CN113929652A - Sulfide-responsive self-releasing linker molecule - Google Patents

Sulfide-responsive self-releasing linker molecule Download PDF

Info

Publication number
CN113929652A
CN113929652A CN202010671832.1A CN202010671832A CN113929652A CN 113929652 A CN113929652 A CN 113929652A CN 202010671832 A CN202010671832 A CN 202010671832A CN 113929652 A CN113929652 A CN 113929652A
Authority
CN
China
Prior art keywords
bonds
compound
sulfide
sulfonamide
ester
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202010671832.1A
Other languages
Chinese (zh)
Inventor
董守良
刘正锟
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lanzhou University
Original Assignee
Lanzhou University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lanzhou University filed Critical Lanzhou University
Priority to CN202010671832.1A priority Critical patent/CN113929652A/en
Publication of CN113929652A publication Critical patent/CN113929652A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention discloses a self-releasing linker compound capable of being activated by in vivo sulfide, belonging to the technical field of medicinal chemical synthesis. The compound of the invention has preferential response capability to glutathione, and can be connected with carrier compounds such as drugs, cytotoxins, detection reagents, diagnostic reagents and the like and released in specific environments to achieve the effect of corresponding carrier compounds. The compounds of the present invention are useful for modification of prodrugs or incorporation into linker moieties of various conjugated drugs, which can be activated by in vivo sulfide and cleaved to release the carried carrier.

