CN105753922B - For oncotherapy tetravalence platinum glycosyl complex and preparation method thereof - Google Patents
For oncotherapy tetravalence platinum glycosyl complex and preparation method thereof Download PDFInfo
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- CN105753922B CN105753922B CN201610084260.0A CN201610084260A CN105753922B CN 105753922 B CN105753922 B CN 105753922B CN 201610084260 A CN201610084260 A CN 201610084260A CN 105753922 B CN105753922 B CN 105753922B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The invention provides a kind of for oncotherapy tetravalence platinum glycosyl complex and preparation method thereof, the compound that the present invention synthesizes has good anti-tumor activity, its anti-tumor activity compares cis-platinum, oxaliplatin is preferable, and and cis-platinum, carboplatin, the divalent platinum class such as oxaliplatin stability that compares is preferable, there is preferable targeting to tumour cell additionally, due to glycosylation modified tetravalence platinum, it improves to the highly selective of tumour cell, in addition, the dissolubility that compound provided by the invention solves previous divalent platinum series antineoplastic medicament is poor, the cumbersome feature of clinical compatibility, it is fat-soluble and water-soluble preferable.Internal availability not only can be improved in tetravalence platinum glycosyl derivatives, heightens the effect of a treatment, and can also reduce previous divalent platinum medicine to the toxic side effect of kidney etc..
Description
Technical field
The present invention relates to a kind of platinum complex, in particular to a kind of platinum complex of tetravalence containing glycosyl for oncotherapy and
The preparation method of this complex.
Background technique
All the time, tumour is all the disease for being medically difficult to cure, and previous drug therapy is in killing tumor cell
Meanwhile can also toxicity be generated to normal cell, to cause the various complication brought by drug therapy, therefore, for tumour
The magnetic target therapy of cell is always the emphasis studied, and selective kill tumour cell just can solve this and threaten the mankind strong
The great difficult problem of health.
Metal platinum medicine is one of representative drug of antineoplaston, and cis-platinum is found to have antitumor work within 1967
Property, it also becomes the anti-tumor drug that history is longer and application time is long later, with second generation carboplatin and third
Gradually it is applied to clinic for oxaliplatin, platinum series antineoplastic medicament has very important status, Zhi Houyou in the treatment of tumour
There is the divalent platinum series antineoplastic medicament that Eptaplatin, Nedaplatin, lobaplatin etc. are clinically widely used.
However the disadvantage of divalent platinum series antineoplastic medicament maximum is exactly that toxic side effect is stronger, internal availability is low, stability
Difference, half-life short etc., meanwhile, divalent platinum medicine also has water-soluble poor, drug resistance of reporting to the leadship after accomplishing a task seriously and can not be for oral use
The disadvantages of medicine.Since the water solubility of this kind of drug is poor, very big difficulty, the Cisplatin note of 100mM are brought to clinical application
After injecting in vivo, last and DNA of tumor cell combine and play a role less than 1%, most of cis-platinums all with intracorporal albumen
Etc. being combined, to reduce bioavilability and increase toxic side effect, carboplatin and oxaliplatin are applied to later
Clinic improves cis-platinum to the reactivity of DNA from structure, but there is no fundamentally solve dissolubility difference and cannot take orally
Deng disadvantage.
In recent years, the extensive concern of people is gradually caused for platinic research, tetravalence platinum medicine shows as octahedral
The structure of body is compared with platinous tetrahedral structure, the stability of drug is fundamentally increased, just because of its height
Stability fundamentally solves divalent platinum medicine so that tetravalence platinum medicine is expected to develop orally available anti-tumor drug
The disadvantages of poorly water-soluble.
Glycosylation modified is the important means of medicines structure transformation and modification.Carbohydrate is the main source of bioenergetic,
Especially cancer cell is larger to the intake of sugar, and cancer cell surfaces have many sugared functional receptors, carries out to tetravalence platinum medicine
It is glycosylation modified, the targeting to tumour cell may be implemented, some biologically active groups or lead compound are set
Meter synthesizes glycosylated derivative, can optimize the pharmacological activity and binding mode of drug molecule, so that it is strong to obtain targeting, Gao Sheng
The noval chemical compound of object availability high activity.
Summary of the invention
In view of this, to be directed to a kind of high stability, the glycosylated tetravalence platinum class of high targeting anti-for the invention
Tumour medicine and preparation method thereof, to overcome the deficiencies in the prior art.
