CN111704560A - Diagnosis and treatment integrated compound, preparation method and application thereof - Google Patents
Diagnosis and treatment integrated compound, preparation method and application thereof Download PDFInfo
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- CN111704560A CN111704560A CN202010452865.7A CN202010452865A CN111704560A CN 111704560 A CN111704560 A CN 111704560A CN 202010452865 A CN202010452865 A CN 202010452865A CN 111704560 A CN111704560 A CN 111704560A
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- vorinostat
- boc
- triiodobenzoic acid
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- triiodoaniline
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000003745 diagnosis Methods 0.000 title abstract description 41
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical class ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 claims abstract description 96
- IOJXKAZOZXDYPY-UHFFFAOYSA-N 2,3,5-triiodo-4-[(2-methylpropan-2-yl)oxycarbonyl]benzoic acid Chemical compound CC(C)(C)OC(=O)C1=C(C=C(C(=C1I)I)C(=O)O)I IOJXKAZOZXDYPY-UHFFFAOYSA-N 0.000 claims abstract description 49
- -1 (2,3, 5-triiodophenyl) amino Chemical group 0.000 claims abstract description 39
- LKXSJUSEJYPVED-UHFFFAOYSA-N 2,3,5-triiodoaniline Chemical compound NC1=CC(I)=CC(I)=C1I LKXSJUSEJYPVED-UHFFFAOYSA-N 0.000 claims abstract description 39
- 229960000237 vorinostat Drugs 0.000 claims abstract description 36
- JGHZJRVDZXSNKQ-UHFFFAOYSA-N methyl octanoate Chemical compound CCCCCCCC(=O)OC JGHZJRVDZXSNKQ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 17
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 16
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 239000005641 Methyl octanoate Substances 0.000 claims abstract description 12
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 12
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
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- 239000000203 mixture Substances 0.000 claims description 45
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
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- 239000007832 Na2SO4 Substances 0.000 claims description 11
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 claims description 11
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- KOVPXZDUVJGGFU-UHFFFAOYSA-N 8-methoxy-8-oxooctanoic acid Chemical compound COC(=O)CCCCCCC(O)=O KOVPXZDUVJGGFU-UHFFFAOYSA-N 0.000 claims description 10
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- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 description 3
- JZRYCEXYUFIPSI-UHFFFAOYSA-N iodo(phenyl)methanol Chemical compound OC(I)C1=CC=CC=C1 JZRYCEXYUFIPSI-UHFFFAOYSA-N 0.000 description 3
- 229960001025 iohexol Drugs 0.000 description 3
- NTHXOOBQLCIOLC-UHFFFAOYSA-N iohexol Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NTHXOOBQLCIOLC-UHFFFAOYSA-N 0.000 description 3
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- 239000000758 substrate Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
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- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- NCNRHFGMJRPRSK-MDZDMXLPSA-N belinostat Chemical compound ONC(=O)\C=C\C1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-MDZDMXLPSA-N 0.000 description 1
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- FWZRWHZDXBDTFK-ZHACJKMWSA-N panobinostat Chemical compound CC1=NC2=CC=C[CH]C2=C1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FWZRWHZDXBDTFK-ZHACJKMWSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention relates to the technical field of medicines, and particularly discloses a diagnosis and treatment integrated compound, and a preparation method and application thereof. A theranostic compound is a vorinostat derivative obtained by introducing at least one iodine atom to the benzene ring of vorinostat; the compound not only has anti-tumor activity, but also has diagnostic imaging function. The preparation method of the diagnosis and treatment integrated compound comprises the following steps: synthesizing Boc-2,3, 5-triiodobenzoic acid, synthesizing 2,3, 5-triiodoaniline, and synthesizing 8-oxo-8- ((2,3, 5-triiodophenyl) amino) methyl octanoate, wherein the preparation method is simple; an application of a diagnosis and treatment integrated compound is applied to an anti-tumor drug; for the anti-tumor therapy and the diagnostic imaging function of tumor patients.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a diagnosis and treatment integrated compound, a preparation method and application thereof.
Background
Cancer is one of the leading causes of death worldwide, causing nearly 800 million deaths each year and posing a significant socio-economic hazard to all humans. Unfortunately, no effective and clinically effective cancer treatment has been developed yet, and there is an urgent need for novel effective and specific anticancer drugs.
Histone Acetyltransferases (HATs) and Histone Deacetylases (HDACs) have recently become important targets for cancer therapy. Indeed, several HDAC inhibitors have been used to treat T cell lymphomas, including SAHA (sulfinanilide hydroxamic acid, vorinostat) and Belinostat. Panobinostat has recently been approved for the treatment of multiple myeloma.
At the same time, early diagnosis of cancer is also important to prolong the survival time of patients. Therefore, the search and development of more effective anticancer drugs having diagnostic imaging functions can be used as better cancer treatment methods.
Disclosure of Invention
The invention aims to provide a diagnosis and treatment integrated compound which not only has anti-tumor activity, but also has the function of diagnosis and imaging.
Another object of the present invention is to provide a method for preparing a diagnosis and treatment integrated compound, which is simple.
The invention also aims to provide application of the diagnosis and treatment integrated compound to antitumor treatment and diagnostic imaging functions of tumor patients.
The technical problem to be solved by the invention is realized by adopting the following technical scheme.
In a first aspect, embodiments of the present invention provide a medicinally useful compound, which is a vorinostat derivative obtained by introducing at least one iodine atom into the benzene ring of vorinostat.
Further, in some embodiments of the present invention, the above vorinostat derivative is prepared by introducing three iodine atoms on the benzene ring of vorinostat.
