CN114835759A - Melatonin-platinum (IV) -carbon nitrogen long-chain complex, preparation method and application thereof in tumor drugs - Google Patents
Melatonin-platinum (IV) -carbon nitrogen long-chain complex, preparation method and application thereof in tumor drugs Download PDFInfo
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- CN114835759A CN114835759A CN202210526985.6A CN202210526985A CN114835759A CN 114835759 A CN114835759 A CN 114835759A CN 202210526985 A CN202210526985 A CN 202210526985A CN 114835759 A CN114835759 A CN 114835759A
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Abstract
The invention discloses a melatonin-platinum (IV) -carbon nitrogen long-chain complex, a preparation method and application thereof in tumor drugs; melatonin is introduced into one side of an axial site of a Pt (IV) coordination center, and a carbon-nitrogen long chain is introduced into the other side of the axial site, so that the lipophilicity of the complex is improved; compared with unmodified platinum drugs, the traditional Chinese medicine has better tumor killing capability, improves cytotoxicity by tens of times compared with cisplatin, and has more obvious killing effect on sex hormone-related tumors such as ovarian cancer, cervical cancer and breast cancer cells; meanwhile, the melatonin has potential anti-tumor effect and reduces the drug resistance of cisplatin, and compared with a pure melatonin-platinum (IV) complex, the sustained-release effect of the melatonin is better. The medicine has simple synthesis process and low cost, greatly improves the curative effect of combined medication, has the advantages of good curative effect, small side effect and the like compared with the traditional bivalent platinum and similar tetravalent platinum medicines, and provides a new idea for the modification of tetravalent platinum.
Description
Technical Field
The invention belongs to the technical field of anti-cancer chemical drugs, and particularly relates to a melatonin-platinum (IV) -carbon-nitrogen long-chain complex, a preparation method and application thereof in tumor drugs.
Background
Cancer has now become a great threat to human health. The clinical existing cancer treatment means mainly comprise operations, radiotherapy and chemotherapy. Surgical resection can only be directed to a large concentrated area of tumor tissue, and complete eradication of cancer cells cannot be achieved. Radiotherapy has great locality in cancer treatment, is mainly suitable for residual cancer cell parts in the primary lesion excision process, metastatic lesions concentration or postoperative prevention, has a small application range and cannot realize whole-body control; meanwhile, the radiotherapy has certain damage to the skin, and radiation pneumonia and the like are easy to occur. Therefore, chemotherapy is still an important strategy for the current breast cancer comprehensive treatment, and the development of novel high-efficiency low-toxicity chemotherapy drugs with tumor multiple targeting is the key point of our main research.
Commonly used antineoplastic agents include: bioalkylating agents (nitrogen mustards); antimetabolites such as DNA synthase inhibitors (gemcitabine), thymidylate synthase inhibitors (pentafluorouracil); metal drugs (cisplatin, oxaliplatin, carboplatin); antibiotic drugs (bleomycin, doxorubicin); plant drugs (paclitaxel), etc. Among them, cisplatin is popular in the field of cancer chemotherapy because of its unique DNA targeting function, so that it occupies a first line for a long time and is once called "penicillin" in anticancer drugs. Unfortunately, in the long-term chemotherapy process, due to the problems of lack of selectivity of tumor cells, poor solubility and the like of the medicine, patients gradually suffer hepatotoxicity, ototoxicity, neurotoxicity, bone marrow suppression, common gastrointestinal reactions, hyperuricemia, hypomagnesium/calcium anemia, anaphylactoid reactions and the like; meanwhile, the problem of drug resistance inherent or acquired by the body further aggravates the occurrence of toxic and side effects. Therefore, the search for new development directions of platinum drugs is the focus of research.
In the recent development of platinum drug research, the tetravalent platinum pt (iv) structure stands out in numerous studies by virtue of its unique stability and superior plasticity. The Pt (IV) compound has higher d stability 6 The octahedron configuration reduces the reaction of platinum in a divalent state with in vivo nucleophiles such as glutathione, sulfur-containing protein and other biomolecules, and improves the condition of non-target inactivation of the drug. On the other hand, Pt (IV) maintains the coordination points of the equatorial positions of the original Pt (II), and simultaneously two axial positions are added to provide huge development space for subsequent chemical modification, and the Pt (IV) has outstanding effects on regulating the solubility of the drugs, improving the cell uptake way, improving the targeting property of the drugs, playing a synergistic effect, overcoming the drug resistance, reducing the toxic and side effects and the like. In addition, the axial ligand is utilized to connect the prodrug to structures such as tumor targeting active small molecules, a nano delivery system, a tracing system, optical/acoustic power and the like, so that the defect of combined administration in the traditional form caused by pharmacokinetic difference is avoided, the bioavailability is improved, the targeting property and the specificity are enhanced, and the like.
Melatonin (MT) is a hormone ubiquitous in organisms ranging from algae to humans, has been put on the market as a health product as early as 1993, and is once popular all over the world. MT is a hormone secretion from pineal bodies and is mainly used for regulating time rhythm response to darkness, and more data in recent years show that MT has the effects of resisting tumors and preventing tumors, has good treatment effects on various cancers such as breast cancer, prostatic cancer and the like, and especially can play a better anti-tumor effect when being used together with other anti-tumor drugs (such as cis-platinum, 5-FU and the like). Introducing melatonin molecules and carbon-nitrogen long-chain molecules into the axial position of Pt (IV) has the following advantages that 1) researches show that the melatonin has a potential anti-tumor effect, melatonin receptors have high expression characteristics in multiple cancer species, meanwhile, the melatonin can inhibit HIF-1 alpha and Stat3 which are high in expression at tumor positions, and the introduction of the melatonin can enable platinum medicines to have multiple targeting properties, so that the curative effect of the tumor medicines is greatly improved; 2) because the introduction of the carbon chain molecules increases the stability of the platinum drug, enhances the fat solubility and transmembrane capability of the Pt (IV) molecule, promotes the absorption of the platinum drug, improves the antitumor activity of the platinum drug, and has the effects of drug attenuation and slow release; 3) the endogenous drug which is approved by FDA and used for improving sleep does not cause harm to human body, has short half-life period in vivo, can be metabolized quickly, and has remarkably reduced drug toxicity by introducing Pt (IV).
The patent No. 2018115158228 previously filed by the present inventor discloses a structure in which a platinum (IV) coordination side or opposite sides are respectively connected to melatonin molecules, and it is proved that the anti-tumor effect is significantly improved compared to that of pure cisplatin, but the effect is more concentrated in duration.