In order to achieve the above objectives, the technical solution of the invention is achieved in that
A kind of tetravalence platinum glycosyl complex for oncotherapy, has a structure that
Wherein, X, Y are independent ligand or combined type ligand, and X, Y are same or different, are NH3、R3-NH2、R3-NH-R4、
Alky-substituted aromatic amine that aromatic amine, carbon atom number are 1-4, the aromatic heterocycle containing 5-8 carbon atom, carbon atom number 1-4
The chain-like alkyl aromatic heterocycle, one of the nonaromatic heterocycles that replace；
R1And R2It is independent ligand or combined type ligand for leaving group, and R1、R2It is same or different, it is that chlorine is former
Son,Aromatic radical, carbon atom number be the alky-substituted aromatic base of 1-4, the aromatic heterocycle containing 5-8 carbon atom,
Carbon atom number is aromatic heterocycle, one of the nonaromatic heterocycles that the chain-like alkyl of 1-4 replaces；
L1 isOne of, L2 isIn one
Kind；
Wherein, R3And R4It is same or different, it is the chain of n≤8 or the alkyl substitution that cyclic alkyl, carbon atom number are 1-4
The aromatic heterocycle, non-aromatic that aromatic radical, the aromatic heterocycle containing 5-8 carbon atom, the chain-like alkyl that carbon atom number is 1-4 replace
One of heterocycle；
R5For the chain-like alkyl of n≤20 or the cyclic alkyl of n=4-8, aromatic heterocycle, carbon containing 5-8 carbon atom
Atomicity is aromatic heterocycle, one of the nonaromatic heterocycles that the chain-like alkyl of 1-4 replaces,
Sug is full acetyl glucosamine ammonia, full acetyl galactose ammonia, full acetylated mannan sugar ammonia, full acetyl rhamnose ammonia, Quan Yi
Acyl maltose ammonia, full acetyl lactose ammonia, full acetylated sucrose ammonia, glucosamine, galactolipin ammonia, mannose ammonia, rhamnose ammonia, malt
Sugared ammonia, lactose ammonia or sucrose ammonia；
Hetero atom in above-mentioned heterocycle is nitrogen, sulphur or phosphorus atoms.
Further, for the tetravalence platinum glycosyl complex of oncotherapy, the glycosyl comprising 4 kinds of different structures shown in formula 1
Change tetravalence platinum complexes:
Further, in formula 1 and 2For cis-platinum, carboplatin, Eptaplatin, Nedaplatin, Ao Shali
Platinum, lobaplatin, Miboplatin, picoplatin, NDDP,One of.
The invention also includes a kind of preparation method of tetravalence platinum glycosyl complex, the preparation method is by change shown in formula 2
The DMF solution and 2- (7- azo benzotriazole)-N, N, N' of object are closed, the DMF solution of N'- tetramethylurea hexafluorophosphoric acid ester mixes
The DMF mixed liquor of formula 3 and n,N-diisopropylethylamine is stirred 10~20 minutes and then is added, room temperature is protected from light 24~48h
After obtain the corresponding compound of formula 1,
The wherein structural formula of formula 2 are as follows:
The structural formula of formula 3 are as follows:
Wherein, Sug* is full acetyl glucosamine, full acetyl galactose, full acetylated mannan sugar, full acetyl rhamnose, full acetyl
Maltose, full acetyl lactose, full acetylated sucrose, glucose, galactolipin, mannose, rhamnose, maltose, lactose or sucrose,For chain amino.
Application of the tetravalence platinum glycosyl complex of the invention in preparation tumor therapeutic agent, wherein the drug
Include tetravalence platinum glycosyl complex and pharmaceutically acceptable carrier.
Compared with the existing technology, have described in the invention in the tetravalence platinum glycosyl complex of oncotherapy following excellent
Gesture: using the stability that tetravalence platinum difference divalent platinum is special in the present invention, while tumour cell in saccharification study biology is utilized
Characteristic for the first time links glycosyl derivatives and tetravalence platinum, is desirably to obtain first tetravalence platinum series antineoplastic medicament that can be taken orally,
Its advantages are as follows:
1, using the highly expressed saccharide transporter of tumor cell surface, drug is improved to the targeting of tumour cell, is mentioned
High bioavilability reduces the toxic side effect to normal cell；
2, the water solubility for improving platinum medicine improves ester water partition coefficient, improves tumour cell and takes the photograph to drug
Enter amount；
3, by adjusting the length of tetravalence platinum axial ligand chain, its reduction potential is adjusted, the activity of drug is affected；
4, by the modification to tetravalence platinum axial ligand, improve the stability of drug, extend half-life period, reduce to
Dose improves body to the maximal tolerance dose of drug；
5, the effective combination for improving drug and DNA of tumor cell is better than divalent platinum medicine using tetravalence platinum medicine structure
Special stability, obtained orally available anti-tumor drug.
Detailed description of the invention
The attached drawing for constituting a part of the invention is used to provide to further understand the invention, present invention wound
The illustrative embodiments and their description made are used to explain the present invention creation, do not constitute the improper restriction to the invention.?