Description

Sulfide-responsive self-releasing linker molecule
Technical Field
The invention belongs to the technical field of medicinal chemical synthesis, and particularly relates to a special self-release linker compound structure, wherein the linker compound can be used for prodrug modification or is integrated into linker parts of various coupling drugs, and can be activated by sulfide in vivo and be broken to release a carried carrier.
Background
In humans, aberrant levels of biological thiols at focal sites make them important biomarkers and are widely used in drug design and release, tumor imaging, and diagnosis. The intracellular or extracellular sulfides such as glutathione, cysteine, homocysteine, hydrogen sulfide and the like in many types of cancer cells have higher concentrations than those in corresponding normal cells, and the method has very important application value in developing a drug precision delivery system (DDS) and a precision visualization diagnosis system. Many sulfide-activatable self-releasing response molecules have been designed and incorporated into prodrugs, conjugate drug molecules or diagnostic reagents to specifically release carrier molecules at the site of a lesion for therapeutic or diagnostic purposes. However, because of the large concentration difference of various sulfides in vivo, the contents of different sulfides in different parts are different. It is therefore important to develop a response molecule that is selective and can be preferentially activated by one sulfide and unaffected or less affected by other sulfides.
Disulfide self-releasing linkers (linkers) are the most studied and most widely used sulfide-responsive molecules currently in DDS, as well as in vivo sulfide probe development (see fig. 1). Early on, the antibody conjugated drug (ADC) and the design of a targeting diagnostic reagent are widely adopted, but the low stability and the selectivity to sulfide reduce the targeting of the drug. Researchers have developed various modifications to increase the stability and specificity of disulfide linkages, but at the same time have introduced more problems such as too high stability which increases the difficulty of cleaving the release vector, increasing the difficulty of synthesis and integration into ADC drugs. The release process is complicated and uncontrollable, the time and the difficulty of the controlled release of the medicament are increased, the unique bystander effect (bystander effect) of the ADC medicament is lost, the killing range of the medicament is reduced, and the like. In addition to disulfide bonds, the 2,4-dinitrobenzene sulfonate (2,4-dinitrobenzene sulfonate, DNBS) group is also a useful sulfide (GSH-based) responsive group, and DNBS is very reactive to the major sulfides in vivo, and is less selective and unstable than disulfide-based linkers, thus greatly limiting its application. Related reports are few, and the actual medicinal value is still to be improved.
The thiol-Michael addition reaction (thiol-Michael addition reaction) is an important organic chemical synthesis method, and the reaction is simple and rapid, has mild conditions, is suitable for various solvents, particularly aqueous solutions, and is therefore applied to material chemistry and biochemistry for a long time, but is less applied to design of sulfide-responsive self-release linker molecules. Only recently, almost concurrently with the work of this patent, Caixia Yin et al reported a self-releasing fluorescent imaging molecule based on thiol-chromene click chemistry (j.am. chem. soc.2020,142,1614-1620), but it did not have good selectivity for the three major sulfides, and was too sensitive and unstable in vivo, thus limiting its practical application.
Based on the Michael reaction of alpha, beta-unsaturated ketone and sulfhydryl, we designed and synthesized a self-releasing linker which can be activated by sulfide in vivo, and compared with other sulfides, the molecule can be preferentially activated by glutathione, and has very good selectivity. In addition, the molecule has a plurality of modifiable sites and a release cleavage site, and can form a prodrug compound activated by sulfide, especially glutathione, or a precise diagnostic system through coupling with a drug molecule or a diagnostic reagent. Or target molecules, such as antibody molecules, target small molecules, polypeptides and the like, can be integrated through the modification sites and then coupled with drug molecules or diagnostic reagents to form novel coupled drug molecules and target diagnostic molecules which can be activated by sulfides, particularly glutathione.
The invention discloses a novel sulfide-responsive self-releasing linker molecule which has excellent selectivity and stability and provides more choices for designing prodrug molecules, targeted coupled drug molecules and targeted diagnostic reagents.
