CN109790191B - Platinum complexes and methods of use thereof - Google Patents

Platinum complexes and methods of use thereof Download PDF

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CN109790191B
CN109790191B CN201780049195.0A CN201780049195A CN109790191B CN 109790191 B CN109790191 B CN 109790191B CN 201780049195 A CN201780049195 A CN 201780049195A CN 109790191 B CN109790191 B CN 109790191B
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CN109790191A (en
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支志明
胡迪
陈丽凤
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Versitech Ltd
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    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
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Abstract

Disclosed herein are platinum (II) complexes, which may include complexes of the formula or pharmaceutically acceptable salts thereof,
Figure DEST_PATH_IMAGE001
wherein: r1And R2Independently selected from the group consisting of amines, optionally substituted amines, and optionally substituted heterocyclic amines; or a pair of R1And R2Linked together to form a bidentate ligand containing a nitrogen atom; r3Selected from the group consisting of H, optionally substituted alkyl, optionally substituted aryl, optionally substituted thienyl, and polyethylene glycol; r4、R5、R6And R7Independently selected from H, halogen, -OR, optionally substituted alkyl and polyethylene glycol, OR R4And R5、R5And R6、R6And R7Are connected together to form

Description

Platinum complexes and methods of use thereof
Technical Field
Platinum (II) complexes are disclosed herein. More particularly, the platinum (II) complex may comprise a luminescent 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligand. Also disclosed are methods of using the platinum (II) complexes in cancer therapy and cellular monitoring.
Background
Cisplatin (cis-diamminedichloroplatinum) is a member of the platinum (II) complex family used in the treatment of cancer. It is one of the more potent anticancer drugs; however, cisplatin may have drawbacks. For example, patients may exhibit drug resistance or may have serious side effects. Carboplatin (cis-diamine (1, 1-cyclobutane dicarboxylate) platinum) is another anticancer drug in the platinum (II) complex family. Carboplatin has an amine non-leaving ligand similar to cisplatin, but a different leaving ligand. Experimental evidence suggests that the anticancer mechanism of cisplatin and carboplatin involves displacement of the leaving group by water or other biological nucleophiles and formation of the ion [ (NH)3)2PtII]2+It can bind to nuclear DNA and cause cell death. Although cisplatin and carboplatin have similar anti-cancer mechanisms, they may exhibit different clinical responses. For example, there may be fewer side effects associated with carboplatin. There is an increasing interest in developing luminescent transition metal complexes that are therapeutically active and allow simultaneous monitoring of cancer progression. The photophysical properties of such complexes enable their visualization and tracking in vitro and in vivo, thereby providing real-time tracking of cellular distribution, structural changes, and biotransformation pathways of anticancer platinum (II) complexes. However, not all platinum (II) complexes have the necessary photophysical properties to enable disease monitoring.
Thus, there is a need for new platinum (II) complexes that may have therapeutic benefits and/or may have photophysical properties that allow monitoring and tracking of disease progression.
Summary of The Invention
Provided herein are platinum (II) complexes and methods of use thereof. In one embodiment, the platinum (II) complex may comprise a complex of formula I or a pharmaceutically acceptable salt thereof,
Figure 829838DEST_PATH_IMAGE001
wherein: r1And R2Independently selected from amines, optionally substituted amines and optionally substituted heterocyclic amines; or a pair of R1And R2Linked together to form a bidentate ligand containing a nitrogen atom; r3Selected from the group consisting of H, optionally substituted alkyl, optionally substituted aryl, optionally substituted thienyl, and polyethylene glycol; r4、R5、R6And R7Independently selected from H, halogen, -OR, optionally substituted alkyl and polyethylene glycol, OR R4And R5、R5And R6、R6And R7Are connected together to form
Figure 95734DEST_PATH_IMAGE002
Y is selected from the group consisting of a sulfur atom, an oxygen atom and NR (wherein R is selected from the group consisting of H and optionally substituted alkyl); z is selected from carbon atoms and nitrogen atoms; and X is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
In another specific embodiment, the method for treating a subject having cancer comprises administering a therapeutically effective amount of at least one platinum (II) complex of formula I.
In another embodiment, a method of monitoring cells can comprise administering an effective amount of at least one platinum (II) complex of formula I and detecting a fluorescent signal of the platinum (II) complex.
Brief description of the drawings
In the following detailed description, reference is made to the accompanying drawings that depict exemplary, non-limiting, and non-exhaustive embodiments of the invention. So that the manner in which the above recited features of the present invention can be understood in detail, a more particular description of the invention, briefly summarized above, may be had by reference to embodiments, some of which are illustrated in the appended drawings. It is to be noted, however, that the appended drawings illustrate only typical embodiments of this invention and are therefore not to be considered limiting of its scope, for the invention may admit to other equally effective embodiments.
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the office upon request and payment of the necessary fee.
FIG. 1 shows the chemical structure of a non-limiting example of a platinum (II) complex containing a 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone (Hbt) ligand, according to some embodiments.
FIG. 1a shows the chemical structure of a platinum (II) complex containing Hbt ligand as a labile leaving group.
FIG. 2 shows a non-limiting example of a synthetic method for preparing Hbt ligand, and a synthetic method for preparing a platinum (II) complex, according to some embodiments.
FIG. 2a shows the in vivo tumor growth inhibition effect of 1a, 2a and 3a, examined via intravenous injection using nude mice bearing NCI-H460 xenografts. (A) Mean tumor volume after two or three weekly treatments with 10 mg/kg of 1a, 5 mg/kg of 2a, 20 mg/kg of 3a or solvent (. p-value <0.05, n = 5). (B) Body weights of nude mice in 1a, 2a, 3a treated group and solvent control group. (C) Representative photographs of tumors obtained from nude mice in 1a, 2a, 3a treated groups and solvent control groups.
Fig. 3 shows UV-visible absorption spectra of some exemplary platinum (II) complexes with Hbt ligand in PBS solution, according to some embodiments.
FIG. 3a shows body weights of nude mice in cisplatin (1 mg/kg and 3 mg/kg) and complex 1a (10 mg/kg and 20 mg/kg) treatment groups. Mice treated with 3 mg/kg cisplatin lost more than 10% of total body weight. In contrast, mice treated with 20 mg/kg of 1a had consistent body weights and no evidence of significant adverse effects was observed.