Disclosure of Invention
In order to solve the technical problems, the invention provides a melatonin-platinum (IV) -carbon nitrogen long-chain complex, a preparation method and application thereof in tumor drugs. Based on the combined administration of Cisplatin (cissplatin, CDDP) and Melatonin (Melatonin, MT), a series of tetravalent platinum prodrug molecules related to Melatonin are designed and synthesized, and meanwhile, in order to improve the uptake and stability of pt (iv), fat chains with different lengths are introduced into the other axial hydroxyl group of platinum. The design of the novel melatonin-platinum (IV) -carbon nitrogen long-chain prodrug aims at reducing the toxic and side effect of the platinum drug and achieving the effect of cooperative sensitization.
The technical scheme adopted by the invention is as follows: a melatonin-platinum (IV) -carbon-nitrogen long-chain complex has platinum (IV) coordination center axially connected to melatonin molecule at one side and carbon-nitrogen long-chain group at the other side.
Preferably, as shown in formula 1:
wherein the content of the first and second substances,
R 1 is-C n H 2n N is an integer and 1. ltoreq. n.ltoreq.6, preferably-C n H 2n -is a linear group,
R 2 is-NH-C m H 2m+1 or-C m H 2m NO and 1. ltoreq. m.ltoreq.20, preferably-NH-C m H 2m+1 Is a straight chain group.
Preferably, n.ltoreq.2, -C n H 2n -is a linear group.
Preferably, m.ltoreq.17, preferably, 2. ltoreq. m.ltoreq.17, -NH-C m H 2m+1 Is a straight chain group.
Preferably, the compound is represented by any one of formulae 2 to 17:
the method for preparing the melatonin-platinum (IV) -carbon nitrogen long-chain complex comprises the following steps:
carrying out esterification reaction on a compound shown in a formula 21 and a compound shown in a formula 22 in the presence of a first condensing agent and a first acid-binding agent to obtain an intermediate compound shown in a formula 20;
carrying out esterification reaction on a compound of a formula 20 and a compound of a formula 23 to obtain the melatonin-platinum (IV) -carbon nitrogen long-chain complex;
wherein the content of the first and second substances,
preferably, the first and second liquid crystal display panels are,
is cisplatin, oxaliplatin or carboplatin;
R 1 is-C n H 2n N is an integer and 1. ltoreq. n.ltoreq.6, preferably-C n H 2n -is a linear group,
R 2 is-NH-C m H 2m+1 or-C m H 2m NO and 1. ltoreq. m.ltoreq.20, preferably-NH-C m H 2m+1 Is a straight chain group.
Preferably, the process for preparing the compound of formula 21 comprises:
carrying out acylation reaction on the melatonin as shown in the formula 24 and a compound (succinic anhydride or glutaric anhydride) as shown in the formula 25 in the presence of a second condensing agent and a second acid-binding agent to obtain a compound as shown in the formula 21;
preferably, the second condensing agent is DMAP; the second acid-binding agent is triethylamine.
Preferably, the first condensing agent is TBTU; the first acid-binding agent is triethylamine; the raw material ratio in the reaction is as follows: a compound of formula 21: a compound of formula 22: a first condensing agent: the first acid-binding agent is 1-1.2: 1: 1.2-2: 1.2-2;
preferably, the reaction is carried out under protection from light and inert gas.
Application of melatonin-platinum (IV) -carbon nitrogen long-chain complex in preparing antitumor drugs.
Preferably, the compound is used for preparing anti-ovarian cancer, cervical cancer, breast cancer, lung cancer, liver cancer and gastrointestinal cancer medicaments.
The invention has the advantages and positive effects that: melatonin-platinum (IV) -carbon-nitrogen long-chain complex for treating cancer, its cytotoxic IC 50 The value is tens of times lower than that of cisplatin, the cisplatin-containing compound has good anti-proliferation capacity on cancer cells, and particularly has more obvious killing capacity on breast cancer cells, cervical cancer cells and ovarian cancer cells; melatonin is an endogenous drug approved by FDA and used for improving sleep, does not cause harm to human bodies, has short half-life period in vivo and can be metabolized quickly; besides potential anti-tumor effect, melatonin has the effects of regulating biological rhythm, improving organism immunity, delaying aging, improving sleep and the like, can relieve the system toxicity caused by cisplatin and reduce the drug resistance of cisplatin;
introducing melatonin into a carboxyl at a secondary amine position through amidation reaction, and then introducing a carbon-nitrogen long chain into a tetravalent platinum intermediate through simple condensation and oxidation reaction; the design of the novel melatonin-platinum (IV) -carbon nitrogen long-chain prodrug aims to reduce the toxic and side effects of the platinum drug and achieve the effect of cooperative sensitization; the prodrug has simple synthesis process and low cost, greatly improves the curative effect of combined medication, has the advantages of good curative effect, small side effect and the like compared with the traditional bivalent platinum and similar tetravalent platinum medicaments, and provides a new idea for the modification of tetravalent platinum.
Drawings
FIG. 1 shows the intracellular release of Compound 7 of example nine;
FIG. 2 shows the body weight changes of mice in different administration groups in the tenth example;
FIG. 3 shows the tumor volume changes of mice of different administration groups in the example ten;
FIG. 4 is the final mouse tumor weight in the tenth example;
FIG. 5 shows the survival rate of mice in the different administration groups of the tenth example;
FIG. 6 is the distribution of the final Pt in each tissue in the tenth example;
FIG. 7 is a final picture of the tumor in the tenth example;
FIG. 8H & E staining of mouse kidney and tumor tissue.
Detailed Description
Embodiments of the present invention are described below with reference to the drawings.
The invention discloses a melatonin-platinum (IV) -carbon-nitrogen long-chain complex.A melatonin molecule is connected to one axial side of a platinum (IV) coordination center, and a carbon-nitrogen long-chain group is connected to the other axial side of the platinum (IV) coordination center to form a disubstituted tetravalent platinum complex; the long carbon nitrogen chain group is capable of binding to HSA. Melatonin is introduced into one side of an axial site of a Pt (IV) coordination center, so that the platinum medicine has multiple targeting properties, the anti-tumor curative effect is improved, and the medicine toxicity is reduced; and a carbon-nitrogen fatty chain capable of being combined with HSA is introduced to the other side, so that the platinum drug uptake is improved, and the drug stability is increased to achieve the effects of attenuation and slow release.
Compared with the unmodified platinum drug, the designed and synthesized novel anti-tumor melatonin-platinum (IV) -carbon nitrogen long-chain prodrug has better tumor killing capability and cytotoxicity IC 50 Compared with cisplatin, the value is improved by tens of times, and especially the killing effect on tumor ovarian cancer, cervical cancer and breast cancer cells related to sex hormone is more obvious. Besides the potential anti-tumor effect, the melatonin also has the effects of regulating biological rhythm, improving the immunity of the organism, delaying senility, improving sleep and the like, can relieve the systemic toxicity caused by the cisplatin and reduce the drug resistance of the cisplatin. In the invention, melatonin is subjected to amidation reaction to introduce carboxyl at a secondary amine position, and carbon-nitrogen long chain is introduced into a tetravalent platinum intermediate through simple condensation reaction to obtain the novel anti-tumor melatonin-platinum (IV) -carbon-nitrogen long chain prodrug. The novel medicament has simple synthesis process and low cost, greatly improves the curative effect of combined medication, has the advantages of good curative effect, small toxic and side effect and the like compared with the traditional bivalent platinum and similar tetravalent platinum medicaments, and provides a new thought for the modification of tetravalent platinum.