In attached drawing:
Fig. 1 is the Anticancer Effect and Mechanism of tetravalence glycosyl derivatives in the invention；
Fig. 2 is compound A1 and A5 and cis-platinum described in the invention embodiment and oxaliplatin about concentration -3T3
Cell survival rate schematic diagram；
Fig. 3 is compound B-11 described in the invention embodiment, B6, B7 and B8 and cis-platinum and oxaliplatin about dense
The cell survival rate schematic diagram of degree -3T3.
Specific embodiment
Unless otherwise stated, term used herein all has the meaning that those skilled in the art routinely understand, in order to
It is easy to understand the present invention, some terms used herein have been subjected to following definitions.
It using in the specification and in the claims, singular type "one" and " this " they include plural reference, unless on
Hereafter separately there is clear statement.For example, term " (one) cell " includes the cell of plural number, including its mixture.
All number marks, such as pH, temperature, time, concentration, including range, are all approximations.It is to be understood that although
Term " about " is all added before always not describing all number marks explicitly.While it will also be understood that, although always not clear
Narration, reagent described herein is only example, and equivalent is known in the art.
Different glycosylation of the invention, which closes object, to be to be prepared by routine techniques well known by persons skilled in the art or is outer
Purchase reagent, such as synthesis of full acetylated glucosamine；Specific synthetic route referring to 1.C.M.Appeldoorn C,
A.F.Joosten J,Ait el Maate F,etal.Novel Multivalent Mannose Compounds and
their Inhibition of the Adhesion of type 1 Fimbriated Uropathogenic
E.Coli.Tetrahedron Asymmetry,2005,16(2):361-372.2.Hayes W,M.I.Osborn H,
D.Osborne S,etal.One-pot synthesis of multivalent arrays of mannose monoand
disaccharides.Tetrahedron,2003,35(4):7983–7996.
The synthetic method of tetravalence cis-platinum carboxylic acid as described herein be it is well known to those skilled in the art, referring to Dhar S, Liu
Z,Thomale J,etal.Targeted Single-Wall Carbon Nanotube-Mediated Pt(IV)Prodrug
Delivery Using Folate as a Homing Device.Journal of the American Chemical
Society,2008,130(34)11467-76.
In addition to illustrating, various reagents mentioned in this article are all from the commercially available high-purity reagent for meeting requirement of experiment.
Using the stability that tetravalence platinum difference divalent platinum is special in the present invention, at the same it is thin using tumour in saccharification study biology
Born of the same parents are different from normal cell, and more to the intake of sugar and sugared function that tumor cell surface is more receptor changes previous
The problems such as poor dissolubility of divalent platinum-like compounds, glycosyl derivatives and tetravalence platinum are linked for the first time, are desirably to obtain first
A tetravalence platinum series antineoplastic medicament that can be taken orally.
Tetravalence glycosyl derivatives can be restored by substances such as intracorporal reducing substances such as VC, NADPH in the present invention, after reduction
Tetravalence glycosyl derivatives by playing antitumor action in conjunction with the DNA of tumour cell, mechanism of action is as shown in Figure 1.
Drug of the invention realizes the connection of the sugar and tetravalence platinum axial ligand of different structure with chemical synthesis means, closes
Target product is glycosylated at the tetravalence platinum of different series；The anti-tumor activity of goal in research compound inquires into its structure-activity relationship；Sieve
It selects high activity target compound and studies its activity in vivo and anxious toxicity；Test strongly active glycosylation modified tetravalence platinum compounds
It induces Apoptosis situation and intracellular platinum element takes in situation；It studies such compound and is reduced to platinous difficulty or ease, and
With the binding ability of DNA etc., its possible mechanism of action is explored；Inquire into strongly active compound and large biological molecule human albumin
The interaction of (human serum albumin, HSA) etc., to predict HSA to the transport capacity of target compound.This is
The original innovations Journal of Sex Research such as design, synthesis and the anticancer activity of column glycosylation tetravalence platinum antineoplastic compound and mechanism of action,
It is expected to discovery and possesses the wide spectrum of independent intellectual property right, anticancer activity molecule efficiently, less toxic, provided for cancer clinical treatment novel
Molecule drug candidate.Original innovation drug research project on such source, to national economy and social development and people's health
Deng all will be with important theoretical value and practical significance.
Below with reference to examples and drawings come the present invention will be described in detail create.
Tetravalence platinum glycosyl complex provided by the present invention, representative compound can be provided by following table 1, but
It is to be not limited only to following compound:
Several typical structures of tetravalence platinum glycosyl complex in the present invention are exemplified below:
By taking glucose as an example, a kind of a kind of complete synthetic route reaction equation of embodiment of composition is as follows in formula 1:
Said synthesis route is not unique, and the specific reaction condition document according to disclosed in the prior art can be looked into,
The reaction route that he can obtain goal response object can be implemented.