FIG. 4 shows some exemplary platinum (II) complexes with Hbt ligands at CH, according to some embodiments2Cl2Emission spectrum in (1).
Figure 4a shows a series of platinum (II) complexes with differently substituted Hbt ligands.
Fig. 5 shows, according to some embodiments, a) the UV-visible absorption spectra of some exemplary platinum (II) complexes in PBS solution at different time intervals, and b) the UV-visible absorption spectra of some exemplary platinum (II) complexes in PBS solution in the presence of GSH at different time intervals.
Fig. 6 shows emission spectra of some exemplary platinum (II) complexes in the presence of GSH in PBS solution, according to some embodiments. a) The emission spectra of complexes 1 and 2 in the presence of GSH were recorded at different time points, with excitation wavelength at λ ex = 381 nm. b) Time course of emission intensity of complexes 1 and 2 at 450 nm in the presence of GSH.
Fig. 7 shows a) the emission spectra of some exemplary platinum (II) complexes in the presence of ctDNA at different molar ratios. b) ctDNA causes an enrichment in luminescence intensity of some exemplary platinum (II) complexes.
Fig. 8 shows luminescent imaging of some exemplary platinum (II) complexes with Hbt ligands inside a cell, according to some embodiments.
Fig. 9 shows a luminescent imaging time series of some exemplary platinum (II) complexes inside living cells, according to some embodiments.
Fig. 10 shows cellular uptake and DNA binding fractions of some exemplary platinum (II) complexes and oxaliplatin in cells, according to some embodiments.
Fig. 11 shows average tumor volumes of a) nude mice bearing HeLa xenografts after treatment with some exemplary platinum (II) complexes or solvents via intraperitoneal injection, according to some embodiments. b) Body weights of nude mice bearing HeLa xenografts in the platinum (II) complex treated group and the solvent control group.
Fig. 12 shows representative photographs of a) tumors obtained from nude mice in the platinum (II) complex treated group and the solvent control group, according to some embodiments. b) Representative photographs of nude mice in the platinum (II) complex treated group and the solvent control group.
Detailed Description
In the following specification and claims, reference will be made to a number of terms, which shall be defined to have the following meanings:
the term "alkyl" as used herein refers to straight, branched or cyclic saturated hydrocarbon groups typically, although not necessarily, containing from 1 to about 20 carbon atoms, preferably from 1 to about 12 carbon atoms, from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like. Typically, although not necessarily, the term "cycloalkyl" means a cyclic alkyl group, typically having from 4 to 8, preferably from 5 to 7 carbon atoms. The term "substituted alkyl" refers to an alkyl group substituted with one or more substituents, and the terms "heteroatom-containing alkyl" and "heteroalkyl" refer to an alkyl group in which at least one carbon atom is replaced with a heteroatom. The term "alkyl", if not otherwise stated, includes straight-chain, branched-chain, cyclic, unsubstituted, substituted and/or heteroatom-containing alkyl groups.
The term "bidentate ligand containing a nitrogen atom" as used herein refers to a bidentate ligand containing a 10-to 64-membered, preferably 10-to 48-membered or 10-to 36-membered heterocyclic molecule, consisting of carbon atoms and one to six, preferably 1,2, 3, 4 or 5 heteroatoms selected from nitrogen, oxygen and sulfur, wherein such heterocyclic molecule contains at least one nitrogen atom. Examples of such heterocyclic molecules include, but are not limited to, pyrazole, triazole, tetrazole, pyridine, pyrazine, azepine, benzimidazole, benzothiazole, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, oxazoline, isoxazoline, thiazoline, morpholine, bipyridine, bipyrazine, terpyridine, phenanthroline, bathophenanthroline, bisoxazoline, bisthiazoline, bisisoquinoline, bisquinolylpyridine, quinolylphenanthroline, and the like.
The term "heterocycle" in the context of the present invention refers to a stable 5-to 32-membered, preferably 5-to 24-membered or 5-to 18-membered heterocyclic group consisting of carbon atoms and one to six, preferably 1,2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur. The term "5-to 32-membered heterocyclic group" as used herein means a heterocyclic group having a skeleton of 5 to 32 atoms. For the purposes of the present invention, the heterocycle may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include bonded or fused ring systems; and the heterocyclic group may be partially or fully saturated or aromatic (heteroaryl). Examples of heterocyclic groups include, but are not limited to, pyrazole, triazole, tetrazole, pyridine, pyrazine, azepine, benzimidazole, benzothiazole, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, oxazoline, isoxazoline, thiazoline, morpholine, bipyridine, bipyrazine, terpyridine, phenanthroline, bathophenanthroline, bisoxazoline, bisthiazoline, bisquinoline, bisisoquinoline, quinolinylpyridine, quinolinylphenanthroline, and the like. These heterocyclic ligands may be optionally substituted.
The terms "alkenyl" and "alkynyl" refer to straight or branched hydrocarbon chain groups having one or more carbon-carbon double or triple bonds, respectively, and from two to twelve carbon atoms, and which are attached to the remainder of the molecule by single bonds. In one embodiment of the invention, the alkenyl or alkynyl group has two to eight, two to six, two or three carbon atoms. The double bond of the alkenyl group or the triple bond of the alkynyl group may be unconjugated or conjugated to another unsaturated group. Suitable alkenyl groups include, but are not limited to, alkenyl groups such as vinyl, allyl, butenyl, butadienyl, or pentadienyl. Suitable alkynyl groups include, but are not limited to, alkynyl groups such as-CCH, -CH2CCH、-CCCH3、-CH2CCCH3。
The term "aryl" refers to an aromatic group having 6 to 24, preferably 6 to 18, more preferably 6 to 16, even more preferably 6 to 10 carbon atoms, comprising 1,2, 3 or 4 aromatic rings bonded by a carbon-carbon bond or fused, for example and in a non-limiting sense including phenyl, naphthyl, diphenyl, indenyl, anthryl, phenanthryl, pyrenyl and the like. "aryl" preferably means phenyl.
The term "halogen" refers to bromine, chlorine, iodine or fluorine.