Further, in some embodiments of the invention, the formula is: c14H17I3N2O3。
Further, in some embodiments of the present invention, the formula is:
in a second aspect, an embodiment of the present invention further provides a method for preparing the diagnosis and treatment integrated compound, including the following steps: synthesis of Boc-2,3, 5-triiodobenzoic acid: 2,3, 5-triiodobenzoic acid was dissolved in t-BuOH. DPPA and TEA were then added and the mixture was stirred at 85-95 ℃ for 1.5-2.5 hours under a nitrogen atmosphere, then the solvent was removed from the mixture under reduced pressure, the residue was dissolved in DCM and saturated NaHCO was used3Washing to obtain an organic phase, and then using anhydrous Na for the organic phase2SO4Drying, concentrating the organic phase, purifying the residue by silica gel column chromatography, eluting with PE/EA to obtain Boc-2,3, 5-triiodobenzoic acid; synthesizing 2,3, 5-triiodoaniline: dissolving Boc-2,3, 5-triiodobenzoic acid in CH2Cl2In solution, to Boc-2,3, 5-triiodobenzoic acid CH at-5-5 deg.C2Cl2TFA was added to the solution and after consumption of starting material, the mixture was evaporated and then saturated NaHCO was added3Aqueous solution, organic layer washed with brine and anhydrous Na2SO4Drying and purifying the crude product by silica gel chromatography eluting with PE/EA to give 2,3, 5-triiodoaniline; synthesis of methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate: oxalyl chloride is dropped into monomethyl suberate in anhydrous CH at-5-5 DEG C2Cl2Is stirred for 11-13h, then the solvent and excess oxalyl chloride are evaporated under reduced pressure and then CHCl is added3Then adding 2,3, 5-triiodoaniline and triethylamine, refluxing for 4-5 hours at 60-70 ℃, then evaporating the solvent under reduced pressure, and purifying the crude product by silica gel chromatography, eluting with PE/EA to obtain 8-oxo-8- ((2,3, 5-triiodophenyl) amino) methyl octanoate; synthesis of vorinostat derivatives: adding a methanol solution of sodium methoxide into a methanol solution of hydroxylamine hydrochloride, stirring for 8-12 minutes, filtering out NaCl, adding the synthesized 8-oxo-8- ((2,3, 5-triiodophenyl) amino) methyl octanoate into the filtrate, stirring the obtained mixture at 23-27 ℃ for 3-5 hours, then removing the solvent under reduced pressure, dissolving the product in ethanol, then adding oxalic acid into the solution, then filtering the precipitate and crystallizing from water to obtain the vorinostat derivative.
Further, in some embodiments of the present invention, the PE/EA elutes in a 10:1 volume ratio during the synthesis of Boc-2,3, 5-triiodobenzoic acid.
Further, in some embodiments of the present invention, the PE/EA elutes in a volume ratio of 5:1 during the synthesis of 2,3, 5-triiodoaniline.
Further, in some embodiments of the present invention, the PE/EA elutes at a volume ratio of 5:1 during the synthesis of methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate as described above.
In a third aspect, the embodiment of the invention also provides an application of the diagnosis and treatment integrated compound, and the diagnosis and treatment integrated compound is applied to an anti-tumor drug.
Further, in some embodiments of the invention, it is applied to a tumor contrast agent.
The diagnosis and treatment integrated compound, the preparation method and the application thereof provided by the embodiment of the invention at least have the following beneficial effects:
in a first aspect, embodiments of the present invention provide a medicinally useful compound, which is a vorinostat derivative obtained by introducing at least one iodine atom into the benzene ring of vorinostat.
Because iodine atoms have good X-ray blocking ability, iodinated compounds such as iodobenzyl alcohol, iohexol, iodixanol, and sodium diatrizoate are used for CT imaging, and there are many reports of probes based on these iodinated compounds, but when a contrast agent is linked to a drug molecule through a covalent bond, it more or less reduces the drug activity; on the other hand, vorinostat is used for treating T cell lymphoma, because vorinostat has a cap group, and introduction of an iodine atom into the cap group of vorinostat can attenuate X-rays as a CT contrast agent and maintain the binding activity of vorinostat to HDAC (as an HDAC inhibitor), so that such vorinostat derivatives have a diagnosis and treatment integrated function.
In a second aspect, an embodiment of the present invention further provides a method for preparing the diagnosis and treatment integrated compound, including the following steps: synthesis of Boc-2,3, 5-triiodobenzoic acid: 2,3, 5-triiodobenzoic acid was dissolved in t-BuOH. DPPA and TEA were then added and the mixture was stirred at 85-95 ℃ for 1.5-2.5 hours under a nitrogen atmosphere, then the solvent was removed from the mixture under reduced pressure, the residue was dissolved in DCM and saturated NaHCO was used3Washing to obtain an organic phase, and then using anhydrous Na for the organic phase2SO4Drying, concentrating the organic phase, purifying the residue by silica gel column chromatography, eluting with PE/EA to obtain Boc-2,3, 5-triiodobenzoic acid; synthesizing 2,3, 5-triiodoaniline: dissolving Boc-2,3, 5-triiodobenzoic acid in CH2Cl2In solution, to Boc-2,3, 5-triiodobenzoic acid CH at-5-5 deg.C2Cl2TFA was added to the solution and after consumption of starting material, the mixture was evaporated and then saturated NaHCO was added3Aqueous solution, organic layer washed with brine and anhydrous Na2SO4Drying and purifying the crude product by silica gel chromatography eluting with PE/EA to give 2,3, 5-triiodoaniline; synthesis of methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate: oxalyl chloride is dropped into monomethyl suberate in anhydrous CH at-5-5 DEG C2Cl2Is stirred for 11-13h, then the solvent and excess oxalyl chloride are evaporated under reduced pressure and then CHCl is added3Then adding 2,3, 5-triiodoaniline and triethylamine, refluxing for 4-5 hours at 60-70 ℃, then evaporating the solvent under reduced pressure, and purifying the crude product by silica gel chromatography, eluting with PE/EA to obtain 8-oxo-8- ((2,3, 5-triiodophenyl) amino) methyl octanoate; synthesis of vorinostat derivatives: adding a methanol solution of sodium methoxide into a methanol solution of hydroxylamine hydrochloride, stirring for 8-12 minutes, filtering out NaCl, adding the synthesized 8-oxo-8- ((2,3, 5-triiodophenyl) amino) methyl octanoate into the filtrate, stirring the obtained mixture at 23-27 ℃ for 3-5 hours, then removing the solvent under reduced pressure, dissolving the product in ethanol, then adding oxalic acid into the solution, then filtering the precipitate and crystallizing from water to obtain the vorinostat derivative.