Disclosure of Invention
Aiming at the defects of the in vivo sulfide response self-release linker which is reported and applied at present and mainly exists in a disulfide linker, the invention provides a novel sulfide response self-release compound which has preferential response capability to glutathione.
The invention provides a novel sulfide-responsive self-releasing compound, which has the molecular structural characteristics shown as a formula I:
Figure BDA0002582577900000021
in the structure of the compound I, n is an integer of 0-8.
In the structure of the compound I, R1 is a group which is independently optionally substituted on the benzene ring hydrogen at the position, and the group includes but is not limited to alkanyl, cycloalkyl, heterocycloalkyl, halohydrocarbon, alkene, alkyne, aromatic ring, heteroaromatic ring, halogen, nitro, hydroxyl, amino, sulfydryl, disulfide bond, alkoxy, amido, ester group and sulfonamide.
In the structure of the compound I, R2 is selected from the following groups: alkyl, cycloalkyl, heterocycloalkyl, halohydrocarbon, alkene, alkyne, aromatic, heteroaromatic, hydrogen, halogen, nitro, hydroxyl, amino, mercapto, alkoxy, amide, ester, sulfonamide;
the compound I has a structure in which X is selected from O, N and S, preferably O;
in the structure of the compound I, Y is a connecting group, and the group comprises any one of the following groups: hydroxyl, amino, mercapto, sulfonyl.
The invention also provides a compound which can be activated by in vivo sulfide, and the molecular structural characteristics of the compound are shown as the formula II:
Figure BDA0002582577900000031
in the structure of the compound II, n is an integer of 0-8.
In the structure of compound II, R1 is a group independently substituted at any position of benzene ring hydrogen, and the group includes but is not limited to alkanyl, cycloalkyl, heterocycloalkyl, halohydrocarbon, alkene, alkyne, aromatic ring, heteroaromatic ring, halogen, nitro, hydroxyl, amino, sulfhydryl, disulfide bond, alkoxy, amido, ester group, sulfonamide.
In the structure of the compound II, R2 is selected from the following groups: alkyl, cycloalkyl, heterocycloalkyl, halohydrocarbon, alkene, alkyne, aromatic, heteroaromatic, hydrogen, halogen, nitro, hydroxyl, amino, mercapto, alkoxy, amide, ester, sulfonamide;
in the structure of the compound II, X is selected from O, N and S; o is preferred.
In the structure of compound ii, Y' is a bond, which includes, but is not limited to: ether bonds, disulfide bonds, thioether bonds, carbamate bonds, carbonate bonds, ammonia bonds, primary amine bonds, quaternary ammonium bonds, amide bonds, ester bonds, sulfonamide bonds.
In the structure of compound ii, R3 is a carrier compound linked by a Y' bond that is ultimately released, including but not limited to: a drug, cytotoxin, detection reagent, diagnostic reagent, or targeting vector; further preferably, the drug is a cytotoxin, an antineoplastic drug, an antiviral drug or an anti-infective drug, a protein inhibitor, a DNA alkylating agent, a DNA chimericide, an enzyme inhibitor, an antimetabolite, a peptide or nucleotide, an anti-inflammatory drug molecule, and an autoimmune disease drug molecule; further preferably, the detection reagent is a fluorescent molecule, a light-absorbing molecule, or an isotopically labeled molecule. In certain embodiments, R3 is preferably a p-nitroaniline light signaling molecule; in certain embodiments, R3 is preferably an antineoplastic camptothecin molecule;
the invention provides a compound capable of being activated by in vivo sulfide, which has the molecular structural characteristics shown as a formula III:
Figure BDA0002582577900000032
compound iii structure wherein: n is 1, 2 or 3, preferably 1;
in the structure of the compound III, R1 is selected from one or any combination of the following groups: alkyl, cycloalkyl, heterocycloalkyl, halohydrocarbon, alkene, alkyne, aromatic, heteroaromatic, polyethylene glycol, halogen, nitro, hydroxyl, amino, mercapto, disulfide bond, alkoxy, amide, ester, sulfonamide;
in the structure of the compound III, X is selected from O, N and S, preferably O;
in the structure of the compound III, Y is the following group: hydroxy, amino, mercapto, sulfonyl;
the invention provides a compound capable of being activated by in vivo sulfide, which has the molecular structural characteristics shown as a formula IV:
Figure BDA0002582577900000041
compound iv in the structure, wherein: n is 1, 2 or 3, preferably 1;
in the structure of the compound IV, R1 is selected from one or any combination of the following groups: alkyl, cycloalkyl, heterocycloalkyl, halohydrocarbon, alkene, alkyne, aromatic, heteroaromatic, polyethylene glycol, halogen, nitro, hydroxyl, amino, mercapto, disulfide bond, alkoxy, amide, ester, sulfonamide;
