding catalyst, regulating pH value of buffer solution to 4-11,
the compound of A and B directly generates the compound shown in the formula 1 in a buffer solution, wherein R1 is a biological macromolecule, and R2 and R3 are chemical micromolecules.
2. The method for synthesizing a novel biomacromolecule useful for preparing ADC drugs according to claim 1, wherein the catalyst is potassium bifluoride or sodium bifluoride.
3. The method of claim 1, wherein the buffer solution is PBS buffer, which is mixed with acetonitrile 1: 1 and mixing.
4. The method of claim 1, wherein the biomacromolecule is a protein molecule.
5. The method for synthesizing a novel biomacromolecule used for preparing ADC drugs according to claim 1, wherein in the synthesis method, the reaction equivalent is 1 equivalent of the biomacromolecule, 5-1000 equivalents of the chemical micromolecule and 1-5 equivalents of the catalyst; the solution concentration was 1 umol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110330067.1A CN113121634A (en) | 2021-03-29 | 2021-03-29 | Synthesis method of novel biomacromolecule for preparing ADC (azodicarbonamide) medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110330067.1A CN113121634A (en) | 2021-03-29 | 2021-03-29 | Synthesis method of novel biomacromolecule for preparing ADC (azodicarbonamide) medicine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113121634A true CN113121634A (en) | 2021-07-16 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110330067.1A Pending CN113121634A (en) | 2021-03-29 | 2021-03-29 | Synthesis method of novel biomacromolecule for preparing ADC (azodicarbonamide) medicine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113121634A (en) |
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2021
- 2021-03-29 CN CN202110330067.1A patent/CN113121634A/en active Pending
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Application publication date: 20210716 |