The above groups may optionally be taken at one or more available positions by one or more suitable groupsAnd radicals such as OR ', O-, SR ', SOR ', SO2R'、OSO2R'、SO3R'、SO3 -、NO2、N(R')2、N(R')3 +、N(R')COR'、N(R')SO2R ', CN, halogen, COR', CO2R'、CO2 -、OCOR'、OCO2R'、OCONHR'、OCON(R')2、CONHR'、CON(R')2Substituted or unsubstituted C1-C18Alkyl, substituted or unsubstituted C2-C12Alkenyl, substituted or unsubstituted C2-C12An alkynyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic group, wherein each R' group is independently selected from hydrogen, substituted or unsubstituted C1-C18Alkyl, substituted or unsubstituted C2-C12Alkenyl, substituted or unsubstituted C2-C12Alkynyl groups, substituted or unsubstituted aryl groups, and substituted or unsubstituted heterocyclic groups. When such groups are themselves substituted, the substituents may be selected from the aforementioned list.
The platinum (II) complex may include, but is not limited to, a complex of formula I:
Figure 32466DEST_PATH_IMAGE003
wherein:
R1and R2Independently selected from amines, e.g. -NH3Optionally substituted amines, and optionally substituted heterocyclic amines; or a pair of R1And R2Linked together to form a bidentate ligand containing a nitrogen atom;
R3selected from the group consisting of H, optionally substituted alkyl, optionally substituted aryl, optionally substituted thienyl, and polyethylene glycol;
R4、R5、R6and R7Independently selected from H, halogen, -OR, optionally substituted alkyl and polyethylene glycol, OR R4And R5、R5And R6、R6And R7Are connected together to form
Figure 550166DEST_PATH_IMAGE004
Y is selected from the group consisting of a sulfur atom, an oxygen atom and-NR, wherein R is selected from the group consisting of H and optionally substituted alkyl;
z is selected from carbon atoms and nitrogen atoms; and
x is a counterion, which may include, but is not limited to: halide ions including fluoride, chloride, bromide and iodide; trifluoromethanesulfonic acid radical; acetate radical; nitrate radical; perchlorate radicals; hexafluorophosphate radicals; sulfate and phosphate radicals.
In a particular embodiment, the platinum (II) complex may include, but is not limited to, complexes having a 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone (Hbt) ligand. The 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone (Hbt) ligand may be fluorescent and may be a leaving group of a platinum (II) complex suitable for luminescence. Modification of the substituents on the Hbt ligand may optimize the anticancer activity of the platinum (II) complexes, such as by modulating their lipophilicity and/or their reaction kinetics. The platinum (II) complex containing the Hbt ligand can exhibit anti-cancer activity and photoluminescence characteristics.
The 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligands may include, but are not limited to, ligands of formula II:
Figure 764110DEST_PATH_IMAGE005
wherein:
R3selected from the group consisting of H, optionally substituted alkyl, optionally substituted aryl, optionally substituted thienyl, and polyethylene glycol; r4、R5、R6And R7Independently selected from-H, halogen, -OR, optionally substituted alkyl and polyethylene glycol, OR R4And R5、R5And R6、R6And R7Are connected together to form
Figure 325541DEST_PATH_IMAGE006
Y is selected from the group consisting of a sulfur atom, an oxygen atom and NR, wherein R is selected from the group consisting of H and optionally substituted alkyl.
The 1- (3-hydroxybenzo [ b ] thiophene-2-yl) ethanone ligand can form a single complex with positive charge with platinum (II) ions. The platinum (II) complex may include, but is not limited to, a counter anion coordinated to the platinum (II) complex, thereby balancing charge.
In a particular embodiment, the platinum (II) complex may include, but is not limited to, a ligand of formula III:
Figure 890515DEST_PATH_IMAGE007
wherein:
x is a counterion, which may include, but is not limited to: halogen ions such as fluorine, chlorine, bromine and iodine, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
In a particular embodiment, the platinum (II) complex may include, but is not limited to, a complex of formula IV:
Figure 677818DEST_PATH_IMAGE008
wherein:
x is a counterion, which may include, but is not limited to: halide ions (including fluoride, chloride, bromide, and iodide), triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
Methods of treating a subject with cancer may include, but are not limited to, administering a therapeutically effective amount of at least one platinum (II) complex of formula I. The method can induce cancer cell death and/or inhibit cell proliferation in vitro and/or in vivo. The platinum (II) complex is administered intravenously in physiological saline as a short-term infusion to treat solid malignancies.
Without wishing to be bound by theory, the platinum (II) complex may have therapeutic functions similar to those of cisplatin-based drugs. For example, one or more platinum (II) complexes may bind to DNA strands, which may lead to DNA strand cross-linking and ultimately to apoptosis.
A number of pharmaceutical dosage forms are available for administering the platinum (II) complex, including sterile aqueous solutions or dispersions or sterile powders comprising the platinum (II) complex. These platinum (II) complexes are suitable for the convenient preparation of sterile injectable or infusible solutions or dispersions. The dosage form may be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or excipient may be a solvent or liquid dispersion medium comprising, for example, water, ethanol, polyol, vegetable oil, nontoxic glyceryl esters, and suitable mixtures thereof.
The treatment can be used for many types of cancers. For example, the method can be used for sarcomas, such as small cell lung cancer, squamous cell carcinoma of the head and neck, and ovarian cancer; lymphoma; bladder cancer; testicular cancer; cervical cancer; and germ cell tumors.
A method of monitoring a cell may comprise administering at least one platinum (II) complex of formula I and detecting a fluorescent signal of the platinum (II) complex. The monitoring may include, but is not limited to, monitoring the cellular distribution and/or structural changes of the platinum (II) complex in living cells. Structural changes to the platinum (II) complex may include, but are not limited to, the release of the ligand 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligand from the platinum (II) complex. The method of monitoring cells may include real-time monitoring.