The melatonin-platinum (IV) -carbon-nitrogen long-chain complex is shown in a formula 1:
wherein the content of the first and second substances,
wherein, RR 1 is-C n H 2n -, n is an integer and n.gtoreq.1, preferably n.gtoreq.6, more preferably n.gtoreq.2, -C n H 2n The effect is better when the radical is a straight chain radical; r 2 is-NH-C m H 2m+1 or-C m H 2m O and m.gtoreq.1, preferably m.gtoreq.20, more preferably m.gtoreq.17, still more preferably 2. gtoreq.m.gtoreq.17, -NH-C m H 2m+1 It is more effective to be a straight chain group. In certain embodiments of the present invention, the compounds may be represented by any one of formulae 2-9:
the melatonin-platinum (IV) complex may be an intermediate, represented by the following formula 20:
wherein the content of the first and second substances,
wherein R is 1 is-C n H 2n -, n is an integer and n.gtoreq.1, preferably, n.ltoreq.6, more preferably, n.ltoreq.2; -C n H 2n -is a linear group.
The method for preparing the melatonin-platinum (IV) -carbon-nitrogen long-chain complex comprises the following specific steps:
carrying out esterification reaction on a compound shown in a formula 21 and a compound shown in a formula 22 in the presence of a first condensing agent and a first acid-binding agent to obtain an intermediate compound shown in a formula 20;
carrying out esterification reaction on a compound of a formula 20 and a compound of a formula 23 to obtain the melatonin-platinum (IV) -carbon nitrogen long-chain complex;
wherein the content of the first and second substances,
preferably, the first and second liquid crystal materials are,
is cisplatin, carboplatin, or oxaliplatin;
R 1 is-C n H 2n -, n is an integer and n.gtoreq.1, preferably, -C n H 2n -is a linear group; r 2 is-NH-C m H 2m+1 or-C m H 2m O, m are integers and m.gtoreq.1, preferably-NH-C m H 2m+1 Is a straight chain group.
Wherein the first condensing agent is TBTU, the first acid-binding agent is triethylamine, and the reaction comprises the following raw materials in proportion: a compound of formula 21: a compound of formula 22: a first condensing agent: the first acid-binding agent is 1-1.2: 1: 1.2-2: 1.2-2; the reaction is carried out under protection from light and inert gas.
Wherein, the preparation method of the compound of the formula 21 comprises the following steps:
carrying out acylation reaction on the melatonin as shown in the formula 24 and a compound (succinic anhydride or glutaric anhydride) as shown in the formula 25 in the presence of a second condensing agent and a second acid-binding agent to obtain a compound as shown in the formula 11;
wherein the second condensing agent is DMAP; the second acid-binding agent is triethylamine.
The melatonin-platinum (IV) -carbon nitrogen long-chain complex can be used for preparing antitumor drugs, such as drugs for resisting ovarian cancer, cervical cancer, breast cancer, lung cancer, liver cancer and gastrointestinal cancer; is especially suitable for sex hormone-related medicines for treating ovarian cancer, cervical cancer and breast cancer.
The present invention will be described with reference to specific examples, wherein the experimental methods without specific descriptions of the operation steps are performed according to the corresponding commercial specifications, and the instruments, reagents, and consumables used in the examples can be purchased from commercial companies without specific descriptions.
Example one
The structural formula of the melatonin-platinum (IV) -carbon-nitrogen long-chain complex a in the embodiment is as follows:
the synthetic route of the preparation method of the melatonin-platinum (IV) -carbon nitrogen long-chain complex is as follows:
Step 2, Melatonin (MT) reacts with succinic anhydride, and 4-Dimethylaminopyridine (DMAP) and triethylamine (Et) are added in the reaction 3 N), reacting for 48 hours at 50 ℃ under the protection of argon during the reaction process, concentrating the reaction liquid into oil, separating by a silica gel chromatographic column, and eluting dichloromethane and methanol to obtain milky white precipitate a 2.
And 4, dissolving the product a3 obtained in the step 3 in dry DMF, adding hexyl isocyanate, stirring at normal temperature for 5 hours, removing the DMF by using a rotary evaporator, adding a little DCM for dissolution, purifying the product by using silica gel column chromatography with DCM and MA in a ratio of 10:1 as a developing agent, finally concentrating to be oily, adding water to obtain a solid, and centrifuging to obtain a light yellow product a.
1 H NMR(400MHz,DMSO-d 6 ):δ8.21(d,J＝9.0Hz,1H),8.06(t,J＝5.6Hz, 1H),7.69(s,1H),7.14(d,J＝2.5Hz,1H),6.92(dd,J＝9.0,2.5Hz,1H),6.63(s,6H), 6.57(m,1H),3.81(s,3H),3.38(d,J＝7.2Hz,2H),3.11(t,J＝6.5Hz,2H),2.88(dd, J＝12.6,6.3Hz,2H),2.78(t,J＝7.1Hz,2H),2.72(t,J＝6.2Hz,2H),1.81(s,3H), 1.34(d,J＝8.2Hz,2H),1.26(s,6H),0.85(t,J＝6.8Hz,3H). 13 C NMR(101MHz, DMSO-d 6 ):δ179.48,170.43,169.20,163.85,155.80,131.39,129.82,123.56,119.07, 116.77,112.86,101.82,55.32,40.95,38.17,31.10,30.74,29.78,26.09,24.79,22.67, 22.09,13.94.HR-MS calcd for C 24 H 39 Cl 2 N 5 O 7 Pt(M+H) + ,775.5880；found: 776.1926.
Example two
The structural formula of the melatonin-platinum (IV) -carbon-nitrogen long-chain complex b in the embodiment is as follows:
the route is as follows:
Step 2, Melatonin (MT) reacts with glutaric anhydride, and 4-Dimethylaminopyridine (DMAP) and triethylamine (Et) are added in the reaction 3 N), reacting for 48 hours at 50 ℃ under the protection of argon in the reaction process, concentrating the reaction liquid into oil, separating by a silica gel chromatographic column, and eluting dichloromethane and methanol to obtain milky white precipitate b 2.
And 4, dissolving the product b3 obtained in the step 3 in dry DMF, adding hexyl isocyanate, stirring at normal temperature for 5 hours, removing the DMF by using a rotary evaporator, adding a little DCM for dissolution, purifying the product by using silica gel column chromatography with the ratio of DCM to MA being 10:1 as a developing agent, finally concentrating the product to be oily, adding water to obtain a solid, and centrifuging to obtain a light yellow product b.