The preparation method is very simple and low in cost, and the vorinostat derivative prepared by the method can keep the original activity of vorinostat to the maximum extent and has the sensitive X-ray contrast activity.
In a third aspect, the embodiment of the invention also provides an application of the diagnosis and treatment integrated compound, and the diagnosis and treatment integrated compound is applied to an anti-tumor drug. The antitumor drug can be used for treating tumors, can also be used for diagnosis, and integrates diagnosis and treatment.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is an X-ray in vitro imaging graph of vorinostat derivatives at different concentrations in water and empty tubes in the present invention;
FIG. 2 shows CT values of vorinostat derivatives at different concentrations in the present invention;
FIG. 3 shows the results of Western blot analysis of AcH3 and AcTub in U973 cells after treatment with vorinostat or vorinostat derivatives at different concentrations in accordance with the present invention;
FIG. 4 is a NMR spectrum of Boc-2,3, 5-triiodobenzoic acid of the present invention;
FIG. 5 is a NMR spectrum of 2,3, 5-triiodoaniline of the present invention;
FIG. 6 shows NMR spectra of methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate in accordance with the present invention;
FIG. 7 shows the NMR spectrum of vorinostat derivatives in the present invention;
FIG. 8 is a nuclear magnetic resonance carbon spectrum of a vorinostat derivative according to the invention;
fig. 9 is a high resolution mass spectrum of vorinostat derivatives in the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail below with reference to specific examples.
In a first aspect, embodiments of the present invention provide a medicinally useful compound, which is a vorinostat derivative obtained by introducing at least one iodine atom into the benzene ring of vorinostat.
Because iodine atoms have good X-ray blocking ability, iodinated compounds such as iodobenzyl alcohol, iohexol, iodixanol, and sodium diatrizoate are used for CT imaging, and there are many reports of probes based on these iodinated compounds, but when a contrast agent is linked to a drug molecule through a covalent bond, it more or less reduces the drug activity; on the other hand, vorinostat is used for treating T cell lymphoma, because vorinostat has a cap group, and introduction of an iodine atom into the cap group of vorinostat can attenuate X-rays as a CT contrast agent and maintain the binding activity of vorinostat to HDAC (as an HDAC inhibitor), so that such vorinostat derivatives have a diagnosis and treatment integrated function.
Further, in some embodiments of the present invention, the above vorinostat derivative is prepared by introducing three iodine atoms on the benzene ring of vorinostat. Three iodine atoms are introduced into a benzene ring of the vorinostat, so that the obtained vorinostat derivative can keep the original activity of the vorinostat to the maximum extent and has the activity of sensitive X-ray radiography.
Further, in some embodiments of the invention, the formula is: c14H17I3N2O3. The vorinostat derivative can keep the original activity of vorinostat to the maximum extent, and has the activity of sensitive X-ray radiography.
Further, in some embodiments of the present invention, the formula is:
the vorinostat derivative can keep the original activity of vorinostat to the maximum extent, and has the activity of sensitive X-ray radiography.
In a second aspect, an embodiment of the present invention further provides a method for preparing the diagnosis and treatment integrated compound, including the following steps: synthesis of Boc-2,3, 5-triiodobenzoic acid: dissolving 2,3, 5-triiodobenzoic acid in t-BuOH, adding DPPA and TEA, stirring the mixture at 85-95 deg.C under nitrogen for 1.5-2.5 hr, removing solvent under reduced pressure, dissolving the residue in DCM, adding saturated NaHCO3Washing to obtain an organic phase, and then using anhydrous Na for the organic phase2SO4Drying, concentrating the organic phase, purifying the residue by silica gel column chromatography, eluting with PE/EA to obtain Boc-2,3, 5-triiodobenzoic acid; synthesizing 2,3, 5-triiodoaniline: dissolving Boc-2,3, 5-triiodobenzoic acid in CH2Cl2In solution, to Boc-2,3, 5-triiodobenzoic acid CH at-5-5 deg.C2Cl2TFA was added to the solution and after consumption of starting material, the mixture was evaporated and then saturated NaHCO was added3Aqueous solution, organic layer washed with brine and anhydrous Na2SO4Drying and purifying the crude product by silica gel chromatography eluting with PE/EA to give 2,3, 5-triiodoaniline; synthesis of methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate: oxalyl chloride is dropped into monomethyl suberate in anhydrous CH at-5-5 DEG C2Cl2Is stirred for 11-13h, then the solvent and excess oxalyl chloride are evaporated under reduced pressure and then CHCl is added3Then adding 2,3, 5-triiodoaniline and triethylamine, refluxing for 4-5 hours at 60-70 ℃, then evaporating the solvent under reduced pressure, and purifying the crude product by silica gel chromatography, eluting with PE/EA to obtain 8-oxo-8- ((2,3, 5-triiodophenyl) amino) methyl octanoate; synthesis of vorinostat derivatives: adding methanol solution of sodium methoxide into methanol solution of hydroxylamine hydrochloride, stirring for 8-12 min, filtering to remove NaCl, adding synthetic 8-oxo-8- ((2,3, 5-triiodophenyl) amino) methyl octanoate into filtrate, stirring the obtained mixture at 23-27 deg.C for 3-5 hr, removing solvent under reduced pressure, dissolving the product in ethanol, adding oxalic acid into the solutionThen the precipitate is filtered and crystallized from water to give the vorinostat derivative.