The present application includes the following embodiments:
1. a platinum (II) complex comprising:
Figure 136481DEST_PATH_IMAGE009
or a pharmaceutically acceptable salt thereof, wherein:
R1and R2Independently selected from the group consisting of amines, optionally substituted amines, and optionally substituted heterocyclic amines; or a pair of R1And R2Linked together to form a bidentate ligand containing a nitrogen atom;
R3selected from the group consisting of H, optionally substituted alkyl, optionally substituted aryl, optionally substituted thienyl, and polyethylene glycol;
R4、R5、R6and R7Independently selected from H, halogen, -OR, optionally substituted alkyl and polyethylene glycol, OR R4And R5、R5And R6、R6And R7Are connected together to form
Figure 744180DEST_PATH_IMAGE010
Y is selected from the group consisting of a sulfur atom, an oxygen atom and NR (wherein R is selected from the group consisting of H and optionally substituted alkyl);
z is selected from carbon atoms and nitrogen atoms; and
x is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
2. The platinum (II) complex of any of the above embodiments, comprising:
Figure 671815DEST_PATH_IMAGE011
wherein Z is a carbon atom;
R1and R2Independently selected from ammonia (-NH)3) Optionally substituted amine, and optionally substituted heterocyclic amine, or a pair of R1And R2Linked together to form a bidentate ligand containing a nitrogen atom;
R3selected from the group consisting of-H, optionally substituted alkyl, optionally substituted aryl, optionally substituted thienyl, and polyethylene glycol;
R4、R5、R6and R7Independently selected from-H, halogen, -OR, optionally substituted alkyl and polyethylene glycol, OR R4And R5、R5And R6、R6And R7Are connected together to form
Figure 124794DEST_PATH_IMAGE012
Y is selected from the group consisting of a sulfur atom, an oxygen atom and NR (wherein R is selected from the group consisting of-H and optionally substituted alkyl); and
x is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
3. The platinum (II) complex of any of the above embodiments, comprising:
Figure 703542DEST_PATH_IMAGE013
wherein Y is a sulfur atom;
z is a carbon atom;
R1and R2Independently selected from ammonia (-NH)3) Optionally substituted amine, and optionally substituted heterocyclic amine, or a pair of R1And R2Linked together to form a bidentate ligand containing a nitrogen atom;
R3selected from the group consisting of-H, optionally substituted alkyl, optionally substituted aryl, optionally substituted thienyl, and polyethylene glycol;
R4、R5、R6and R7Independently selected from-H, halogen, -OR, optionally substituted alkyl and polyethylene glycol, OR R4And R5、R5And R6、R6And R7Are connected together to form
Figure 91930DEST_PATH_IMAGE014
X is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
4. The platinum (II) complex of any of the above embodiments, comprising:
Figure 631495DEST_PATH_IMAGE015
wherein Y is a sulfur atom;
z is a nitrogen atom;
R1and R2Independently selected from ammonia (-NH)3) Optionally substituted amine, and optionally substituted heterocyclic amine, or a pair of R1And R2Linked together to form a bidentate ligand containing a nitrogen atom;
R3selected from the group consisting of-H, optionally substituted alkyl, optionally substituted aryl, optionally substituted thienyl, and polyethylene glycol;
R5、R6and R7Independently selected from-H, halogen, -OR, optionally substituted alkyl and polyethylene glycol, OR R4And R5、R5And R6、R6And R7Are connected together to form
Figure 278377DEST_PATH_IMAGE016
X is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
5. The platinum (II) complex of any of the above embodiments, comprising:
Figure 586999DEST_PATH_IMAGE017
wherein Y is a sulfur atom;
z is a carbon atom;
R3is-CH3；
R4、R5、R6And R7Each is H;
R1and R2Independently selected from ammonia (-NH)3) Optionally substituted amine, and optionally substituted heterocyclic amine, or a pair of R1And R2Linked together to form a bidentate ligand containing a nitrogen atom; and
x is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
6. The platinum (II) complex of any of the above embodiments, comprising:
Figure 146287DEST_PATH_IMAGE018
wherein Y is a sulfur atom;
z is a nitrogen atom;
R3is-CH3；
R5、R6And R7Each is-H;
R1and R2Independently selected from ammonia (-NH)3) Optionally substituted amine, and optionally substituted heterocyclic amine, or a pair of R1And R2Linked together to form a bidentate ligand containing a nitrogen atom; and
x is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
7. The platinum (II) complex of any of the above embodiments, comprising:
Figure 907570DEST_PATH_IMAGE019
wherein Y is a sulfur atom;
z is a carbon atom;
R1and R2Linked together to form (1R, 2R) -1, 2-cyclohexanediamine;
R3is-CH3；
R4、R5、R6And R7Each is-H; and
x is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
8. The platinum (II) complex of any of the above embodiments, comprising:
Figure 358143DEST_PATH_IMAGE020
wherein Y is a sulfur atom;
z is a carbon atom;
R1and R2Each is-NH3；
R3is-CH3；
R4、R5、R6And R7Each is-H; and
x is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
9. The platinum (II) complex of any of the above embodiments, comprising:
Figure 521271DEST_PATH_IMAGE021
wherein Y is a sulfur atom;
z is a carbon atom;
R1and R2Linked together to form 2, 2' -bipyridine;
R3is-CH3；
R4、R5、R6And R7Each is-H; and
x is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
13. A method of treating a subject having cancer, comprising:
administering a therapeutically effective amount of a platinum (II) complex comprising:
Figure 254390DEST_PATH_IMAGE022
or a pharmaceutically acceptable salt thereof, wherein:
R1and R2Independently selected from the group consisting of amines, optionally substituted amines, and optionally substituted heterocyclic amines; or a pair of R1And R2Linked together to form a bidentate ligand containing a nitrogen atom,
R3selected from the group consisting of H, optionally substituted alkyl, optionally substituted aryl, optionally substituted thienyl, and polyethylene glycol;
R4、R5、R6and R7Independently selected from H, halogen, -OR, optionally substituted alkyl and polyethylene glycol, OR R4And R5、R5And R6、R6And R7Are connected together to form
Figure 893182DEST_PATH_IMAGE023
Y is selected from the group consisting of a sulfur atom, an oxygen atom and NR (wherein R is selected from the group consisting of H and optionally substituted alkyl);
z is selected from carbon atoms and nitrogen atoms; and
x is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
14. The method of any of the above embodiments, wherein the platinum (II) complex comprises:
Figure 757233DEST_PATH_IMAGE024
wherein Z is a carbon atom;
R1and R2Independently selected from ammonia (-NH)3) Optionally substituted amine, and optionally substituted heterocyclic amine, or a pair of R1And R2Linked together to form a bidentate ligand containing a nitrogen atom;