1 H NMR(400MHz,DMSO-d 6 ):δ8.22(d,J＝8.9Hz,1H),8.04(t,J＝5.2Hz, 1H),7.69(s,1H),7.14(d,J＝1.9Hz,1H),6.92(dd,J＝8.9,2.0Hz,1H),6.67(s,6H), 6.53(s,1H),3.81(s,3H),3.39(s,2H),3.02(t,J＝7.1Hz,2H),2.89(d,J＝5.1Hz, 2H),2.78(t,J＝7.0Hz,2H),2.37(t,J＝6.6Hz,2H),1.92–1.83(m,2H),1.82(s, 3H),1.35(d,J＝5.9Hz,2H),1.23(s,6H),0.86(t,J＝6.6Hz,3H). 13 C NMR(101 MHz,DMSO-d 6 ):δ179.99,171.21,169.23,163.99,155.79,131.39,129.74,123.84, 118.91,116.71,112.86,101.83,55.32,40.95,38.25,34.53,33.99,31.10,29.78,26.09, 24.81,22.69,22.09,20.74,13.95.HR-MS calcd for C 25 H 41 Cl 2 N 5 O 7 Pt(M+H)+, 790.6150；found:790.2081.
EXAMPLE III
The structural formula of the melatonin-platinum (IV) -carbon-nitrogen long-chain complex c in the embodiment is as follows:
the synthetic route of the preparation method of the melatonin-platinum (IV) -carbon nitrogen long-chain complex is as follows:
Step 2, Melatonin (MT) reacts with succinic anhydride, and 4-Dimethylaminopyridine (DMAP) and triethylamine (Et) are added in the reaction 3 N), reacting for 48 hours at 50 ℃ under the protection of argon in the reaction process, concentrating the reaction liquid into oil, separating by a silica gel chromatographic column, and eluting dichloromethane and methanol to obtain milky white precipitate c 2.
And 4, dissolving the product c3 obtained in the step 3 in dry DMF, adding dodecyl isocyanate, stirring at normal temperature for 24h, removing the DMF by using a rotary evaporator, adding a little DCM for dissolution, purifying the product by using silica gel column chromatography with the ratio of DCM to MA being 10:1 as a developing agent, finally concentrating the product into oil, adding water to obtain a solid, and centrifuging to obtain a light yellow product c.
1 H-NMR(400MHz,DMSO-d 6 ):δ(ppm)＝9.65(d,J＝85.5Hz,1H),8.72(s, 1H),8.34-7.93(m,4H),7.70(s,1H),7.14(d,J＝2.1Hz,1H),6.90(dd,J＝9.0,2.2 Hz,1H),6.77(t,J＝5.2Hz,1H),3.81(s,3H),3.40-3.35(m,2H),2.95-2.82(m,2H), 2.78(t,J＝7.1Hz,2H),2.74-2.67(m,2H),2.11(d,J＝0.5Hz,2H),1.81(s,3H), 1.62-1.06(m,28H),0.85(t,J＝6.6Hz,3H). 13 C-NMR(101MHz,DMSO-d 6 ):δ(ppm) ＝170.31,169.30,164.03,163.04,155.70,131.58,129.99,123.71,118.96,116.36, 112.70,101.68,55.30,40.75,38.15,31.26,30.78,29.61,29.05,26.26,24.80,23.38, 22.65,22.05,13.90.
Example four
The structural formula of the melatonin-platinum (IV) -carbon-nitrogen long-chain complex d in the embodiment is as follows:
the synthetic route of the preparation method of the melatonin-platinum (IV) -carbon nitrogen long-chain complex is as follows:
Step 2, Melatonin (MT) reacts with glutaric anhydride, and 4-Dimethylaminopyridine (DMAP) and triethylamine (Et) are added in the reaction 3 N), under the protection of argon gas in the reaction process, reacting for 48 hours at the reaction temperature of 50 ℃, concentrating the reaction liquid into oil, and separating by a silica gel chromatographic column, wherein the eluent is dichloromethane and methanol to obtain milky white precipitate d 2.
And 4, dissolving the product d3 obtained in the step 3 in dry DMF, adding dodecyl isocyanate, stirring at normal temperature for 24h, removing the DMF by using a rotary evaporator, adding a little DCM for dissolution, purifying the product by using silica gel column chromatography, taking DCM and MA in a ratio of 10:1 as a developing agent, concentrating the product into oil, adding water to obtain a solid, and centrifuging to obtain a light yellow product d.
1 H-NMR(400MHz,DMSO-d 6 ):δ(ppm)＝9.77(d,J＝85.9Hz,1H),8.63(s, 1H),8.18(dd,J＝57.4,48.7Hz,4H),7.64(s,1H),7.14(s,1H),6.92(d,J＝8.4Hz, 1H),6.84-6.64(m,1H),3.81(s,3H),3.37(s,2H),3.05-2.71(m,6H),2.12(d,J＝ 9.6Hz,2H),1.94-1.83(m,2H),1.81(s,3H),1.68-0.93(m,28H),0.84(d,J＝6.3Hz, 3H). 13 C-NMR(101MHz,DMSO-d 6 ):δ(ppm)＝179.82,170.48,169.18,163.48, 155.84,131.31,129.78,123.58,118.96,116.61,112.87,101.82,54.92,38.17,33.82, 31.26,29.05,28.68,26.25,24.78,23.40,22.64,22.06,20.44,13.92.
EXAMPLE five
The structural formula of the melatonin-platinum (IV) -carbon-nitrogen long-chain complex e in the embodiment is as follows:
the synthetic route of the preparation method of the melatonin-platinum (IV) -carbon nitrogen long-chain complex is as follows:
Step 2, Melatonin (MT) reacts with glutaric anhydride, and 4-Dimethylaminopyridine (DMAP) and triethylamine (Et) are added in the reaction 3 N), reacting for 48 hours at 50 ℃ under the protection of argon in the reaction process, concentrating the reaction liquid into oil, separating by a silica gel chromatographic column, and eluting dichloromethane and methanol to obtain milky white precipitate e 2.
Step 3Mixing the product e2 obtained in the step 2 with dried dimethyl sulfoxide (DMSO), adding o-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU), activating for a period of time, and adding Et 3 And (2) reacting the N with the product a1(Oxoplatin) in the step 1 at normal temperature for 24 hours, adding ethanol, precipitating with ether, drying, and further purifying by a silica gel chromatographic column, wherein the eluent is dichloromethane and methanol to obtain a light yellow precipitate e 3.
Step 4, e4 (5-aminolevulinic acid methyl ester hydrochloride) was mixed with DMF and Boc anhydride and Et were added 3 Activating at 0 ℃ for 2h, and then reacting at normal temperature for 12h to obtain a reaction solution which is a yellow suspension. The reaction solution was extracted with ethyl acetate and spin-dried to give e 5. E5 and THF are mixed, LiOH solution is slowly added dropwise, and reaction is carried out for 3 hours at normal temperature. The reaction solution was extracted with ethyl acetate, which was further purified by silica gel column chromatography eluting with dichloromethane and methanol to give e 6.