The preparation method is very simple and low in cost, and the vorinostat derivative prepared by the method can keep the original activity of vorinostat to the maximum extent and has the sensitive X-ray contrast activity.
Further, in some embodiments of the present invention, the PE/EA elutes in a 10:1 volume ratio during the synthesis of Boc-2,3, 5-triiodobenzoic acid. The Boc-2,3, 5-triiodobenzoic acid obtained by adopting the proportion for elution has good purity and high recovery rate.
Further, in some embodiments of the present invention, the PE/EA elutes in a volume ratio of 5:1 during the synthesis of 2,3, 5-triiodoaniline. The elution is carried out according to the proportion, so that the obtained 2,3, 5-triiodoaniline has good purity and high recovery rate.
Further, in some embodiments of the present invention, the PE/EA elutes at a volume ratio of 5:1 during the synthesis of methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate as described above. The elution is carried out according to the proportion, so that the obtained 8-oxo-8- ((2,3, 5-triiodophenyl) amino) methyl octanoate has good purity and high recovery rate.
In a third aspect, the embodiment of the invention also provides an application of the diagnosis and treatment integrated compound, and the diagnosis and treatment integrated compound is applied to an anti-tumor drug. The antitumor drug can be used for treating tumors, can also be used for diagnosis, and integrates diagnosis and treatment.
Further, in some embodiments of the invention, it is applied to a tumor contrast agent. The antitumor drug can be used for diagnosis and tumor treatment, and integrates diagnosis and treatment.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
The preparation method of the diagnosis and treatment integrated compound comprises the following steps: synthesis of Boc-2,3, 5-triiodobenzoic acid: 2,3, 5-triiodobenzoic acid was dissolved in t-BuOH. Then DPPA and TEA were added andthe mixture was stirred at 85 ℃ for 1.5h under nitrogen, then the mixture was freed of solvent under reduced pressure, the residue was dissolved in DCM and taken up with saturated NaHCO3Washing to obtain an organic phase, and then using anhydrous Na for the organic phase2SO4Drying and then concentrating the organic phase and purifying the residue by silica gel column chromatography eluting with PE/EA (V: V ═ 10:1) to give Boc-2,3, 5-triiodobenzoic acid;
synthesizing 2,3, 5-triiodoaniline: dissolving Boc-2,3, 5-triiodobenzoic acid in CH2Cl2In solution, to Boc-2,3, 5-triiodobenzoic acid CH at-5 deg.C2Cl2TFA was added to the solution and after consumption of starting material, the mixture was evaporated and then saturated NaHCO was added3Aqueous solution, organic layer washed with brine and anhydrous Na2SO4Drying and purifying the crude product by silica gel chromatography eluting with PE/EA (V: V ═ 5:1) to give 2,3, 5-triiodoaniline;
synthesis of methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate: oxalyl chloride was added dropwise to monomethyl suberate in anhydrous CH at-5 deg.C2Cl2Is stirred for 11h, then the solvent and excess oxalyl chloride are evaporated under reduced pressure and then CHCl is added3Then 2,3, 5-triiodoaniline and triethylamine are added and refluxed at 60 ℃ for 4-5 hours, then the solvent is evaporated under reduced pressure and the crude product is purified by silica gel chromatography eluting with PE/EA (V: V ═ 5:1) to give methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate;
synthesis of vorinostat derivatives: adding a methanol solution of sodium methoxide into a methanol solution of hydroxylamine hydrochloride, stirring for 8 minutes, filtering out NaCl, adding the synthesized methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) caprylate into the filtrate, stirring the obtained mixture at 23 ℃ for 3 hours, then removing the solvent under reduced pressure, dissolving the product into ethanol, then adding oxalic acid into the solution, and then filtering and crystallizing the precipitate from water to obtain the vorinostat derivative.
Example 2
The preparation method of the diagnosis and treatment integrated compound comprises the following steps: synthesis of Boc-2,3, 5-triiodobenzoic acid: dissolving 2,3, 5-triiodobenzoic acid in t-BuOHIn (1). DPPA and TEA were then added and the mixture was stirred at 95 ℃ for 2.5 hours under a nitrogen atmosphere, then the solvent was removed from the mixture under reduced pressure, the residue was dissolved in DCM and saturated NaHCO was used3Washing to obtain an organic phase, and then using anhydrous Na for the organic phase2SO4Drying and then concentrating the organic phase and purifying the residue by silica gel column chromatography eluting with PE/EA (V: V ═ 10:1) to give Boc-2,3, 5-triiodobenzoic acid;
synthesizing 2,3, 5-triiodoaniline: dissolving Boc-2,3, 5-triiodobenzoic acid in CH2Cl2In solution, to Boc-2,3, 5-triiodobenzoic acid CH at 5 deg.C2Cl2TFA was added to the solution and after consumption of starting material, the mixture was evaporated and then saturated NaHCO was added3Aqueous solution, organic layer washed with brine and anhydrous Na2SO4Drying and purifying the crude product by silica gel chromatography eluting with PE/EA (V: V ═ 5:1) to give 2,3, 5-triiodoaniline;
synthesis of methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate: oxalyl chloride was added dropwise to monomethyl suberate in anhydrous CH at 5 deg.C2Cl2Is stirred for 13h, then the solvent and excess oxalyl chloride are evaporated under reduced pressure and then CHCl is added3Then 2,3, 5-triiodoaniline and triethylamine are added and refluxed at 70 ℃ for 5 hours, then the solvent is evaporated under reduced pressure and the crude product is purified by silica gel chromatography eluting with PE/EA (V: V ═ 5:1) to give methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate;
synthesis of vorinostat derivatives: adding a methanol solution of sodium methoxide to a methanol solution of hydroxylamine hydrochloride, stirring for 12 minutes, filtering out NaCl, adding the synthesized methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate to the filtrate, stirring the resulting mixture at 27 ℃ for 5 hours, then removing the solvent under reduced pressure, dissolving the product in ethanol, then adding oxalic acid to the solution, then filtering the precipitate and crystallizing from water to obtain the vorinostat derivative.