R3selected from the group consisting of-H, optionally substituted alkyl, optionally substituted aryl, optionally substituted thienyl, and polyethylene glycol;
R4、R5、R6and R7Independently selected from-H, halogen, -OR, optionally substituted alkyl and polyethylene glycol, OR R4And R5、R5And R6、R6And R7Are connected together to form
Figure 650234DEST_PATH_IMAGE025
Y is selected from the group consisting of a sulfur atom, an oxygen atom and NR (wherein R is selected from the group consisting of-H and optionally substituted alkyl); and
x is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
15. The method of any of the above embodiments, wherein the platinum (II) complex comprises:
Figure 207117DEST_PATH_IMAGE026
wherein Y is a sulfur atom;
z is a carbon atom;
R1and R2Independently selected from ammonia (-NH)3) Optionally substituted amine, and optionally substituted heterocyclic amine, or a pair of R1And R2Joined together to form a bidentate ligand containing a nitrogen atomA body;
R3selected from the group consisting of H, optionally substituted alkyl, optionally substituted aryl, optionally substituted thienyl, and polyethylene glycol;
R4、R5、R6and R7Independently selected from H, halogen, -OR, optionally substituted alkyl and polyethylene glycol, OR R4And R5、R5And R6、R6And R7Are connected together to form
Figure 802046DEST_PATH_IMAGE027
X is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
16. The method of any of the above embodiments, wherein the platinum (II) complex comprises:
Figure 469788DEST_PATH_IMAGE028
wherein Y is a sulfur atom;
z is a nitrogen atom;
R1and R2Independently selected from ammonia (-NH)3) Optionally substituted amine, and optionally substituted heterocyclic amine, or a pair of R1And R2Linked together to form a bidentate ligand containing a nitrogen atom;
R3selected from the group consisting of-H, optionally substituted alkyl, optionally substituted aryl, optionally substituted thienyl, and polyethylene glycol;
R5、R6and R7Independently selected from-H, halogen, -OR, optionally substituted alkyl and polyethylene glycol, OR R4And R5、R5And R6、R6And R7Are connected together to form
Figure 217295DEST_PATH_IMAGE029
X is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
17. The method of any of the above embodiments, wherein the platinum (II) complex comprises:
Figure 945080DEST_PATH_IMAGE030
wherein Y is a sulfur atom;
z is a carbon atom;
R3is-CH3；
R4、R5、R6And R7Each is-H;
R1and R2Independently selected from ammonia (-NH)3) Optionally substituted amine, and optionally substituted heterocyclic amine, or a pair of R1And R2Linked together to form a bidentate ligand containing a nitrogen atom; and
x is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
18. The method of any of the above embodiments, wherein the platinum (II) complex comprises:
Figure 27305DEST_PATH_IMAGE031
wherein Y is a sulfur atom;
z is a nitrogen atom;
R3is-CH3；
R5、R6And R7Each is-H;
R1and R2Independently selected from ammonia (-NH)3) Optionally substituted amines, and optionally substitutedOr a pair of R1And R2Linked together to form a bidentate ligand containing a nitrogen atom; and
x is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
19. The method of any of the above embodiments, wherein the platinum (II) complex comprises:
Figure 108525DEST_PATH_IMAGE032
wherein Y is a sulfur atom;
z is a carbon atom;
R1and R2Linked together to form (1R, 2R) -1, 2-cyclohexanediamine;
R3is-CH3；
R4、R5、R6And R7Each is-H; and
x is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
20. A method of monitoring a cell, comprising:
applying at least one platinum (II) complex comprising:
Figure 100752DEST_PATH_IMAGE033
or a pharmaceutically acceptable salt thereof, wherein:
R1and R2Independently selected from the group consisting of amines, optionally substituted amines, and optionally substituted heterocyclic amines; or a pair of R1And R2Linked together to form a bidentate ligand containing a nitrogen atom;
R3selected from the group consisting of H, optionally substituted alkyl, optionally substituted aryl, optionally substituted thienyl, and polyethylene glycol;
R4、R5、R6and R7Independently selected from H, halogen, -OR, optionally substituted alkyl and polyethylene glycol, OR R4And R5、R5And R6、R6And R7Are connected together to form
Figure 124071DEST_PATH_IMAGE034
Y is selected from the group consisting of a sulfur atom, an oxygen atom and NR (wherein R is selected from the group consisting of H and optionally substituted alkyl);
z is selected from carbon atoms and nitrogen atoms; and
x is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate; and
detecting the fluorescence signal of the platinum (II) complex.
The invention further includes an embodiment of the platinum (II) complex according to the invention wherein the bidentate ligand containing a nitrogen atom comprises a bidentate ligand containing a 10-to 64-membered heterocyclic molecule, consisting of carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur, wherein such heterocyclic molecule contains at least one nitrogen atom.
The invention further includes an embodiment of the use of a platinum (II) complex of the invention in the manufacture of a medicament for treating a subject having cancer.
The invention further includes embodiments of the use of the platinum (II) complexes of the invention in the manufacture of compounds for use in the methods of monitoring cells of the invention.
Examples
The examples and embodiments described herein are for illustrative purposes only and various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application. Furthermore, any element or limitation of any invention or embodiment thereof disclosed herein may be combined (alone or in any combination) with any and/or all other elements or limitations of any other invention or embodiment thereof disclosed herein, and all such combinations are contemplated, without limiting the scope of the invention thereto.
Example 1: synthesis and characterization of platinum (II) complexes
Example 1 is a composition containing 1- (3-hydroxybenzo [ b ]]Synthesis and characterization of a non-limiting example of a platinum (II) complex of a thien-2-yl) ethanone (Hbt) ligand. Hbt ligand was prepared according to the reported procedure (Chan, Low et al 2011). Reacting the complex Fe (acac)3(0.20 mmol) and 2-thiosalicylic acid (0.20 mmol) were added to a round bottom flask with a stir bar followed by ethylene glycol (4 ml). The mixture was heated at 120 ℃ for 4-24 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was treated with HCl (aqueous solution, 37 wt%, 20 ml) for 0.5 h, followed by extraction with chloroform (3 × 30 ml). Chloroform extract over MgSO4Dried and evaporated to remove the solvent. The crude product was purified by column chromatography on silica gel (eluent: pure n-hexane to n-hexane/EtOAc (30:1 v/v)).