in the structure of the compound IV, X is selected from O, N and S; preferably O;
in the structure of compound IV, Y' is a connecting bond, and the bond includes but is not limited to: ether bonds, disulfide bonds, thioether bonds, carbamate bonds, carbonate bonds, ammonia bonds, primary amine bonds, quaternary ammonium bonds, amide bonds, ester bonds, sulfonamide bonds.
In the structure of compound iv, R2 is a carrier compound linked by a Y' linkage and ultimately released, including but not limited to: a drug, cytotoxin, detection reagent, diagnostic reagent, or targeting vector; further preferably, the drug is a cytotoxin, an antineoplastic drug, an antiviral drug or an anti-infective drug, a protein inhibitor, a DNA alkylating agent, a DNA chimericide, an enzyme inhibitor, an antimetabolite, a peptide or nucleotide, an anti-inflammatory drug molecule, and an autoimmune disease drug molecule; further preferably, the detection reagent is a fluorescent molecule, a light-absorbing molecule, or an isotopically labeled molecule. In certain embodiments, R2 is preferably a p-nitroaniline light signaling molecule; in certain embodiments, R2 is preferably an antineoplastic camptothecin molecule;
the structural formula of the preferable linker of the invention is shown as formula TC 6:
Figure BDA0002582577900000042
the structural formula of the preferred compound of the invention is shown as formula TC 6-PNA:
Figure BDA0002582577900000051
the possible process of exciting and releasing the signal molecule p-nitroaniline by TC6-PNA in the presence of sulfide is shown in the following chart:
Figure BDA0002582577900000052
preferred compounds of the invention are of the formula:
Figure BDA0002582577900000053
drawings
FIG. 1 is a schematic diagram showing the application of disulfide bond type self-releasing linker in vector release and the release mechanism. X and Y are respectively O or N; n is 1, 2, or 3; r is a modifying group or a targeting group;
FIG. 2(A) is a graph showing the light absorption spectrum of 80mins for 10. mu.M TC6-PNA reacted with 100. mu.M Na 2S; (B) shown is a time plot of 10. mu.M TC6-PNA reacted with 100. mu.M GSH, Cys, Hcy and Na2S, respectively;
FIG. 3 shows the cytotoxicity test of TC6-CPT in Hela cells;
FIG. 4 shows the anti-tumor ability of TC6-CPT in mice: (A) tumor volume change in tumor-bearing mice during treatment; (B) is the body weight change of tumor-bearing mice during the treatment period.
Detailed description of the preferred embodiments
Embodiments of the present invention will now be described in detail with reference to the following examples, it being emphasized that those skilled in the art will understand that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. 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 commercially available.
Example 1 synthesis of molecule TC 6:
Figure BDA0002582577900000061
compound 1 (1-fold amount) and 2-cyclohexen-1-one (2-fold amount) were dissolved in 1/1(V/V) tetrahydrofuran/water solution, imidazole (1-fold amount) was added, and the reaction was carried out at room temperature for 72 hours. The reaction is observed on a TLC dot plate, and the reaction is generally not complete. After most of the raw materials are consumed, water is added for dilution, ethyl acetate is used for extraction, the organic phase is collected after being washed by brine, dried by anhydrous sodium sulfate, concentrated and purified by column chromatography silica gel column to obtain TC6, wherein the yield is 40%. The identification data for TC6 are as follows:1H NMR(600MHz,cdcl3)δ7.37(d,J＝2.3Hz,1H),6.95(d,J＝1.7Hz,1H),6.82(d,J＝1.6Hz,1H),4.98(ddd,J＝10.5,5.9,2.3Hz,1H),4.61(s,2H),3.89(s,3H),2.58(d,J＝16.1Hz,2H),2.43–2.34(m,1H),2.14–2.02(m,2H),1.69(dd,J＝24.0,12.1Hz,1H),1.29–1.21(m,1H).13C NMR(151MHz,cdcl3)δ197.52(s),147.85(s),144.30(s),134.61(s),131.50(s),130.50(s),122.52(s),119.94(s),113.41(s),74.97(s),64.78(s),56.11(s),38.75(s),29.58(s),17.87(s).ESI-MS:(C15H16O4) Calculated as 260.10, found M/z 261.11[ M + H ]]+。
Example 2 synthesis of molecule TC 6-PNA:
Figure BDA0002582577900000062
at room temperature, TC6(1 time) is dissolved in tetrahydrofuran, p-nitrobenzene isocyanate (1.5 times) is added, then DBTL (dibutyltin dilaurate) with a catalytic amount is added, the reaction is stopped after heating to 50 ℃ and reacting for one hour under the protection of nitrogen, then the reaction is stopped after concentration in a vacuum rotary evaporator, and a product TC6-PNA is obtained by purifying with a silica gel chromatographic column, wherein the yield is 67%, and the identification data of TC6-PNA are as follows:1H NMR(600MHz,dmso)δ10.45(s,1H),8.17(d,J＝9.2Hz,2H),7.67(d,J＝9.2Hz,2H),7.30(d,J＝2.0Hz,1H),7.12(d,J＝1.3Hz,1H),7.07(s,1H),5.07(s,2H),4.99–4.90(m,1H),3.77(s,3H),2.39(d,J＝5.5Hz,3H),1.91(dd,J＝22.0,11.6Hz,2H),1.66(dd,J＝21.5,10.6Hz,1H).13C NMR(151MHz,dmso)δ196.98(s),153.48(s),147.80(s),146.03(s),144.78(s),142.13(s),131.53(s),130.07(s),129.71(s),125.48(s),122.71(s),122.11(s),118.08(s),115.91(s),74.95(s),66.73(s),56.21(s),38.79(s),29.40(s),17.66(s).ESI-MS:(C22H20N2O7) Calculated as 424.13, found M/z 425.10[ M + H ]]+。