Example 3
The preparation method of the diagnosis and treatment integrated compound comprises the following steps: synthesis of Boc-2,3, 5-triiodobenzoic acid: the process comprises the steps of mixing the raw materials 2,3, 5-triiodobenzoic acid was dissolved in t-BuOH. DPPA and TEA were then added and the mixture was stirred at 90 ℃ for 2 hours under a nitrogen atmosphere, then the solvent was removed from the mixture under reduced pressure, the residue was dissolved in DCM and saturated NaHCO was used3Washing to obtain an organic phase, and then using anhydrous Na for the organic phase2SO4Drying and then concentrating the organic phase and purifying the residue by silica gel column chromatography eluting with PE/EA (V: V ═ 10:1) to give Boc-2,3, 5-triiodobenzoic acid;
synthesizing 2,3, 5-triiodoaniline: dissolving Boc-2,3, 5-triiodobenzoic acid in CH2Cl2In solution, to Boc-2,3, 5-triiodobenzoic acid CH at 0 deg.C2Cl2TFA was added to the solution and after consumption of starting material, the mixture was evaporated and then saturated NaHCO was added3Aqueous solution, organic layer washed with brine and anhydrous Na2SO4Drying and purifying the crude product by silica gel chromatography eluting with PE/EA (V: V ═ 5:1) to give 2,3, 5-triiodoaniline;
synthesis of methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate: oxalyl chloride was added dropwise to monomethyl suberate in anhydrous CH at 0 deg.C2Cl2Is stirred for 12h, then the solvent and excess oxalyl chloride are evaporated under reduced pressure and then CHCl is added3Then 2,3, 5-triiodoaniline and triethylamine are added and refluxed at 65 ℃ for 4.5 hours, then the solvent is evaporated under reduced pressure and the crude product is purified by silica gel chromatography eluting with PE/EA (V: V ═ 5:1) to give methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate;
synthesis of vorinostat derivatives: adding a methanol solution of sodium methoxide into a methanol solution of hydroxylamine hydrochloride, stirring for 10 minutes, filtering out NaCl, adding the synthesized methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) caprylate into the filtrate, stirring the obtained mixture at 23-27 ℃ for 4 hours, then removing the solvent under reduced pressure, dissolving the product into ethanol, then adding oxalic acid into the solution, then filtering the precipitate and crystallizing from water to obtain the vorinostat derivative.
Example 4
The preparation method of the diagnosis and treatment integrated compound comprises the following steps: combination of Chinese herbsBoc-2,3, 5-triiodobenzoic acid: 2,3, 5-triiodobenzoic acid was dissolved in t-BuOH. DPPA and TEA were then added and the mixture was stirred at 88 ℃ for 1.8 hours under a nitrogen atmosphere, then the solvent was removed from the mixture under reduced pressure, the residue was dissolved in DCM and saturated NaHCO was used3Washing to obtain an organic phase, and then using anhydrous Na for the organic phase2SO4Drying and then concentrating the organic phase and purifying the residue by silica gel column chromatography eluting with PE/EA (V: V ═ 10:1) to give Boc-2,3, 5-triiodobenzoic acid;
synthesizing 2,3, 5-triiodoaniline: dissolving Boc-2,3, 5-triiodobenzoic acid in CH2Cl2In solution, to Boc-2,3, 5-triiodobenzoic acid CH at-3 deg.C2Cl2TFA was added to the solution and after consumption of starting material, the mixture was evaporated and then saturated NaHCO was added3Aqueous solution, organic layer washed with brine and anhydrous Na2SO4Drying and purifying the crude product by silica gel chromatography eluting with PE/EA (V: V ═ 5:1) to give 2,3, 5-triiodoaniline;
synthesis of methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate: oxalyl chloride was added dropwise to monomethyl suberate in anhydrous CH at-3 deg.C2Cl2Is stirred for 11.5h, then the solvent and excess oxalyl chloride are evaporated under reduced pressure and then CHCl is added3Then 2,3, 5-triiodoaniline and triethylamine were added and refluxed at 63 ℃ for 4.2 hours, then the solvent was evaporated under reduced pressure and the crude product was purified by silica gel chromatography eluting with PE/EA (V: V ═ 5:1) to give methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate;
synthesis of vorinostat derivatives: adding a methanol solution of sodium methoxide to a methanol solution of hydroxylamine hydrochloride, stirring for 9 minutes, filtering out NaCl, adding the synthesized methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate to the filtrate, stirring the resulting mixture at 23-27 ℃ for 3.5 hours, then removing the solvent under reduced pressure, dissolving the product in ethanol, then adding oxalic acid to the solution, then filtering the precipitate and crystallizing from water to obtain the vorinostat derivative.