By reacting cis- [ PtI2(NH3)2](245 mg, 0.51 mmol) AgNO in a 50 ml two-necked flask3(170 mg, 1.0 mmol) MeOH/H2Synthesis of Complex 1 was carried out in O (20 ml; volume: 1:1) solution. A yellow precipitate formed immediately. The reaction was stirred for 1 hour, then filtered through celite to remove yellow precipitate. Freshly prepared 2-acetylbenzo [ b ] was added over a period of 10 minutes under nitrogen protection]Thiophene-3-ol sodium (Kbt) solution (4 mL KOH (aq., 0.128M) and 96 mg Hbt in MeOH/H2O (5 ml; volume: 1: 1). After heating at 60 ℃ overnight, the organic solution was removed by rotary evaporator. 195 mg of the product was obtained by filtration from the aqueous solution (yield: 93%). DeltaH(300 MHz, DMSO) 7.93 (1 H, d, J 7.8), 7.87 (1 H, d, J 8.2), 7.73 (1 H, t, J7.1), 7.45 (1 H, t, J 7.2), 4.77-4.87 (6 H, m), 2.27 (3 H, s).HRMS (ESI, [M – NO3]+): m/z C10H13N2O2Calculated PtS value 420.0346, found 420.0359.
Figure 568959DEST_PATH_IMAGE035
By reacting (bpy) PtCl2(210 mg, 0.5 mmol) MeOH/H containing AgOTf (257 mg, 1.0 mmol) added to a 50 mL two-necked flask2Synthesis of Complex 2 was carried out in O (20 ml; volume: 1:1) solution. A white precipitate formed immediately. The reaction was stirred for 1 hour, then filtered through celite to remove the precipitate. Freshly prepared 2-acetylbenzo [ b ] was added over a period of 10 minutes under nitrogen protection]Thiophene-3-sodium alkoxide (Nabt) solution (2 mL NaOH (aq., 0.25M) and 96 mg Hbt in MeOH/H2O (5 ml; volume: 1: 1). After heating at 66 ℃ overnight, a yellow precipitate formed. Filtration from aqueous solution gave 280 mg of product, which was washed with 5 ml of MeOH (yield: 81%). DeltaH(400 MHz, DMSO) 8.98 (1 H, d, J 5.5), 8.83 (1 H, d, J 5.6), 8.54 (1 H, d, J8.0), 8.50 (1 H, d, J 8.2), 8.41 (1 H, t, J 7.8), 8.35 (1 H, t, J 7.8), 8.26 (1 H, d, J 8.0), 7.89 – 7.84 (2 H, m), 7.81 (1 H, t, J 6.6), 7.76 (1 H, dt, J7.6, 0.9), 7.46 (1 H, t, J 7.5), 2.46 (3 H, s).δ F (376 MHz, DMSO) -77.72.HRMS (ESI, [M –OTf]+): m/z C20H15N2O2Calculated PtS value 542.0504, found 542.0516.
Figure 450940DEST_PATH_IMAGE036
Example 1 a: synthesis and characterization of additional platinum (II) complexes
By reacting cis- [ PtI2(NH3)2](245 mg, 0.51 mmol) AgNO in a 50 ml two-necked flask3(170 mg, 1.0 mmol) MeOH/H2O (20 mm)Lifting; volume: 1:1) solution to carry out the synthesis of the complex 1 b. A yellow precipitate formed immediately. The reaction was stirred for 1 hour, then filtered through celite to remove yellow precipitate. Freshly prepared KFbt solution (4 mL KOH (aq., 0.128M) and 105 mg HFbt in MeOH/H) were added over a 10 minute period under nitrogen blanket2O (5 ml; volume: 1: 1). After heating at 60 ℃ overnight, the organic solution was removed by rotary evaporator. The product was obtained by filtration from the aqueous solution.
By reacting cis- [ PtI2(NH3)2](245 mg, 0.51 mmol) AgNO in a 50 ml two-necked flask3(170 mg, 1.0 mmol) MeOH/H2Synthesis of Complex 1c was carried out in O (20 ml; volume: 1:1) solution. A yellow precipitate formed immediately. The reaction was stirred for 1 hour, then filtered through celite to remove yellow precipitate. Freshly prepared KBrbt solution (4 ml KOH (aq., 0.128M) and 135.6 mg HBrbt in MeOH/H under nitrogen blanket were added over a period of 10 minutes2O (5 ml; volume: 1: 1). After heating at 60 ℃ overnight, the organic solution was removed by rotary evaporator. The product was obtained by filtration from the aqueous solution.
By reacting cis- [ PtI2(NH3)2](245 mg, 0.51 mmol) AgNO in a 50 ml two-necked flask3(170 mg, 1.0 mmol) MeOH/H2Synthesis of Complex 1d was carried out in O (20 ml; volume: 1:1) solution. A yellow precipitate formed immediately. The reaction was stirred for 1 hour, then filtered through celite to remove yellow precipitate. Freshly prepared KMebt solution (4 ml KOH (aq., 0.128M) and 103 mg HMebt in MeOH/H under nitrogen blanket were added over a 10 minute period2O (5 ml; volume: 1: 1). After heating at 60 ℃ overnight, the organic solution was removed by rotary evaporator. The product was obtained by filtration from the aqueous solution.
By reacting cis- [ PtI2(NH3)2](245 mg, 0.51 mmol) AgNO in a 50 ml two-necked flask3(170 mg of a mixture of these,1.0 mmole) of MeOH/H2Synthesis of Complex 1e was carried out in O (20 ml; volume: 1:1) solution. A yellow precipitate formed immediately. The reaction was stirred for 1 hour, then filtered through celite to remove yellow precipitate. Freshly prepared KPhbt solution (4 ml KOH (aq, 0.128M) and 127 mg HPhbt in MeOH/H under nitrogen blanket were added over a 10 minute period2O (5 ml; volume: 1: 1). After heating at 60 ℃ overnight, the organic solution was removed by rotary evaporator. The product was obtained by filtration from the aqueous solution.