EXAMPLE 3 light absorption assay experiment demonstrating the Release Capacity of the molecule TC6-PNA in the Presence of sulfide
As shown in FIG. 2, we determined the reaction time curve of TC6-PNA and four sulfides (all 100 μ M) in 0-80mins, and since the reaction of TC6-PNA with sulfides is characterized by a rate-type of decreasing absorption at the left and increasing absorption at the right, we more accurately represent the reaction curve by the ratio of the absorption at 385nm at the right to the absorption at 325nm at the left, as shown in FIG. 2B, TC6-PNA clearly shows a more rapid reaction characteristic to GSH, the reaction is substantially complete and reaches equilibrium within half an hour, unlike the other three sulfides, and is not completely reacted even after 80 minutes (FIG. 2A shows that TC6-PNA and Na PNA are reacted with each other)2Time absorption spectrum of S reaction, it can be seen that the reaction is not complete), TC6-PNA shows higher reactivity to GSH, but at the same time has low reactivity to the other three sulfides, especially H2S is lower. And thus can exhibit better selectivity. The stability of TC6-PNA was also better (TC 6-PNA dot line graph in FIG. 2B). Therefore, TC6-PNA has more excellent reaction kinetics and better selectivity to GSH.
EXAMPLE 4 Synthesis of molecule TC6-CPT
Figure BDA0002582577900000071
Triphosgene (triphosgene) and DMAP (dimethylaminopyridine) were mixed in Dichloromethane (DCM) and stirred for half an hour at room temperature, then a solution of Camptothecin (CPT) in DCM was added dropwise and reacted for 3 hours at room temperature, then a solution of compound TC6 in dichloromethane was added dropwise and Diisopropylethylamine (DIEA) was added and reacted overnight. After the reaction is completed, ethyl acetate is added for dilutionThe reaction solution is washed once by water, saturated brine system is used for the first time, anhydrous sodium sulfate is dried, and the white solid product TC6-CPT is obtained by silica gel chromatographic column purification, wherein the yield is 60%. The identification data of TC6-CPT are as follows:1H NMR(600MHz,cdcl3)δ8.38(s,1H),8.20–8.14(m,1H),7.93(d,J＝8.2Hz,1H),7.86–7.79(m,1H),7.66(t,J＝8.1Hz,1H),7.26(s,1H),7.20(d,J＝9.5Hz,1H),6.88(d,J＝22.8Hz,1H),6.80(d,J＝8.9Hz,1H),5.70(d,J＝17.0Hz,1H),5.38(d,J＝17.0Hz,1H),5.30(s,2H),5.10–4.98(m,2H),4.87–4.72(m,1H),3.85(d,J＝16.3Hz,3H),2.47(d,J＝12.9Hz,2H),2.32–2.20(m,2H),2.19–2.08(m,1H),2.02(d,J＝16.9Hz,1H),1.95–1.83(m,1H),1.62–1.57(m,1H),0.99(t,J＝8.1Hz,3H).13C NMR(151MHz,cdcl3)δ196.93(s),167.28(s),157.22(s),153.61(s),152.22(s),148.87(s),147.87(d,J＝15.0Hz),146.41(s),145.74(s),145.18(d,J＝16.6Hz),131.14(s),130.91(d,J＝14.3Hz),130.66(s),130.46(d,J＝10.0Hz),129.78(d,J＝5.9Hz),128.48(d,J＝4.2Hz),128.25–127.97(m),122.55(s),121.82(s),120.20(s),114.63(s),95.86(s),78.05(s),74.92(s),70.12(s),67.02(s),56.14(s),49.99(s),38.60(s),31.89(s),29.66(s),17.76(s),7.59(s).ESI-MS:(C36H30N2O9) Calculated as 634.20, found M/z 635.20[ M + H ]]+。
EXAMPLE 4 intracellular antitumor Effect of the molecule TC6-CPT
The antineoplastic drug CPT is selected and is connected with the self-releasing molecule TC6 through a carbonic ester bond to form a CPT prodrug TC 6-CPT. The cytotoxicity of naked drug CPT, prodrug TC6-CPT and TC6 carrying no CPT on Hela cells is evaluated by a typical MTT method, as shown in figure 3, TC6-CPT shows similar cytotoxicity to the parent drug CPT, and the TC6-CPT can be successfully released in cells and acts on the cells, and the killing effect at high concentration exceeds that of the parent drug.
EXAMPLE 5 antitumor Effect of molecule TC6-CPT in mice
The in vivo anti-tumor experiment of TC6-CPT was performed in mice with HCC cells derived from mouse, the tumor-bearing mice were administered CPT and TC6-CPT via tail vein at 5mg/Kg body weight (the same molar amount of TC6-CPT and CPT), and PBS was injected into tail vein as control. Due to the death cases, 4 mice per group were counted by the last treatment. The results are shown in fig. 4A, where the tumor volume increase was significantly inhibited in the mice given TC6-CPT compared to the saline control group, which was significantly different from the TC6-CPT treated group at day 10 of treatment. And the TC6-CPT treatment group has a significant difference with the CPT treatment group in treatment effect. FIG. 4B is a graph of body weight change in tumor mice treated with TC6-CPT showing less toxicity than CPT.