Example 5
Diagnosis and treatment integrated compoundThe preparation method comprises the following steps: synthesis of Boc-2,3, 5-triiodobenzoic acid: 2,3, 5-triiodobenzoic acid was dissolved in t-BuOH. DPPA and TEA were then added and the mixture was stirred at 92 ℃ for 2.3 hours under a nitrogen atmosphere, then the solvent was removed from the mixture under reduced pressure, the residue was dissolved in DCM and saturated NaHCO was used3Washing to obtain an organic phase, and then using anhydrous Na for the organic phase2SO4Drying and then concentrating the organic phase and purifying the residue by silica gel column chromatography eluting with PE/EA (V: V ═ 10:1) to give Boc-2,3, 5-triiodobenzoic acid;
synthesizing 2,3, 5-triiodoaniline: dissolving Boc-2,3, 5-triiodobenzoic acid in CH2Cl2In solution, to Boc-2,3, 5-triiodobenzoic acid CH at 2 deg.C2Cl2TFA was added to the solution and after consumption of starting material, the mixture was evaporated and then saturated NaHCO was added3Aqueous solution, organic layer washed with brine and anhydrous Na2SO4Drying and purifying the crude product by silica gel chromatography eluting with PE/EA to give 2,3, 5-triiodoaniline;
synthesis of methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate: oxalyl chloride was added dropwise to monomethyl suberate in anhydrous CH at 3 deg.C2Cl2Is stirred for 12.5h, then the solvent and excess oxalyl chloride are evaporated under reduced pressure and then CHCl is added3Then 2,3, 5-triiodoaniline and triethylamine are added and refluxed at 68 ℃ for 4.8 hours, then the solvent is evaporated under reduced pressure and the crude product is purified by silica gel chromatography eluting with PE/EA (V: V ═ 5:1) to give methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate;
synthesis of vorinostat derivatives: adding a methanol solution of sodium methoxide to a methanol solution of hydroxylamine hydrochloride, stirring for 11 minutes, filtering out NaCl, adding the synthetic methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate to the filtrate, stirring the resulting mixture at 26 ℃ for 4.5 hours, then removing the solvent under reduced pressure, dissolving the product in ethanol, then adding oxalic acid to the solution, then filtering the precipitate and crystallizing from water to obtain the vorinostat derivative.
Example 6
The preparation method of the diagnosis and treatment integrated compound comprises the following steps: synthesis of Boc-2,3, 5-triiodobenzoic acid: 4mmol of 2,3, 5-triiodobenzoic acid were dissolved in 40mL of t-BuOH. 4.8mmol of DPPA and 4.8mmol of TEA are then added and the mixture is stirred at 90 ℃ for 2 hours under a nitrogen atmosphere, the solvent is then removed from the mixture under reduced pressure, the residue is dissolved in 30mL of DCM and saturated NaHCO is used3Washing to obtain an organic phase, and then using anhydrous Na for the organic phase2SO4Drying and then concentrating the organic phase and purifying the residue by silica gel column chromatography eluting with PE/EA (V: V ═ 10:1) to give Boc-2,3, 5-triiodobenzoic acid;
synthesizing 2,3, 5-triiodoaniline: 1mmol of Boc-2,3, 5-triiodobenzoic acid was dissolved in 5ml of CH2Cl2In solution, to Boc-2,3, 5-triiodobenzoic acid CH at 0 deg.C2Cl2After consumption of starting material, the mixture was evaporated and then saturated NaHCO was added3Aqueous solution, organic layer washed with brine and anhydrous Na2SO4Drying and purifying the crude product by silica gel chromatography eluting with PE/EA (V: V ═ 5:1) to give 2,3, 5-triiodoaniline;
synthesis of methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate: 2ml of oxalyl chloride was added dropwise to anhydrous 15ml of CH2Cl2Is stirred for 12h, then the solvent and excess oxalyl chloride are evaporated under reduced pressure and then CHCl is added3Then 1mmol of 2,3, 5-triiodoaniline and triethylamine are added and refluxed at 65 ℃ for 4.5 hours, then the solvent is evaporated under reduced pressure and the crude product is purified by chromatography on silica gel eluting with PE/EA (V: V ═ 5:1) to give methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate;
synthesis of vorinostat derivatives: 6mmol of sodium methoxide in 5ml of methanol is added to 4mmol of hydroxylamine hydrochloride in 8ml of methanol, stirring is carried out for 10 minutes, NaCl is filtered off, methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate, which is synthesized in 1mmol, is added to the filtrate, the mixture obtained is stirred at 23-27 ℃ for 4 hours, the solvent is then removed under reduced pressure, the product is dissolved in 10ml of ethanol, 4mmol of oxalic acid are then added to the solution, and the precipitate is filtered off and crystallized from water to give the vorinostat derivative.
Test example 1: CT in vitro imaging
The objective vorinostat derivatives (0.12mol/L,0.06mol/L,0.03mol/L,0.015mol/L) with different concentrations were prepared in 2ml Eppendorf tubes and placed in a self-designed gantry together with water and empty tubes, and then scanned by 16-layer spiral CT (GE corporation, usa). All scans were done with the following parameters: tube voltage: 100 KV; tube current: 80 mA; layer thickness: 1.25 mm; pitch: 0.562:1. The X-ray in-vitro imaging of vorinostat derivatives with different concentrations, water and empty tubes is shown in figure 1, and the CT values of vorinostat derivatives with different concentrations are shown in figure 2.
From the above experimental results, it can be known that: the vorinostat derivative has better X-ray blocking capacity, which indicates that the vorinostat derivative can be used as a CT contrast agent, and the capacity of the vorinostat derivative is increased along with the increase of concentration and shows a linear increasing trend.
Test example 2: cytotoxicity assays
The compound of interest was dissolved in DMSO and evaluated in 5 human cancer cells (MGC-803, U973, SK-OV-3, T-24, A549) and normal human hepatocyte HL-7702, respectively, growth in each well of a 96-well plate was about 1.0 × 10 at log phase5Individual cells/mL cells, and at 5% CO2Incubated at 37 ℃ for 12 hours. Five different concentrations (2.5, 5,10, 20 and 50 μ M) of test compound were also added to the test wells, and the cells were then incubated at 5% CO2Incubate at 37 ℃ for 48 hours in an atmosphere. The absorbance measured at 570/630nm at two wavelengths was read using an enzyme-labeled instrument. Cytotoxicity was detected as a percentage of cell survival compared to the negative control. Final IC50Values were calculated by the Bliss method (n ═ 5). All tests were repeated three times. IC of vorinostat derivatives and vorinostat on five selected tumor cell lines and human normal cells for 48h, respectively50Values, experimental results are shown in the following table:
from the above results, it can be seen that: vorinostat derivatives have similar anti-tumor activity compared to the marketed drug vorinostat, and are also less toxic to normal cells.