By reacting (bpy) PtCl2(210 mg, 0.5 mmol) MeOH/H containing AgOTf (257 mg, 1.0 mmol) added to a 50 mL two-necked flask2Synthesis of Complex 2b was carried out in O (20 ml; volume: 1:1) solution. A white precipitate formed immediately. The reaction was stirred for 1 hour, then filtered through celite to remove the precipitate. Freshly prepared NaFbt solution (2 mL NaOH (aq., 0.25M) and 105 mg HFbt in MeOH/H were added over a 10 minute period under nitrogen blanket2O (5 ml; volume: 1: 1). After heating at 66 ℃ overnight, a yellow precipitate formed. The product was filtered from the aqueous solution and washed with 5 ml of MeOH.
By reacting (bpy) PtCl2(210 mg, 0.5 mmol) MeOH/H containing AgOTf (257 mg, 1.0 mmol) added to a 50 mL two-necked flask2Synthesis of Complex 2c was carried out in O (20 ml; volume: 1:1) solution. A white precipitate formed immediately. The reaction was stirred for 1 hour, then filtered through celite to remove the precipitate. Freshly prepared NaBrbt solution (2 ml NaOH (aq., 0.25M) and 134.6 mg HBrbt in MeOH/H under nitrogen blanket were added over a 10 minute period2O (5 ml; volume: 1: 1). After heating at 66 ℃ overnight, a yellow precipitate formed. The product was filtered from the aqueous solution and washed with 5 ml of MeOH.
Example 2: stabilization of platinum (II) complexes to GSH
Example 2 is the stabilization of GSH by a non-limiting example of a platinum (II) complex containing a 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligand in PBS solution. Complexes 1 and 2 were dissolved in DMSO/PBS solution (1: 9, v/v) to obtain final concentrations of 20. mu.M complex, respectively. UV-visible absorption spectra were recorded at different time intervals. Complexes 1 and 2 were incubated with GSH (final 2 mM) in DMSO/PBS solution (1: 9, v/v), respectively. UV-visible absorption spectra were recorded at different time intervals.
Complexes 1 and 2 were dissolved in DMSO/PBS solutions (1: 19, v/v), respectively, to obtain final concentrations of 20. mu.M of each complex. GSH was added to these solutions to a final concentration of 2 mM. The emission spectra of the resulting solutions were recorded at different time intervals with excitation wavelength λ ex = 381 nm.
The stability of complexes 1 and 2 in PBS solution was checked by UV-visible spectrophotometry (figure 5 a). For complex 2, no spectral change was observed after 72 hours at room temperature. For complex 1, a modest spectral change was observed. These results indicate that complexes 1 and 2 are relatively stable in aqueous solution.
The reaction of complexes 1 and 2 with GSH was first checked by UV-visible spectrophotometry. Significant spectral changes were obtained when GSH (2 mM) was added to solutions of complexes 1 and 2 (20 μ M) in PBS. The response of complexes 1 and 2 to the presence of GSH was examined by monitoring the change in luminescence intensity (fig. 6). Treatment of complex 1 with GSH produced an increase in emission intensity near 450 nm, and a similar finding was observed for complex 2 in the presence of GSH. This indicates that the 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligand is released from the platinum (II) complex, which may be due to reaction with GSH. The rate of increase of emission intensity at 450 nm may be correlated with the release of 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligand from the platinum (II) complex. The emission intensity of complex 2 (λ em = 450 nm) reached saturation within 2 hours, whereas the emission intensity of complex 1 (λ em = 450 nm) did not reach saturation even after 24 hours of incubation.
Example 3: luminescence of platinum (II) complexes in the Presence of ctDNA
Example 3 is the emission spectrum of a non-limiting example of the platinum (II) complex in the presence of ctDNA. Solutions of complexes 1 and 2 (20. mu.M) in DMSO/PBS (1: 19, v/v) were prepared. Stock solutions of ctDNA were prepared. Aliquots of ctDNA stock solutions were added to the solutions of complexes 1 and 2, respectively. After 5 minutes of incubation, the emission spectrum was recorded with an excitation wavelength λ ex = 424 nm.
Complexes 1 and 2 are weakly emissive in aqueous solution with a λ max at 600 nm for complex 1 and 580 nm for complex 2. In the literature, it has been reported that the emission intensity of luminescent platinum (II) complexes is increased by the presence of biomolecules, such as DNA. The emission intensity of complexes 1 and 2 in the presence of DNA was examined. As shown in FIG. 7, the emission intensity of complex 2 increased 3.1 times when 0.5 equivalents of ctDNA was added and 32 times when 10 equivalents of ctDNA was added. In contrast, for complex 1, only a 1.5-fold increase in emission intensity was found upon addition of 10 equivalents of ctDNA. Previous studies have shown luminescence [ Pt ]II(C^N^C)L]n+Complexes exhibit strong luminescence when bound to double-stranded DNA, while emission is relatively weak when they are not bound in aqueous solution (Liu, Chenng et al 1996, Chen, Yang et al 1999, Ma and Chen 2003, Ma, Shum et al 2005, Zou, Liu et al 2014). As described herein, the different emission intensity enrichment effects for complexes 1 and 2 indicate different interactions between the platinum (II) complex and DNA. It has been suggested that complex 2 may be directly bound to DNA via intercalation.
Example 4: fluorescence imaging of platinum (II) complexes with 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligands in living cells
Example 4 is fluorescence imaging of a non-limiting example of the platinum (II) complex with a 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligand in living cells. The difference in photoluminescent properties between the platinum (II) complexes and the 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligands offers the possibility to determine the fate of these complexes in vitro and even in vivo.
SW480 (human colorectal cancer) cells were seeded in glass petri dishes (MatTek Co.) and allowed to grow for 24 hours, followed by treatment with 25. mu.M of complex 1,2 or the 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligand, respectively, for 30 minutes. After removal of the medium, the cells were washed with Hank Balanced Salt Solution (HBSS) and then covered with 2 ml of HBSS. Carl Zeiss LSM700 inverted confocal microscope with Plan-Apochromat 40X 1.40NA oil immersion objective was used to capture fluorescence and phase contrast images. Complexes 1,2 and 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligands were excited using a 405 nm laser. The emission above 580 nm was collected for complexes 1 and 2 and within 400-500 nm for 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligand.