Wherein about the tetravalence glycosyl complex for oncotherapy in said synthesis route the preparation method is as follows: with
For target glycosyl complex in following reaction equations, method particularly includes:
By the DMF solution of formula 2I compound and HATU (2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea six
Fluorophosphoric acid ester) DMF solution be mixed 10~after twenty minutes, be added formulaWith DIPEA (N, N- diisopropyl
Ethamine) DMF mixed liquor, room temperature is protected from light 24~48h to get to target compound 1I.
It should be noted that starting materials of formulae 2 needed for compound described in the entire synthetic route Chinese style 1 of target glycosyl complex
Or the compound of formula 3 can also be used outsourcing mode in addition to it can synthesize by the way of in above-mentioned route and obtain.
Embodiment 1: the synthesis of tetravalence cis-platinum carboxylic acid
C2 HRMS:Calcd.for Cl2H8N2O2Pt(M+):332.96,found:332.9827.
C3 HRMS:Calcd.for C4H12Cl2N2O5Pt(M+):432.98,found:432.9847.
Embodiment 2: the synthesis of glycosylation tetravalence platinum final product A1
Preparation method are as follows: by C1 (divalent platinum-like compounds cis-platinum) through hydrogen peroxide oxidation under the conditions of 60~70 DEG C, instead
It answers 4 hours, C2 tetravalence cis-Platinum compound can be prepared；C2 (1equiv) and succinic anhydride (4equiv) are dissolved in DMF, nitrogen
Lower 70 DEG C of protective condition after reaction overnight drain by oil pump, after methylene chloride precipitation solid is added, is washed with chloroform, ether etc.
C4 can be prepared；By the DMF solution of C4 and 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester
DMF solution is mixed 10 minutes and then is added the DMF mixing of full acetylated glucosamine and n,N-diisopropylethylamine
Liquid, room temperature is protected from light obtains A1 afterwards for 24 hours.
A1:1H NMR(400MHz,CDCl3) δ 6.41 (d, J=146.8Hz, 4H), 5.47-4.79 (m, 14H), 4.64-
4.08 (m, 5H), 4.02-3.52 (m, 4H), 3.39 (d, J=69.4Hz, 3H), 2.55 (s, 5H), 1.96 (t, J=61.2Hz,
26H), 1.26 (dd, J=167.1,94.1Hz, 5H)13C NMR(100MHz,CDCl3)δ173.56,173.52,171.00,
170.38,170.15,169.59,100.82,90.43,72.70,72.00,71.47,71.25,70.00,68.56,68.52,
67.37,62.07,61.95,60.49,37.40,32.30,29.85,28.85,21.01,20.98,20.94,20.91,
20.88,20.83,20.75,14.35.HRMS:Calcd.for C42H66Cl2N4O26Pt(M+):1307.2988,found:
1307.2979.
Embodiment 3: the synthesis of glycosylation tetravalence platinum final product A2
Preparation method are as follows: by C1 (divalent platinum-like compounds cis-platinum) through hydrogen peroxide oxidation under the conditions of 60~70 DEG C, instead
It answers 8 hours, C2 tetravalence cis-Platinum compound can be prepared；C2 (1equiv) and succinic anhydride (4equiv) are dissolved in DMF, nitrogen
Lower 70 DEG C of protective condition after reaction overnight drain by oil pump, after methylene chloride precipitation solid is added, is washed with chloroform, ether etc.
C4 can be prepared；By the DMF solution of C4 and 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester
DMF solution is mixed 20 minutes and then is added the DMF mixing of full acetylated rhamnose ammonia and n,N-diisopropylethylamine
Liquid, room temperature obtain A2 after being protected from light 48h.
A2:1H NMR(400MHz,CDCl3)δ5.28(s,6H),5.22–4.89(m,5H),4.72(s,1H),3.78(d,J
=34.5Hz, 4H), 3.37 (d, J=54.1Hz, 8H), 2.63 (d, J=73.3Hz, 5H), 1.99 (dd, J=77.6,
46.1Hz, 21H), 1.21 (d, J=11.5Hz, 12H)13C NMR(100MHz,CDCl3)δ170.83,170.76,170.20,
97.45,70.91,69.86,69.63,66.65,66.23,37.60,32.47,29.89,28.85,22.82,21.14,
20.99,17.49.Calcd.for C38H62Cl2N4O22Pt(M+):1191.2878,found:1191.2777.