And 5, dissolving the product e3 in the step 3 in dry DMF, adding the product e6 in the step 4, stirring at normal temperature for 24 hours, removing the DMF by using a rotary evaporator, adding a little DCM for dissolving, purifying the product by using silica gel column chromatography, taking PE and EA in a ratio of 1:2 as a developing agent, concentrating the product into oil, adding water to obtain a solid, and centrifuging to obtain a light yellow product e.
1 H-NMR(400MHz,DMSO-d6):δ(ppm)＝8.21(d,J＝8.9Hz,1H),8.05(s,3H), 7.69(s,1H),7.15(s,1H),6.92(d,J＝8.3Hz,1H),6.50(s,6H),3.99(s,2H),3.81(s, 3H),3.11(d,J＝5.9Hz,4H),2.77(dd,J＝16.1,7.0Hz,4H),2.62(d,J＝5.6Hz,2H), 2.57(d,J＝5.6Hz,2H),1.82(s,3H). 13 C-NMR(101MHz,DMSO-d6):δ(ppm)＝ 203.25,179.41,179.15,170.33,169.21,155.83,131.40,129.76,123.54,119.10, 116.69,112.87,101.77,55.25,46.99,45.68,38.18,35.24,30.67,29.31,22.66.
EXAMPLE six
The structural formula of the melatonin-platinum (IV) -carbon-nitrogen long-chain complex f in the embodiment is as follows:
the synthetic route of the preparation method of the melatonin-platinum (IV) -carbon nitrogen long-chain complex is as follows:
Step 2, Melatonin (MT) reacts with glutaric anhydride, and 4-Dimethylaminopyridine (DMAP) and triethylamine (Et) are added in the reaction 3 N), reacting for 48 hours at 50 ℃ under the protection of argon in the reaction process, concentrating the reaction liquid into oil, separating by a silica gel chromatographic column, and eluting dichloromethane and methanol to obtain milky white precipitate f 2.
Step 4, f4 (5-aminolevulinic acid methyl ester hydrochloride) was mixed with DMF and Boc anhydride and Et were added 3 Activating at 0 ℃ for 2h, and then reacting at normal temperature for 12h to obtain a reaction solution which is a yellow suspension. The reaction solution was extracted with ethyl acetate and spin-dried to give f 5. F5 and THF are mixed, LiOH solution is slowly added dropwise, and reaction is carried out for 3 hours at normal temperature. Extracting the reaction solution with ethyl acetate, spin-drying the ethyl acetate, and further purifying by a silica gel chromatographic column to obtain the eluent, namely dichloromethane and methanol, and spin-drying to obtain f 6.
And 5, dissolving the product f3 in the step 3 in dry DMF, adding the product f6 in the step 4, stirring at normal temperature for 24 hours, removing the DMF by using a rotary evaporator, adding a little DCM for dissolving, purifying the product by using silica gel column chromatography, taking PE and EA in a ratio of 1:2 as a developing agent, concentrating the product into oil, adding water to obtain a solid, and centrifuging to obtain a light yellow product.
1 H-NMR(400MHz,DMSO-d6):δ(ppm)＝8.22(d,J＝8.9Hz,1H),8.05(d,J＝ 9.6Hz,3H),7.67(s,1H),7.14(d,J＝2.3Hz,1H),6.92(dd,J＝9.0,2.3Hz,1H), 6.53(s,6H),4.00(d,J＝4.7Hz,2H),3.81(s,3H),3.02(t,J＝7.2Hz,2H),2.78(t,J ＝7.4Hz,2H),2.63(t,J＝5.9Hz,2H),2.61-2.51(m,4H),2.38(t,J＝7.0Hz,2H), 1.88(dd,J＝15.7,8.6Hz,2H),1.82(s,3H). 13 C-NMR(101MHz,DMSO-d6):δ(ppm) ＝203.46,179.79,178.94,170.82,168.99,155.50,131.27,129.61,123.46,118.61, 116.44,112.67,101.88,55.25,46.91,45.58,38.26,35.35,33.70,29.37,24.56,22.36, 20.48.
EXAMPLE seven
A novel antitumor prodrug melatonin-platinum (IV) -carbon nitrogen long-chain complex 1-8 is characterized by comprising the following specific synthesis steps:
(1) synthesis of Compound 1 Compound a3 was reacted with hexyl isocyanate, in analogy to the first and second steps of the above example, yielding 35mg (56.5%). 1 H NMR(400MHz,DMSO-d 6 ):δ8.21(d,J＝9.0Hz,1H),8.06 (t,J＝5.6Hz,1H),7.69(s,1H),7.14(d,J＝2.5Hz,1H),6.92(dd,J＝9.0,2.5Hz, 1H),6.63(s,6H),6.57(m,1H),3.81(s,3H),3.38(d,J＝7.2Hz,2H),3.11(t,J＝6.5 Hz,2H),2.88(dd,J＝12.6,6.3Hz,2H),2.78(t,J＝7.1Hz,2H),2.72(t,J＝6.2Hz, 2H),1.81(s,3H),1.34(d,J＝8.2Hz,2H),1.26(s,6H),0.85(t,J＝6.8Hz,3H). 13 C NMR(101MHz,DMSO-d 6 ):δ179.48,170.43,169.20,163.85,155.80,131.39, 129.82,123.56,119.07,116.77,112.86,101.82,55.32,40.95,38.17,31.10,30.74, 29.78,26.09,24.79,22.67,22.09,13.94.HR-MS calcd for C 24 H 39 Cl 2 N 5 O 7 Pt(M+H) + , 775.5880；found:776.1926.
(2) Synthesis of Compound 2 Compound a3 was reacted with octyl isocyanate, in analogy to example one, two steps above, to yield 29.8mg (46.4%). 1 H NMR(400MHz,DMSO-d 6 ):δ8.21(d,J＝8.9Hz,1H), 8.05(s,1H),7.69(s,1H),7.14(s,1H),6.92(d,J＝8.3Hz,1H),6.63(s,6H),6.56(m, 1H),3.81(s,3H),3.36(s,2H),3.12(s,2H),2.88(d,J＝5.3Hz,2H),2.78(t,J＝6.5 Hz,2H),2.73(s,2H),1.82(s,3H),1.33(s,2H),1.23(s,10H),0.85(d,J＝6.4Hz, 3H). 13 C NMR(101MHz,DMSO-d 6 ):δ179.48,170.42,169.20,163.86,155.80, 131.39,129.82,123.56,119.07,116.76,112.86,101.82,55.32,40.96,38.17,31.25, 30.75,29.83,28.78,28.71,26.44,24.79,22.67,22.09,13.95.HR-MS(m/s):calcd for C 26 H 43 Cl 2 N 5 O 7 Pt(M+H) + ,803.6420；found:804.2245.