Claims (9)

1. A self-releasing linker which can be activated by in vivo sulfide and has a molecular structure represented by formula I:
Figure FDA0002582577890000011
wherein: n is an integer of 0 to 8;
r1 is selected from any one of the following groups: alkyl, cycloalkyl, heterocycloalkyl, halohydrocarbon, alkene, alkyne, aromatic, heteroaromatic, hydrogen, halogen, nitro, hydroxyl, amino, mercapto, alkoxy, amide, ester, sulfonamide;
r2 is selected from any one of the following groups: alkyl, cycloalkyl, heterocycloalkyl, halohydrocarbon, alkene, alkyne, aromatic, heteroaromatic, hydrogen, halogen, nitro, hydroxyl, amino, mercapto, alkoxy, amide, ester, sulfonamide;
x is selected from any one of O, N and S;
y is selected from any one of the following groups: hydroxyl, amino, mercapto, sulfonyl.
2. A compound which can be activated by in vivo sulfide has a molecular structure shown in formula II:
Figure FDA0002582577890000012
wherein: n is an integer of 0 to 8;
r1 is selected from any one of the following groups: alkyl, cycloalkyl, heterocycloalkyl, halohydrocarbon, alkene, alkyne, aromatic, heteroaromatic, hydrogen, halogen, nitro, hydroxyl, amino, mercapto, alkoxy, amide, ester, sulfonamide;
r2 is selected from any one of the following groups: alkyl, cycloalkyl, heterocycloalkyl, halohydrocarbon, alkene, alkyne, aromatic, heteroaromatic, hydrogen, halogen, nitro, hydroxyl, amino, mercapto, alkoxy, amide, ester, sulfonamide;
x is selected from O, N, S;
y' is a bond selected from any one of the following: ether bonds, disulfide bonds, thioether bonds, carbamate bonds, carbonate bonds, ammonia bonds, primary amine bonds, quaternary ammonium bonds, amide bonds, ester bonds, sulfonamide bonds;
r3 is a carrier compound comprising: a drug, a cytotoxin, a detection reagent, a diagnostic reagent, or a targeting vector.
3. A self-releasing linker which can be activated by in vivo sulfide and has a molecular structure represented by formula III:
Figure FDA0002582577890000021
wherein: n is 1, 2 or 3;
r1 is selected from any one of the following groups: alkyl, cycloalkyl, heterocycloalkyl, halohydrocarbon, alkene, alkyne, aromatic, heteroaromatic, polyethylene glycol, halogen, nitro, hydroxyl, amino, mercapto, disulfide bond, alkoxy, amide, ester, sulfonamide;
x is selected from O, N, S;
y is selected from any one of the following groups: hydroxyl, amino, mercapto, sulfonyl.
4. A compound which can be activated by in vivo sulfide has a molecular structure shown in formula IV:
Figure FDA0002582577890000022
wherein: n is 1, 2 or 3;
r1 is selected from any one of the following groups: alkyl, cycloalkyl, heterocycloalkyl, halohydrocarbon, alkene, alkyne, aromatic, heteroaromatic, polyethylene glycol, halogen, nitro, hydroxyl, amino, mercapto, disulfide bond, alkoxy, amide, ester, sulfonamide;
x is selected from O, N, S;
y' is a bond selected from any one of the following: ether bonds, disulfide bonds, thioether bonds, carbamate bonds, carbonate bonds, ammonia bonds, primary amine bonds, quaternary ammonium bonds, amide bonds, ester bonds, sulfonamide bonds;
r2 is a carrier compound comprising: a drug, a cytotoxin, a detection reagent, a diagnostic reagent, or a targeting vector.
5. The connector of claim 3, wherein: the structural formula of the linker is shown as formula TC 6:
Figure FDA0002582577890000023
6. the compound of claim 4, wherein: the structural formula of the compound is shown as formula TC 6-PNA:
Figure FDA0002582577890000031
7. use of a compound according to claim 6 for the preparation of a diagnostic agent.
8. The compound of claim 4, wherein: the compound has a structural formula as follows:
Figure FDA0002582577890000032
9. the use of a compound according to claim 8 in the preparation of an anti-tumor medicament.
CN202010671832.1A 2020-07-14 2020-07-14 Sulfide-responsive self-releasing linker molecule Pending CN113929652A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010671832.1A CN113929652A (en) 2020-07-14 2020-07-14 Sulfide-responsive self-releasing linker molecule