Test example 3: HDAC inhibitory activity:
HDAC3/6 inhibition biological activity verification A proper amount of vorinostat derivative and vorinostat are weighed and dissolved into 1 mmol.L by DMSO1mL respectively-1And (4) mother liquor. 200. mu.L of each mother liquor was taken and 200. mu.L of DMSO was added to prepare a mixture having a concentration of 500. mu. mol. L-1The solution of (4) is ready for use. Separately adding 100 μ L of each mother liquor into 900 μ L of DMSO to obtain 100 μmol/L-1The solution of (4) is ready for use. The small molecule solutions to be tested with 2 concentrations were diluted 4-fold with buffer in the kit, while the TSA solution was diluted 10-fold. Blank wells (containing no HDAC and no sample to be tested) and enzyme wells (containing HDAC and no sample to be tested) were set according to the instructions. And (4) detecting the fluorescence intensity by using a microplate reader. REG，RS，RECRespectively representing the fluorescence intensity of a blank well, a sample well to be tested, a TSA well or an enzyme well. Calculating the inhibition rate of the samples to be detected with different concentrations on HDAC3 and HDAC6, wherein the calculation formula is that the inhibition rate is (R)EC-RS)/(REC-REG) × 100%. vorinostat derivatives and IC of vorinostat for HDAC3, HDAC650The values are shown in the following table:
from the above results, it can be seen that: the vorinostat derivative has similar HDAC3 and HDAC6 inhibitory activities compared with the marketed drug vorinostat.
Test example 4: western Blot assay HDAC inhibitory activity:
expression levels of the known substrates, acetylhistone 3(AcH3) and acetyl- α -tubulin (AcTub), for HDAC3 and HDAC6 in U973 cells were measured using Western Blot expression levels of the known substrates, acetyl- α -tubulin (AcTub), for AcH3 and HDAC6 in U973 cells were measured using Western BlotCulturing, adding vorinostat derivative and vorinostat at the given concentrations (5,10 and 20 μ M) and 15 μ M thereto, and culturing in a suitable medium at 5% CO2And incubating the mixture at 37 ℃ for 24 hours. After 24 hours of incubation, cells were harvested by centrifugation and washed twice with ice-cold PBS buffer. The pellet was then resuspended in lysis buffer. After the cells were lysed on ice for 30 minutes, the lysate was centrifuged at 4 ℃ for 5 minutes using a centrifuge 12000 r/min. The protein concentration in the supernatant was checked using BCA protein assay reagent (Imgenex, USA). Equal amounts of protein per row were separated on 12% SDS polyacrylamide gel electrophoresis and transferred to PVDF Hybond-P membrane (GE Healthcare). The membrane was incubated with 5% skim milk in Tris salt buffer with Tween 20(TBST) buffer for 1 hour, then gently spun at 4 ℃ overnight. The membrane was then incubated with a primary antibody against AcH3, AcTub overnight at 4 ℃. The membranes were then incubated with peroxidase-labeled secondary antibodies for 2 hours, then all membranes were washed three times for 15 minutes with TBST buffer and western blots were detected with chemiluminescent reagent (Thermo fischer sciences Ltd.). The results are shown in FIG. 3.
From the above experimental results, it can be known that: the action of the vorinostat derivative on U973 cells up-regulates the levels of AcH3 and AcTub, which indicates that the vorinostat derivative can inhibit the activity of HDAC 3/6.
In summary, the diagnosis and treatment integrated compound, the preparation method and the application thereof provided by the embodiment of the invention at least have the following beneficial effects:
in a first aspect, embodiments of the present invention provide a medicinally useful compound, which is a vorinostat derivative obtained by introducing at least one iodine atom into the benzene ring of vorinostat.
Because iodine atoms have good X-ray blocking ability, iodinated compounds such as iodobenzyl alcohol, iohexol, iodixanol, and sodium diatrizoate are used for CT imaging, and there are many reports of probes based on these iodinated compounds, but when a contrast agent is linked to a drug molecule through a covalent bond, it more or less reduces the drug activity; on the other hand, vorinostat is used for treating T cell lymphoma, because vorinostat has a cap group, and introduction of an iodine atom into the cap group of vorinostat can attenuate X-rays as a CT contrast agent and maintain the binding activity of vorinostat to HDAC (as an HDAC inhibitor), so that such vorinostat derivatives have a diagnosis and treatment integrated function.