Embodiment 4: the synthesis of glycosylation tetravalence platinum final product A3
Preparation method are as follows: by C1 (divalent platinum-like compounds cis-platinum) through hydrogen peroxide oxidation under the conditions of 60~70 DEG C, instead
It answers 2 hours, C2 tetravalence cis-Platinum compound can be prepared；C2 (1equiv) and succinic anhydride (4equiv) are dissolved in DMF, nitrogen
Lower 70 DEG C of protective condition after reaction overnight drain by oil pump, after methylene chloride precipitation solid is added, is washed with chloroform, ether etc.
C4 can be prepared；By the DMF solution of C4 and 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester
DMF solution is mixed 15 minutes and then is added the DMF mixing of full acetylated rhamnose ammonia and n,N-diisopropylethylamine
Liquid, room temperature obtain A3 after being protected from light 36h.
A3:1H NMR(400MHz,CDCl3) δ 6.58 (d, J=274.5Hz, 6H), 5.37-4.64 (m, 6H), 3.62 (dd,
J=133.1,48.2Hz, 9H), 2.58 (d, J=55.1Hz, 6H), 2.33-1.50 (m, 18H), 1.02 (d, J=136.3Hz,
13H).13C NMR(100MHz,CDCl3)δ181.94,173.50,170.43,170.29,170.02,97.32,70.74,
69.51,69.32,66.46,54.03,53.53,42.31,39.09,29.64,20.94,20.86,20.80,18.62,
17.42,17.35,12.17.Calcd.for C36H58Cl2N4O22Pt(M+):1163.2565,found:1163.2526.
Embodiment 5: the synthesis of glycosylation tetravalence platinum final product A4
Preparation method are as follows: by C1 (divalent platinum-like compounds cis-platinum) through hydrogen peroxide oxidation under the conditions of 60~70 DEG C, instead
It answers 6 hours, C2 tetravalence cis-Platinum compound can be prepared；C2 (1equiv) and succinic anhydride (4equiv) are dissolved in DMF, nitrogen
Lower 70 DEG C of protective condition after reaction overnight drain by oil pump, after methylene chloride precipitation solid is added, is washed with chloroform, ether etc.
C4 can be prepared；By the DMF solution of C4 and 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester
DMF solution is mixed 12 minutes and then is added the DMF mixing of full acetylated mannose ammonia and n,N-diisopropylethylamine
Liquid, room temperature obtain A4 after being protected from light 30h.
A4:1H NMR(400MHz,CDCl3) δ 6.39 (d, J=157.4Hz, 6H), 5.39-5.03 (m, 5H), 4.81 (s,
2H), 4.25 (s, 2H), 4.10 (d, J=11.7Hz, 2H), 3.97 (s, 2H), 3.75 (s, 2H), 3.61-3.11 (m, 5H),
2.55 (d, J=37.4Hz, 8H), 2.23-1.49 (m, 27H), 1.19 (dd, J=15.9,9.0Hz, 5H)13C NMR
(100MHz,CDCl3)δ182.41,173.59,171.01,170.49,169.92,97.70,69.58,69.45,68.62,
66.49,66.17,62.72,37.32,32.35,32.17,29.07,21.07,20.95,20.90.HRMS:Calcd.for
C42H66Cl2N4O26Pt(M+):1307.2988,found:1307.3002.
Embodiment 6: the synthesis of glycosylation tetravalence platinum final product A5
A5:1H NMR(400MHz,CDCl3) δ 6.42 (d, J=190.6Hz, 6H), 5.28 (dd, J=16.8,9.1Hz,
6H), 4.87 (s, 2H), 4.26 (dd, J=12.2,4.8Hz, 2H), 4.14 (d, J=10.4Hz, 2H), 3.99 (s, 2H), 3.78
(s, 2H), 3.58 (d, J=9.3Hz, 3H), 3.41 (s, 2H), 2.58 (d, J=38.5Hz, 8H), 2.08 (dd, J=39.8,
21.5Hz, 24H), 0.88 (dd, J=14.7,8.2Hz, 3H)13C NMR(100MHz,CDCl3)δ170.95,170.82,
170.49,170.36,169.77,97.64,69.37,68.68,67.08,66.19,66.02,62.59,39.42,29.67,
29.33,20.94,20.88,20.80,20.75,20.70,20.64,20.58,20.53.HRMS:Calcd.for
C40H62Cl2N4O26Pt(M+):1279.2675,found:1279.2678.