(3) Synthesis of Compound 3 in analogy to the example one, two steps above, Compound a3 was reacted with dodecyl isocyanate, yielding 33mg (48.1%). 1 H NMR(400MHz,DMSO-d 6 ):δ8.21(d,J＝8.9Hz, 1H),8.05(s,1H),7.69(s,1H),7.14(s,1H),6.92(dd,1H),6.63(s,6H),6.56(m,1H), 3.81(s,3H),3.37(s,2H),3.12(s,2H),2.88(d,J＝4.9Hz,2H),2.79(t,J＝6.5Hz, 2H),2.73(s,2H),1.82(s,3H),1.33(s,2H),1.23(s,18H),0.85(s,3H). 13 C NMR (101MHz,DMSO-d 6 ):δ179.48,170.42,169.20,163.85,155.80,131.39,129.82, 123.55,119.06,116.76,112.85,101.81,55.31,40.96,38.17,31.28,30.74,29.83, 29.07,29.04,29.02,28.90,28.71,26.45,24.79,22.67,22.09,13.95.HR-MS calcd for C 30 H 51 Cl 2 N 5 O 7 Pt(M+H) + ,859.7500；found:860.2859.
(4) Synthesis of Compound 4 in analogy to the example one, two steps above, Compound a3 was reacted with hexadecyl isocyanate, yielding 40mg (54.7%). 1 H NMR(400MHz,DMSO-d 6 ):δ8.21(d,J＝9.0Hz, 1H),8.03(t,J＝5.6Hz,1H),7.68(s,1H),7.14(d,J＝2.4Hz,1H),6.92(dd,J＝9.0, 2.5Hz,1H),6.61(s,6H),6.55(d,J＝5.4Hz,1H),3.81(s,3H),3.44–3.34(m,2H), 3.12(t,J＝6.5Hz,2H),2.93–2.83(m,2H),2.78(t,J＝7.1Hz,2H),2.72(t,J＝6.3 Hz,2H),1.81(s,3H),1.33(s,2H),1.23(s,26H),0.85(t,J＝6.7Hz,3H). 13 C NMR (101MHz,DMSO-d 6 ):δ179.48,170.42,169.19,163.85,155.79,131.39,129.82, 123.56,119.06,116.76,112.85,101.81,55.30,40.96,38.16,31.27,30.72,29.83, 29.04,28.98,28.90,28.69,26.45,24.79,22.67,22.08,13.94.HR-MS calcd for C 34 H 59 Cl 2 N 5 O 7 Pt(M+H) + ,915.8580；found:916.3496.
(5) Synthesis of Compound 5 Compound b3 was reacted with hexyl isocyanate, similar to the first and second steps of the above example, yielding 30mg (47.6%). 1 H NMR(400MHz,DMSO-d 6 ):δ8.22(d,J＝8.9Hz,1H),8.04 (t,J＝5.2Hz,1H),7.69(s,1H),7.14(d,J＝1.9Hz,1H),6.92(dd,J＝8.9,2.0Hz, 1H),6.67(s,6H),6.53(s,1H),3.81(s,3H),3.39(s,2H),3.02(t,J＝7.1Hz,2H), 2.89(d,J＝5.1Hz,2H),2.78(t,J＝7.0Hz,2H),2.37(t,J＝6.6Hz,2H),1.92–1.83 (m,2H),1.82(s,3H),1.35(d,J＝5.9Hz,2H),1.23(s,6H),0.86(t,J＝6.6Hz,3H). 13 C NMR(101MHz,DMSO-d 6 ):δ179.99,171.21,169.23,163.99,155.79,131.39, 129.74,123.84,118.91,116.71,112.86,101.83,55.32,40.95,38.25,34.53,33.99, 31.10,29.78,26.09,24.81,22.69,22.09,20.74,13.95.HR-MS calcd for C 25 H 41 Cl 2 N 5 O 7 Pt(M+H)+,790.6150；found:790.2081.
(6) Synthesis of Compound 6 in analogy to the example one, two steps above, Compound b3 was reacted with octyl isocyanate to yield 21mg (32.2%). 1 H NMR(400MHz,DMSO-d 6 ):δ8.22(d,J＝8.0Hz,1H),8.04 (s,1H),7.69(s,1H),7.14(s,1H),6.92(d,J＝7.6Hz,1H),6.60(d,J＝54.7Hz,7H), 3.81(s,3H),3.36(s,2H),3.02(s,2H),2.89(dd,J＝1.0,0.4Hz,2H),2.78(s,2H), 2.37(s,2H),1.86(s,2H),1.82(s,3H),1.34(s,2H),1.23(s,10H),0.86(s,3H). 13 C NMR(101MHz,DMSO-d 6 ):δ180.00,171.21,169.23,163.97,155.79,131.39, 129.74,123.84,118.91,116.72,112.86,101.83,55.32,40.94,38.26,34.53,34.00, 31.26,29.83,28.85 28.72,26.45,24.81,22.69,22.09,20.74,13.96.HR-MS calcd for C 26 H 43 Cl 2 N 5 O 7 Pt(M+H) + ,818.6690；found:818.2401.
(7) Synthesis of Compound 7 in analogy to the example one, two steps above, Compound b3 was reacted with dodecyl isocyanate, yielding 36mg (51.6%). 1 H NMR(400MHz,DMSO-d 6 ):δ8.22(d,J＝8.8Hz, 1H),8.05(s,1H),7.69(s,1H),7.14(s,1H),6.92(d,J＝8.3Hz,1H),6.68(s,6H), 6.53(s,1H),3.81(s,3H),3.36(s,2H),3.02(t,J＝6.2Hz,2H),2.88(d,J＝3.8Hz, 2H),2.78(t,J＝6.3Hz,2H),2.37(s,2H),1.92–1.84(m,2H),1.82(s,3H),1.34(s, 2H),1.23(s,18H),0.85(d,J＝6.4Hz,3H). 13 C NMR(101MHz,DMSO-d 6 ):δ 180.01,171.20,169.22,163.98,155.79,131.39,129.75,123.84,118.91,116.71, 112.85,101.83,55.31,40.95,38.26,34.53,34.00,31.28,29.83,29.07,29.04,29.02, 28.90,28.71,26.45,24.81,22.68,22.08,20.75,13.94.HR-MS calcd for C 31 H 53 Cl 2 N 5 O 7 Pt(M+H) + ,874.7770；found:874.3028.