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010671832.1A CN113929652A (en) 2020-07-14 2020-07-14 Sulfide-responsive self-releasing linker molecule

Publications (1)

Publication Number Publication Date
CN113929652A true CN113929652A (en) 2022-01-14

Family

ID=79273724

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010671832.1A Pending CN113929652A (en) 2020-07-14 2020-07-14 Sulfide-responsive self-releasing linker molecule

Country Status (1)

Country Link
CN (1) CN113929652A (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102323233A (en) * 2011-07-09 2012-01-18 山西大学 Reagent and method for detecting homocysteine (HCY)
KR20150104911A (en) * 2014-03-07 2015-09-16 고려대학교 산학협력단 A Prognostic Fluorescence Thiol-marker for Cancerous Biomatrices
CN111393430A (en) * 2020-03-17 2020-07-10 山西大学 Stemona alkaloid analog near-infrared fluorescent probe and preparation method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102323233A (en) * 2011-07-09 2012-01-18 山西大学 Reagent and method for detecting homocysteine (HCY)
KR20150104911A (en) * 2014-03-07 2015-09-16 고려대학교 산학협력단 A Prognostic Fluorescence Thiol-marker for Cancerous Biomatrices
CN111393430A (en) * 2020-03-17 2020-07-10 山西大学 Stemona alkaloid analog near-infrared fluorescent probe and preparation method thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
YUTAO YANG等: "Thiol−Chromene "Click" Reaction Triggered Self-Immolative for NIR Visualization of Thiol Flux in Physiology and Pathology of Living Cells and Mice", 《J. AM. CHEM. SOC》 *
ZHENGKUN LIU等: "Thiol-Michael addition based conjugate for glutathione activation and release", BIOORGANIC CHEMISTRY *

Similar Documents

Publication Publication Date Title
Cai et al. Synthesis and cytotoxicity of 5-fluorouracil/diazeniumdiolate conjugates
CA2627216C (en) Polynucleotide labelling reagent
EP2144633B1 (en) A system for delivering therapeutic agents into living cells and cells nuclei
WO1994005282A1 (en) Water soluble taxol derivatives
US8729009B2 (en) Lysine compounds and their use in site- and chemoselective modification of peptides and proteins
EP2484671A1 (en) Fluorescent molecule and method for detecting target nucleic acid
Gobbo et al. Synthesis of a toolbox of clickable rhodamine B derivatives
CN104877982A (en) Method and reagent for preparing peptide/protein conjugate
Forget et al. 3′-Oligonucleotides conjugation via chemoselective oxime bond formation
Wu et al. Design and synthesis of peptide conjugates of phosphoramide mustard as prodrugs activated by prostate-specific antigen
Deroo et al. Synthesis of an oxyamino-containing phenanthroline derivative for the efficient preparation of phenanthroline oligonucleotide oxime conjugates
CN113929652A (en) Sulfide-responsive self-releasing linker molecule
AU2006316903B8 (en) Polynucleotide labelling reagent
WO2013126034A1 (en) Synthesis of high purity dmt-c3-disulfide phosphoramidite
CN111362837A (en) NQO1 activated Combretastatin A4 prodrug and synthesis method and application thereof
CN114409563B (en) Linker for protein labeling and application thereof in biological medicine
AU2018305726A1 (en) Disulfide bond containing compounds and uses thereof
Mäntylä et al. Design, synthesis and in vitro evaluation of novel water-soluble prodrugs of buparvaquone
Kamimura et al. An effective method for the synthesis of the cap structure of eukaryotic messenger ribonucleic acids
JP2018039773A (en) Nitrogen-containing nine-membered cycloalkyne
Heredia-Moya et al. An improved synthesis of arsenic–biotin conjugates
CN107266407A (en) A kind of nitroreductase that responds kills photaesthesia targeting anti-tumor prodrug of tumour cell and preparation method and application
CN117343125B (en) Synthesis method of antibody-coupled drug linker
WO2023073966A1 (en) External stimulus-responsive click reaction technology
CN112979491B (en) Compound containing hydrogen peroxide/cathepsin L-responsive protective group and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20220114

WD01 Invention patent application deemed withdrawn after publication