Embodiment 7: the synthesis of glycosylation tetravalence platinum final product B1
B1:1H NMR (400MHz, MeOD) δ 5.30-5.13 (m, 1H), 5.00 (dd, J=13.8,5.8Hz, 1H), 4.76
(q, J=8.8Hz, 1H), 3.93-3.68 (m, 2H), 3.62-3.19 (m, 4H), 2.73-2.40 (m, 3H), 2.27-1.91 (m,
69H), 1.82 (ddd, J=13.7,10.7,6.7Hz, 2H), 1.42-1.02 (m, 3H)13C NMR(100MHz,MeOD)δ
183.04,175.74,171.92,171.90,171.82,98.96,72.33,71.19,71.00,67.78,67.00,37.91,
37.86,33.07,30.31,20.89,20.81,20.75,17.92.HRMS:Calcd.for C19H35Cl2N3O12Pt(M+):
762.1242,found:.762.1291.
Embodiment 8: the synthesis of glycosylation tetravalence platinum final product B2
B2:1H NMR (400MHz, MeOD) δ 5.17 (ddd, J=13.4,6.7,2.5Hz, 1H), 4.97 (dd, J=
18.6,8.7Hz, 1H), 3.97-3.36 (m, 5H), 3.00-2.15 (m, 8H), 1.98 (dd, J=56.4,18.1Hz, 9H),
1.83–1.00(m,13H).13C NMR(100MHz,MeOD)δ182.17,174.11,170.36,170.34,170.26,
165.51,165.43,97.47,70.80,69.44,66.26,65.47,61.65,36.34,31.72,31.12,30.91,
28.78,23.77,23.68,19.31,19.29,19.23,16.41.HRMS:Calcd.for C28H46N3O16Pt(M+):
875.2523,found:.875.2513.
Embodiment 9: the synthesis of glycosylation tetravalence platinum final product B3
B3:1H NMR (400MHz, MeOD) δ 5.18 (dtd, J=12.4,3.4,1.7Hz, 2H), 5.05-4.91 (m,
1H), 3.93-3.80 (m, 1H), 3.78-3.66 (m, 1H), 3.61-3.36 (m, 2H), 3.26 (dt, J=3.3,1.6Hz, 2H),
2.59–2.53(m,2H),2.48–2.37(m,2H),2.13–1.81(m,9H),1.18–1.06(m,3H).13C NMR
(100MHz,MeOD)δ183.69,176.07,172.03,171.92,171.89,98.89,72.45,71.08,70.99,
67.82,67.56,40.36,32.98,27.23,20.92,20.87,20.82,17.96.HRMS:Calcd.for
C18H33Cl2N3O12Pt(M+):748.1085,found:.748.1138.
Embodiment 10: the synthesis of glycosylation tetravalence platinum final product B4
B4:1H NMR (400MHz, MeOD) δ 5.55-5.22 (m, 4H), 4.36 (d, J=7.0Hz, 1H), 4.24-4.11
(m, 2H), 3.87 (d, J=4.1Hz, 2H), 3.71 (s, 4H), 3.57 (s, 2H), 2.90 (d, J=10.4Hz, 2H), 2.44-
2.13 (m, 9H), 1.89 (d, J=69.2Hz, 5H), 1.49 (dd, J=27.8,10.6Hz, 3H), 1.37-1.02 (m, 1H)
.HRMS:Calcd.for C28H46N3O16Pt(M+):861.2366,found:.861.2337.
Embodiment 11: the synthesis of glycosylation tetravalence platinum final product B5
B5:1H NMR (400MHz, MeOD) δ 5.25 (dd, J=7.9,4.4Hz, 2H), 4.46-3.97 (m, 4H), 3.87-
3.42 (m, 6H), 3.01 (d, J=2.9Hz, 1H), 2.82-2.32 (m, 3H), 2.24-1.90 (m, 12H), 1.82 (dd, J=
12.0,5.3Hz,2H).13C NMR(100MHz,MeOD)δ183.69,176.07,172.03,171.92,171.89,98.89,
72.45,71.08,70.99,67.82,67.56,40.36,32.98,27.23,20.92,20.87,20.82,17.96.HRMS:
Calcd.for C21H37Cl2N3O14Pt(M++H):821.1373,found:.821.0963.
Embodiment 12: the synthesis of glycosylation tetravalence platinum final product B6
B6:1H NMR (400MHz, MeOD) δ 5.27 (dd, J=9.8,6.8Hz, 3H), 4.59 (m, 1H), 4.29 (dd, J
=12.3,4.8Hz, 1H), 4.20-4.03 (m, 2H), 3.90-3.77 (m, 2H), 3.56 (td, J=10.1,6.1Hz, 2H),
3.19-2.64 (m, 4H), 2.56-2.42 (m, 2H), 2.27 (d, J=11.3Hz, 2H), 2.21-1.94 (m, 12H), 1.93-
1.26(m,8H).13C NMR(100MHz,MeOD)δ176.98,175.32,172.59,171.91,171.83,171.78,
171.70,99.17,71.00,70.90,70.00,67.47,67.24,63.81,37.88,37.82,32.65,32.45,
30.34,25.31,25.24,20.83,20.79,20.76,20.73.HRMS:Calcd.for C30H48N3O18Pt(M+):
933.2578,found:.933.2534.