(8) Synthesis of Compound 8 in analogy to the example one, two steps above, Compound b3 was reacted with hexadecyl isocyanate, yielding 43mg (57.9%). 1 H NMR(400MHz,DMSO-d 6 ):δ8.22(d,J＝8.9Hz, 1H),8.02(t,J＝5.5Hz,1H),7.68(s,1H),7.14(d,J＝2.0Hz,1H),6.66(s,1H),6.53 (m,1H),3.81(s,3H),3.38(d,J＝7.0Hz,2H),3.02(t,J＝7.2Hz,2H),2.88(d,J＝ 6.0Hz,2H),2.78(t,J＝7.2Hz,2H),2.37(t,J＝6.7Hz,2H),1.90–1.84(m,2H),1.82 (s,3H),1.33(s,2H),1.23(s,26H),0.86(d,J＝6.0Hz,3H). 13 C NMR(101MHz, DMSO-d 6 ):δ180.00,171.20,169.21,163.96,155.79,131.39,129.75,123.83,118.91, 116.72,112.85,101.82,55.31,40.96,38.26,43.52,34.00,31.28,29.84,29.05,29.00, 28.91,28.70,26.46,24.82,22.68,22.09,20.74,13.94.HR-MS calcd for C 35 H 61 Cl 2 N 5 O 7 Pt(M+H) + ,930.8850；found:930.3652.
EXAMPLE eight in vitro antitumor Activity assays
To better understand the essence of the present invention, in vitro antitumor activity assays are performed below.
This experiment was carried out byMTT (3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazole bromide) method is used for researching the antitumor activity of 8 synthesized compounds in example 3 and the combination (1:1) of ligands MT and cisplatin, and 5 cancer cells HepG-2 (human liver cancer cell), MCF-7 (human breast cancer cell), HCT-116 (human colon cancer cell), HeLa (human cervical cancer cell) and A549 (non-small cell lung cancer cell) and a normal human cell HUVEC (human umbilical vein blood cell) are used for carrying out cell toxicity experiment research, and all cell strains are subjected to 5% CO 2 At a concentration of 37 ℃ in a saturated humidity incubator. The specific experimental steps are as follows:
collecting cells in logarithmic growth phase, counting, and adjusting cell concentration to 3 × 10 4 cells/mL were inoculated into 96-well plates at 100. mu.L per well, and a Blank (Blank, pure medium) and a Control (Control, no addition set) were set. The plates were incubated overnight in a cell incubator. After adherence, the compound is diluted to the concentration required by the first row of administration holes by using a culture medium, and then the compound is subjected to subsequent hole administration by half dilution, and the mixture is lightly blown and uniformly mixed. After 72h incubation, 10. mu.L (5mg/mL) of MTT solution was added to each well. After further incubation for 4h, the supernatant was removed, 100. mu.L/well DMSO was added, and the OD value was measured with a microplate reader. lambda. ═ 570nm after shaking sufficiently. Three independent repeated experiments are carried out to ensure the reliability of the experimental result.
Table 1 IC 72 hours after Effect of Compounds on cells 50 Value of
a FI,fold increase,IC 50 (cisplatin)/IC 50 (compound 7). b FI,IC 50 (cisplatin+MT)/IC 50 (compound 7). c SI,selectivity index,IC 50 (in HUVEC)/IC 50 (in MCF-7).
As a result of the experiment shown in table 1,the experimental result shows that the trend of gradually increasing cytotoxicity is not shown along with the increase of the carbon chain length of the compound, but the cytotoxicity is greatly improved compared with the cisplatin and the combined administration group of the cisplatin and MT, and the IC of the compound 1 in A549 cells 50 The ratio is 0.799 +/-0.133, and the fold is improved by 3.89 times compared with that of a cisplatin group; and IC of Compound 7 in MCF-7 50 Is 0.068 +/-0.004, and has the highest improvement multiple compared with cisplatin, which is 87.21 times higher; according to the report of the literature, the content of MT receptor in MCF-7 is high, which has a certain relation with the strong action capability in MCF-7, the HUVEC selection index of compound 7 on normal cells is 3.19 times of that of MCF-7, the cisplatin selection index is 0.46, and the HUVEC selection index of compound 7 is improved by about 7 times compared with that of cisplatin, and the result shows that 7 not only improves the killing power on tumor cells, but also reduces the damage on normal cells. Meanwhile, based on the immune regulation and control function of melatonin, the composition has the effects of anxiety resistance, hypnosis, regulation of circadian rhythm and the like. Compared with other tetravalent platinum drugs, the melatonin-platinum (IV) -carbon-nitrogen long chain can relieve mental stress of patients and reduce side effects, and is a good developing drug for tetravalent platinum. In a word, the melatonin-platinum (IV) -carbon nitrogen long-chain twin drug is a novel high-efficiency anti-tumor drug, has broad-spectrum anti-cancer effect, good curative effect and small side effect, and is simple in preparation method, low in cost and easy for industrial production.
Example nine: intracellular reduction experiment
Exploring the intracellular release capacity of the prodrug is crucial to the study of the mechanism of action of tetravalent platinum, which only works if it is reduced in vivo to the divalent platinum form. In order to investigate whether melatonin-platinum (IV) -carbon nitrogen long chain can be reduced by reduced substances (glutathione, ascorbic acid and the like) in cells to release bivalent platinum and simultaneously have a drug slow release effect, an intracellular reduction experiment is carried out. Taking compound 7 as an example, the specific experimental procedure is as follows:
will be 1 × 10 6 Inoculating MCF-7 cells into 6-well plate, allowing cell to adhere, allowing 100 μ M compound 11 to act on cells, culturing for 4 hr, discarding culture medium, washing with PBS for three times, centrifuging to remove PBS, and adding methanol to cellsAnd methylene dichloride for resuspending, transferring the mixture into a grinder for grinding for ten minutes until cells are completely cracked, standing for a period of time after grinding is finished, centrifugally collecting supernate, volatilizing the solvent at room temperature, then resuspending the solid by using 200 mu L of chromatographic methanol, detecting by using a liquid phase, and analyzing the conditions by using the liquid phase: ultraviolet (UV) detection wavelength of 260nm, mobile phase methanol and water (containing 0.1% formic acid), Venusil XBP C18 column (50X 4.6mm, 5 μm), Japan island essence (LC-20A) high performance liquid analyzer, gradient elution, methanol 5% -95% (0-10min), 95% methanol 25min, flow rate of 1 mL/min.
The HPLC detection results are shown in FIG. 1, in which the bands from bottom to top represent the intracellular extraction samples of the cell blank control group without drug treatment, the MT ligand intermediate standard, the melatonin-platinum (IV) -carbon nitrogen long-chain standard compound 7 and the compound 7. Two main peaks can be observed on the strip shown by the intracellular extraction sample of the compound 7, the peak-off time of one peak is 13.7min and is the same as that of the MT ligand intermediate standard, and the peak-off time of the other peak is 17.0min and is the same as that of the melatonin-platinum (IV) -carbon nitrogen long-chain compound 7, so that the compound 7 can be released in vivo. Since the duration of the drug treatment is only 4h, the release of the intermediate is relatively small and 7 is further released during the subsequent action time. The results show that compared with the former patent (melatonin-platinum (IV) complex, a preparation method and application thereof, application number: 201811515822.8), the melatonin-platinum (IV) -carbon nitrogen long-chain complex synthesized by the invention can achieve the slow release effect in cells.