In a second aspect, an embodiment of the present invention further provides a method for preparing the diagnosis and treatment integrated compound, including the following steps: synthesis of Boc-2,3, 5-triiodobenzoic acid: 2,3, 5-triiodobenzoic acid was dissolved in t-BuOH. DPPA and TEA were then added and the mixture was stirred at 85-95 ℃ for 1.5-2.5 hours under a nitrogen atmosphere, then the solvent was removed from the mixture under reduced pressure, the residue was dissolved in DCM and saturated NaHCO was used3Washing to obtain an organic phase, and then using anhydrous Na for the organic phase2SO4Drying, concentrating the organic phase, purifying the residue by silica gel column chromatography, eluting with PE/EA to obtain Boc-2,3, 5-triiodobenzoic acid; synthesizing 2,3, 5-triiodoaniline: dissolving Boc-2,3, 5-triiodobenzoic acid in CH2Cl2In solution, to Boc-2,3, 5-triiodobenzoic acid CH at-5-5 deg.C2Cl2TFA was added to the solution and after consumption of starting material, the mixture was evaporated and then saturated NaHCO was added3Aqueous solution, organic layer washed with brine and anhydrous Na2SO4Drying and purifying the crude product by silica gel chromatography eluting with PE/EA to give 2,3, 5-triiodoaniline; synthesis of methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate: oxalyl chloride is dropped into monomethyl suberate in anhydrous CH at-5-5 DEG C2Cl2Is stirred for 11-13h, then the solvent and excess oxalyl chloride are evaporated under reduced pressure and then CHCl is added3Then adding 2,3, 5-triiodoaniline and triethylamine, refluxing for 4-5 hours at 60-70 ℃, then evaporating the solvent under reduced pressure, and purifying the crude product by silica gel chromatography, eluting with PE/EA to obtain 8-oxo-8- ((2,3, 5-triiodophenyl) amino) methyl octanoate; synthesis of vorinostat derivatives: adding methanol solution of sodium methoxide into methanol solution of hydroxylamine hydrochloride, stirring for 8-12 min, filtering to remove NaCl, adding synthetic 8-oxo-8- ((2,3, 5-triiodophenyl) amino) methyl octanoate into filtrate, and mixing the obtained solutionThe mixture was stirred at 23-27 ℃ for 3-5 hours, then the solvent was removed under reduced pressure, the product was dissolved in ethanol, then oxalic acid was added to the solution, then the precipitate was filtered and crystallized from water to give the vorinostat derivative.
The preparation method is very simple and low in cost, and the vorinostat derivative prepared by the method can keep the original activity of vorinostat to the maximum extent and has the sensitive X-ray contrast activity.
In a third aspect, the embodiment of the invention also provides an application of the diagnosis and treatment integrated compound, and the diagnosis and treatment integrated compound is applied to an anti-tumor drug. The antitumor drug can be used for treating tumors, can also be used for diagnosis, and integrates diagnosis and treatment.
The embodiments described above are some, but not all embodiments of the invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Claims (10)
1. A diagnostically integrated compound, comprising: it is a vorinostat derivative by introducing at least one iodine atom on the phenyl ring of vorinostat.
2. The diagnostically integrated compound according to claim 1, wherein: the vorinostat derivative is prepared by introducing three iodine atoms into a benzene ring of vorinostat.
3. The diagnostically integrated compound according to claim 1, wherein: the molecular formula is as follows: c14H17I3N2O3。
4. The diagnostically integrated compound according to claim 1, wherein: the structural formula is as follows:
5. a process for the preparation of a diagnostically integrated compound according to any one of claims 1 to 4, characterized in that: the method comprises the following steps:
synthesis of Boc-2,3, 5-triiodobenzoic acid: 2,3, 5-triiodobenzoic acid was dissolved in t-BuOH. DPPA and TEA were then added and the mixture was stirred at 85-95 ℃ for 1.5-2.5 hours under a nitrogen atmosphere, then the solvent was removed from the mixture under reduced pressure, the residue was dissolved in DCM and saturated NaHCO was used3Washing to obtain an organic phase, and then using anhydrous Na for the organic phase2SO4Drying, concentrating the organic phase, purifying the residue by silica gel column chromatography, eluting with PE/EA to obtain Boc-2,3, 5-triiodobenzoic acid;
synthesizing 2,3, 5-triiodoaniline: dissolving Boc-2,3, 5-triiodobenzoic acid in CH2Cl2In solution, to Boc-2,3, 5-triiodobenzoic acid CH at-5-5 deg.C2Cl2TFA was added to the solution and after consumption of starting material, the mixture was evaporated and then saturated NaHCO was added3Aqueous solution, organic layer washed with brine and anhydrous Na2SO4Drying and purifying the crude product by silica gel chromatography eluting with PE/EA to give 2,3, 5-triiodoaniline;
synthesis of methyl 8-oxo-8- ((2,3, 5-triiodophenyl) amino) octanoate: oxalyl chloride is dropped into monomethyl suberate in anhydrous CH at-5-5 DEG C2Cl2Is stirred for 11-13h, then the solvent and excess oxalyl chloride are evaporated under reduced pressure and then CHCl is added3Then adding 2,3, 5-triiodoaniline and triethylamine, refluxing for 4-5 hours at 60-70 ℃, then evaporating the solvent under reduced pressure, and purifying the crude product by silica gel chromatography, eluting with PE/EA to obtain 8-oxo-8- ((2,3, 5-triiodophenyl) amino) methyl octanoate;
synthesis of vorinostat derivatives: adding a methanol solution of sodium methoxide into a methanol solution of hydroxylamine hydrochloride, stirring for 8-12 minutes, filtering out NaCl, adding the synthesized 8-oxo-8- ((2,3, 5-triiodophenyl) amino) methyl octanoate into the filtrate, stirring the obtained mixture at 23-27 ℃ for 3-5 hours, then removing the solvent under reduced pressure, dissolving the product in ethanol, then adding oxalic acid into the solution, then filtering the precipitate and crystallizing from water to obtain the vorinostat derivative.
6. The method of claim 5, wherein: in the process of synthesizing Boc-2,3, 5-triiodobenzoic acid, the volume ratio of PE/EA elution is 10: 1.
7. The method of claim 5, wherein: in the process of synthesizing the 2,3, 5-triiodoaniline, the volume ratio of the PE/EA elution is 5: 1.
8. The method of claim 5, wherein: in the process of synthesizing the 8-oxo-8- ((2,3, 5-triiodophenyl) amino) methyl caprylate, the volume ratio of PE/EA elution is 5: 1.
9. Use of a diagnostically integrated compound according to any one of claims 1 to 9, wherein: it can be used as antitumor drug.
10. Use according to claim 9, characterized in that: it is applied to tumor contrast agents.
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