Embodiment 13: the synthesis of glycosylation tetravalence platinum final product B7
B7:1H NMR(400MHz,MeOD)δ5.44–5.12(m,2H),4.39–3.95(m,3H),3.95–3.71(m,
2H), 3.55 (ddd, J=61.9,21.5,4.1Hz, 2H), 3.27-2.78 (m, 2H), 2.75-2.37 (m, 3H), 2.05 (ddd,
J=34.4,29.6,1.9Hz, 12H), 1.31 (t, J=7.3Hz, 1H)
13C NMR(100MHz,MeOD)δ172.65,172.59,171.84,171.77,171.73,171.70,99.08,
70.95,70.83,70.06,67.94,67.49,63.78,49.15,40.37,32.80,32.56,20.82,20.76,
20.72,9.38.HRMS:Calcd.for C20H35Cl2N3O14Pt(M+):806.1140,found:.806.1208.
Embodiment 14: the synthesis of glycosylation tetravalence platinum final product B8
B8:1H NMR (400MHz, MeOD) δ 5.35-5.18 (m, 2H), 4.24 (dt, J=8.6,4.3Hz, 1H), 4.16-
4.05 (m, 1H), 3.81-3.69 (m, 2H), 3.66-3.54 (m, 2H), 3.52-3.36 (m, 2H), 3.04 (d, J=21.8Hz,
1H), 2.92-2.73 (m, 2H), 2.69-2.40 (m, 4H), 2.23 (d, J=8.9Hz, 2H), 2.03 (dt, J=46.6,
22.3Hz,12H),1.80–1.16(m,6H).13C NMR(100MHz,MeOD)δ183.67,181.75,175.40,172.59,
171.80,171.77,171.70,99.09,70.93,70.03,67.91,67.46,63.76,63.20,62.28,40.34,
33.22,32.58,25.30,25.21,20.88,20.85,20.81,20.75.HRMS:Calcd.forC30H48N3O18Pt(M+):
919.2421,found:.919.2133.
Embodiment 15: the synthesis of glycosylation tetravalence platinum final product B9
B9:1H NMR (400MHz, MeOD) δ 5.40-5.02 (m, 2H), 4.29-4.09 (m, 2H), 3.93 (d, J=
14.9Hz, 1H), 3.75 (d, J=11.7Hz, 2H), 3.51 (d, J=4.7Hz, 4H), 2.47 (s, 4H), 2.20-1.89 (m,
12H), 1.79 (d, J=6.0Hz, 2H)13C NMR(100MHz,MeOD)δ172.24,172.19,171.69,171.63,
171.60,171.52,102.14,72.53,72.24,70.55,70.44,69.02,64.92,62.73,46.47,40.70,
40.39,20.94,20.89,20.74,20.63.HRMS:Calcd.for C21H37Cl2N3O14Pt(M+):820.1297,
found:.820.2892.
Embodiment 16: the synthesis of glycosylation tetravalence platinum final product B10
B10:1H NMR(400MHz,MeOD)δ5.41–4.96(m,3H),4.34–4.02(m,3H),3.93–3.36(m,
4H), 2.98 (s, 3H), 2.66-2.20 (m, 4H), 2.02 (ddd, J=32.0,25.6,22.2Hz, 12H), 1.80-1.02 (m,
8H).13C NMR(100MHz,MeOD)δ183.67,175.22,172.27,172.14,171.68,171.66,167.02,
166.95,102.33,72.51,71.95,70.62,69.05,68.82,62.73,40.60,37.59,32.70,30.64,
25.30,25.22,20.93,20.75,20.67,20.65,14.60.HRMS:Calcd.for C30H48N3O18Pt(M+):
933.2578,found:.933.2622.
1 target molecule biological activity test of experimental example
(1) anti tumor activity in vitro is tested
It includes: human cervical carcinoma cell (Hela), human breast cancer cell (Mcf-7), people's lung that cancer cell line is selected in this experiment
Adenocarcinoma cell (A549), human liver cancer cell (HepG2), human mouth epidermal carcinoma (KB), Human Prostate Cancer Cells (LNCap), before people
Column adenocarcinoma cell (PC3), the human lung adenocarcinoma cell of resistance to cis-platinum (A549R).