EXAMPLE ten study of antitumor Activity of drugs in vivo
In order to explore the anti-tumor effect of the melatonin-platinum (IV) -carbon nitrogen long chain, the research on the anti-tumor activity of the medicament in vivo is carried out, and the specific steps are as follows:
firstly, establishing an MCF-7 tumor model by using 4-5-week-old Balb/c nude mice until the tumor volume reaches 50-100 cm 3 Thereafter, the mice were randomly divided into 4 groups, PBS, cisclinin + MT, MT, 7 groups, respectively. The drug was formulated at a Pt concentration of 2.5mg/kg, administered once every 3 days, and the mouse body weight and tumor volume were measured every two days for a total of 6 administrations. Last administrationThree days later, the mice were sacrificed and organs (heart, liver, spleen, lung, kidney) and tumors were extracted. Organ and tumor for H&E staining histological analysis and ICP-MS platinum content determination.
The results of the experiments are shown in figures 2-8 above. As can be seen from the tumor growth curve diagram 3, the tumor weight diagram 4 and the final tumor picture diagram 7, the tumor inhibition effect of the compound 7 is obviously improved compared with that of the blank group, and is basically equal to that of the cis-platinum group and the combined administration group. Most importantly, compound 7 mice had significantly less toxicity than cisplatin and the combination. As can be seen from the change of body weight of mice in FIG. 2, the body weight of the mice in the compound 7 administration group is basically maintained stably and has no obvious difference with the body weight of the mice in the blank group, while the body weight of the mice in the cisplatin and combination administration group shows a significant downward trend. As analyzed from the survival rate graph 5, the final survival rate of the compound 7 group mice was 100%, while the final survival rate of the combination group was 16.67%, and the survival rate of the cisplatin group was decreased by 0% (wherein the dead mice include dead mice and mice whose body weight was decreased to 20% of their own volume). From the ICP-MS results, figure 6, it can be seen that compound 7 showed significantly lower accumulation in the kidney and spleen than cisplatin, which is one of the most severe toxicities, and that low accumulation in the kidney of compound 7 would be effective in alleviating the toxic side effects to the kidney, which is also observed in figure 8 as H & E staining results. In H & E, severe damage to tumor tissue was observed for 7 and cisplatin, with severe damage to renal cisplatin, whereas Compound 7 had little damage to the kidney and no significant difference in other organs. The in vivo anti-tumor experiments fully prove that the toxic and side effects of the 11 are obviously reduced compared with clinical cisplatin, the high-efficiency and low-toxicity treatment targets of the anti-tumor drugs are preliminarily achieved, and the safety and the effectiveness are realized in the treatment process.
The embodiments of the present invention have been described in detail, but the description is only for the preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention. All equivalent changes and modifications made within the scope of the present invention shall fall within the scope of the present invention.
Claims (10)
1. A melatonin-platinum (IV) -carbon nitrogen long-chain complex is characterized in that: one axial side of the platinum (IV) coordination center is connected with melatonin molecules, and the other axial side of the platinum (IV) coordination center is connected with carbon-nitrogen long-chain groups.
2. Melatonin-platinum (IV) -carbon nitrogen long-chain complex as claimed in claim 1, characterized in that: represented by formula 1:
wherein the content of the first and second substances,
R 1 is-C n H 2n N is an integer and 1. ltoreq. n.ltoreq.6, preferably-C n H 2n -is a linear group,
R 2 is-NH-C m H 2m+1 or-C m H 2m NO and 1. ltoreq. m.ltoreq.20, preferably-NH-C m H 2m+1 Is a straight chain group.
3. Melatonin-platinum (IV) -carbon nitrogen long-chain complex according to claim 2, characterized in that: n is less than or equal to 2 and-C n H 2n -is a linear group.
4. Melatonin-platinum (IV) -carbon nitrogen long-chain complex according to claim 2, characterized in that: m.ltoreq.17, preferably 2. ltoreq. m.ltoreq.17, -NH-C m H 2m+1 Is a straight chain group.
5. Melatonin-platinum (IV) -carbon nitrogen long-chain complex as claimed in any one of claims 1 to 4, wherein: represented by any one of formulae 2-19:
6. method for the preparation of melatonin-platinum (IV) -carbon nitrogen long-chain complexes as claimed in any of claims 2 to 4, characterized in that:
carrying out esterification reaction on a compound shown in a formula 21 and a compound shown in a formula 22 in the presence of a first condensing agent and a first acid-binding agent to obtain an intermediate compound shown in a formula 20;
carrying out esterification reaction on a compound of a formula 20 and a compound of a formula 23 to obtain the melatonin-platinum (IV) -carbon nitrogen long-chain complex;
wherein the content of the first and second substances,
preferably, the first and second electrodes are formed of a metal,
is cisplatin, carboplatin, or oxaliplatin;
R 1 is-C n H 2n N is an integer and 1. ltoreq. n.ltoreq.6, preferably-C n H 2n -is a linear group,
R 2 is-NH-C m H 2m+1 or-C m H 2m NO and 1. ltoreq. m.ltoreq.20, preferably-NH-C m H 2m+1 Is a straight chain group.
7. The method for preparing melatonin-platinum (IV) -carbon-nitrogen long-chain complex as claimed in claim 6, wherein: a process for preparing a compound of formula 21 comprising:
carrying out acylation reaction on the melatonin as shown in the formula 24 and the compound as shown in the formula 25 in the presence of a second condensing agent and a second acid-binding agent to obtain a compound as shown in the formula 21;
preferably, the second condensing agent is DMAP; the second acid-binding agent is triethylamine.
8. The method for preparing melatonin-platinum (IV) -carbon-nitrogen long-chain complex as claimed in claim 6 or 7, wherein: the first condensing agent is TBTU; the first acid-binding agent is triethylamine; the raw material ratio in the reaction is as follows: a compound of formula 21: a compound of formula 22: a first condensing agent: the first acid-binding agent is 1-1.2: 1: 1.2-2: 1.2-2; preferably, the reaction is carried out under protection from light and inert gas.
9. Use of melatonin-platinum (IV) -carbon-nitrogen long-chain complex as claimed in any of claims 1 to 5 for the preparation of an antitumor medicament.
10. The use of melatonin-platinum (IV) -carbon-nitrogen long-chain complex as claimed in claim 9 for the preparation of antitumor drugs, wherein: can be used for preparing medicine for resisting ovarian cancer, cervical cancer, breast cancer, lung cancer, hepatocarcinoma, and gastrointestinal cancer.
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| WO2024109935A1 (en) * | 2022-11-24 | 2024-05-30 | 天津市肿瘤医院（天津医科大学肿瘤医院） | Gramine-platinum (iv) complex as well as preparation method therefor and anti-tumor use thereof |
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