Test method: 100 μ L of cell suspending liquid is added to 96 orifice plates, control cell density is the hole 3000-5000/, finally
One column give over to zeroing hole.Place the compound culture that gradient concentration is added in backward 96 orifice plate for 24 hours for 37 DEG C of cell incubator cultures
100 μ L of based sols continues to place 37 DEG C of cell incubator culture 48h.The MTT solution of 5mg/mL is added into the every hole of 96 orifice plates
It is taken out after 20uL, 37 DEG C of cell incubator culture 4h, absorbs culture medium, addition DMSO 150uL is protected from light in 37 DEG C of shaking tables to be shaked
20min.Every hole absorbance is measured with microplate reader at 470nm, calculates its IC50Value, every group of experiment at least repeat three times, measurement knot
Fruit is as shown in Table 1 and Table 2.
Anti-tumor activity data (the IC of 1 A1-A5 of table50Value)
Anti-tumor activity data (the IC of 2 B1-B10 of table50Value)
Above-mentioned anti tumor activity in vitro test result shows that compound A4, A5 show as preferable antitumor action, wherein
A4 shows as effect better than positive drug oxaliplatin to Hela, A549, PC3, and, A5 suitable with positive anti-tumor drug cis-platinum
Anti-tumor activity better than oxaliplatin is shown as to A549, MCF-7, PC3, wherein the antitumous effect of A4, A5 to Lncap
It is substantially better than cis-platinum, respectively the 2.22 and 5.64 of cis-platinum times；Compound B-11, B2, B3, B7 are to Hela, B1, B2, B3, B5, B10
To A549, B1, B5, B6, B7, B8, B10 to MCF-7, B1, B2, B6, B7, B8 to Lncap, B9 to PC3, B1 to HepG-2,
A549R shows as preferable antitumor action, and wherein to Hela, B1, B6, B7, B8 are particularly evident to Lncap effect by B1, B7.
(2) in vitro to normal cell toxotest
Mouse embryonic fibroblasts needed for this project (3T3), Human normal hepatocyte (LO2) it is outsourcing, with above-mentioned MTT
To the killing ability of normal cell, as a result as shown in Figures 2 and 3 method measures target compound.
Fig. 2 and 3 be in vitro to 3T3 carry out cytotoxicity test results, the results show that for tumour cell have compared with
A4, A5, B1, B6, B7 and B8 of good antitumous effect, will be well below positive drug cis-platinum and Austria to the cytotoxicity of 3T3
Husky benefit platinum, wherein when drug concentration is up to 100 μM, cell survival rate be A5 be 70.280%, B1 69.12345%, B6
For 95.93054%, B7 be 55.19827% and B8 is 76.89103%, and cis-platinum has biggish killing to 3T3 at this concentration
Property, cell survival rate is only 9.204%.
In conclusion the compound that the present invention synthesizes has good anti-tumor activity, anti-tumor activity is than cis-platinum, Austria
Husky benefit platinum is preferable, and stability is preferable compared with the divalent platinum class such as cis-platinum, carboplatin, oxaliplatin, additionally, due to glycosylation
The tetravalence platinum of modification has preferable targeting to tumour cell, improves to the highly selective of tumour cell, in addition, of the invention
The feature that the dissolubility that the compound of offer solves previous divalent platinum series antineoplastic medicament is poor, clinical compatibility is cumbersome, liposoluble
Property and it is water-soluble preferable.It is not easy to combine with albumen etc. before being reduced in vivo due to it, tetravalence platinum glycosyl spreads out
Internal availability not only can be improved in biology, heightens the effect of a treatment, and it is secondary to the poison of kidney etc. can also to reduce previous divalent platinum medicine
Effect.
The administration route of drug of the present invention is either intravenous injection, can also change what platinum medicine cannot take orally for the first time
Disadvantage, using the special stability of tetravalence platinum medicine, this drug can also be used to take orally.
The foregoing is merely the preferred embodiments of the invention, are not intended to limit the invention creation, all at this
Within the spirit and principle of innovation and creation, any modification, equivalent replacement, improvement and so on should be included in the invention
Protection scope within.
Claims (4)
1. being used for the tetravalence platinum glycosyl complex of oncotherapy, which is characterized in that have a structure that
2. being used for the tetravalence platinum glycosyl complex of oncotherapy, which is characterized in that have a structure that
3. being used for the tetravalence platinum glycosyl complex of oncotherapy, which is characterized in that have a structure that
4. being used for the tetravalence platinum glycosyl complex of oncotherapy, which is characterized in that have a structure that
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| CN108892700B (en) * | 2018-05-27 | 2020-07-07 | 杭州星鳌生物科技有限公司 | Novel anti-tumor compound and application thereof in preparing anti-tumor medicine |
| CN108743963B (en) * | 2018-06-14 | 2020-11-03 | 华中科技大学 | Anti-cancer conjugate containing tetravalent platinum and preparation method and application thereof |
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| CN117836007A (en) * | 2021-07-13 | 2024-04-05 | 南京大学 | PT conjugate and application thereof |
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