To achieve real-time visualization of complex 2 in living cells, time series experiments were performed using a confocal microscope connected to an LCI TC-L staged incubator. SW480 cells were seeded in a glass petri dish (MatTek Co.) and allowed to grow for 24 hours. A solution of complex 2 (25. mu.M) in HBSS was prepared. The cells were washed with HBSS and subsequently with 5 vol.% CO2The batch incubator of (1) was incubated with Complex 2 (25. mu.M in HBSS) at 37 ℃. Carl Zeiss LSM700 inverted confocal microscope with Plan-Apochromat 40X 1.40NA oil immersion objective was used to capture fluorescence and phase contrast images. Imaging was captured immediately after treatment with complex 2. For the time series experiments, the interval time was set to 2.5 minutes and a total of 20 cycles were captured. Complex 2 and 1- (3-hydroxybenzo [ b ]]Thien-2-yl) ethanone ligands were all excited using a 405 nm laser. Collection of emission over 580 nm for Complex 2, p-1- (3-hydroxybenzo [ b ]]Thien-2-yl) ethanone ligand collects emissions within 400-500 nm.
The photoluminescent properties of the complex 1,2 and 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligands allow real-time tracking inside living cells. These include tracking subcellular localization, monitoring structural changes of these platinum (II) complexes under cellular conditions, and biotransformation pathways. For luminescence imaging of complexes 1 and 2, cells were excited at λ ex = 405 nm and emission at wavelengths above 580 nm was collected. For fluorescence imaging of 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligands, cells were excited at λ ex = 405 nm and the emission at 400-500 nm was collected (fig. 8). After incubation of the cells with 25 μ M of complex 2 for 30 minutes, red emission as well as blue emission was observed. For complex 1, only blue emission was observed. The red emission can be attributed to emission from complex 2, while the blue emission is due to the release of the 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligand from these platinum (II) complexes under physiological conditions. Complex 2 shows red and blue emission inside the nucleus. These results indicate that release of the 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligand from complex 2 occurs and accumulates inside the nucleus after cellular uptake. Notably, complex 2 was found to be specifically localized in the nucleus where red and blue emission was detected. An experiment was performed to track complex 2 inside living cells in real time at different time intervals (fig. 9). Images were captured every 2.5 minutes while complex 2 was added to the cells. The complex 2 is rapidly accumulated inside the cell nucleus, and red emission is detected after 5 minutes of culture; the release of the 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligand takes place inside the nucleus of the cell and a blue emission is clearly observed after 15 min incubation. Previous studies have demonstrated cisplatin accumulation in the nucleus by NanoSIMS in conjunction with fluorescence microscopy (Legin, Schintlmeister et al 2014). It has also been found that some highly charged polynuclear platinum drugs may target the nucleus (Benedetti, Peterson et al 2011, Wedlock, Kilburn et al 2013). However, complex 1 showed blue emission inside the cytoplasm, which finding indicated that complex 1 accumulated inside the cytoplasm and released the 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligand there.
Example 5: in vitro cytotoxicity of platinum (II) complexes and 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligands against cancer cells
Example 5 is the in vitro cytotoxicity of a non-limiting example of this platinum (II) complex with a 1- (3-hydroxybenzo [ b ] thiophen-2-yl) ethanone ligand against various human cancer cell lines. Non-limiting examples of human cancers include cervical epithelial cancer, colorectal cancer, hepatocellular cancer, lung cancer, and ovarian cancer.
Complexes 1 and 2, the Hbt ligand, cisplatin and oxaliplatin were evaluated by MTT assay for colorectal cancer (SW 480, HCT 116), non-small cell lung cancer (NCI-H460), hepatocellular carcinoma (Hep G2), cervical epithelial cancer (HeLa), ovarian cancer (A2780), cisplatin-resistant ovarian cancer (A2780 cis) and normal human fibroblastsIn vitro cytotoxicity of human cancer cell lines of cell-like cells (CCD-19 Lu). Cytotoxicity of each complex was measured by plotting a dose-dependent cell viability curve, and the concentration of complex with 50% reduction in cell viability was determined as IC50Values (table 1).
Complexes 1 and 2 can exhibit dose and time dependent cytotoxicity against these cancer cell lines. The complex 2 shows higher anticancer effect, and has less cytotoxicity to normal human fibroblast-like CCD-19Lu cells and IC50The value was about 30. mu.M. Complex 1 shows cytotoxicity equivalent to that of reference complex cisplatin, and has low cytotoxicity to CCD-19Lu cells and IC50The value exceeded 60. mu.M. Complexes 1 and 2 were cytotoxic to ovarian cancer cell lines and they showed comparable IC to cisplatin-sensitive A2780 cells and cisplatin-resistant A2780 cis cells50The value is obtained. However, the anticancer activity of cisplatin and oxaliplatin on A2780 cells is higher than that of A2780 cis cells and IC50The value was 30-fold lower than that of A2780 cis cells. The Hbt ligand has no cytotoxicity to cancer cells and normal cells, and IC50The value is greater than 100. mu.M.
Table 1 shows the in vitro cytotoxicity IC of complexes 1 and 2, cisplatin, oxaliplatin and this Hbt ligand for 72 hours on human colorectal cancer cells (SW 480 and HCT 116), human hepatoma cells (Hep G2), human non-small cell lung cancer cells (NCI-H460), human cervical epithelial cancer cells (HeLa), human ovarian cancer cells (A2780) and its cisplatin-resistant variants (A2780 cis) and normal human fibroblast-like cells (CCD-19 Lu)50The value is obtained.
TABLE 1
Figure 297673DEST_PATH_IMAGE037
Additional tests have been performed in the same manner on the following complexes, the results of which are shown below:
complexes 1a, 2a and 3a were cytotoxic to various cancer cell lines, while Hbt ligand showed no cytotoxicity.
TABLE 1a. Complex 1a, 2a, 3a and Hbt ligandsIn vitro cytotoxicity IC on various human cancer cell lines and Normal cell lines50Value of
Figure 226315DEST_PATH_IMAGE038
SW480 and HCT116 = colorectal cancer; NCl-H460= non-small cell lung cancer; hep G2= hepatocellular carcinoma; HeLa = cervical epithelial cancer; NCM460= normal human colonic mucosal epithelial cells; CCD-19Lu = normal human fibroblast-like cells.
Complexes 1a, 2a and 3a showed comparable cytotoxicity against cisplatin-sensitive and cisplatin-resistant cancer cells.
TABLE 2 in vitro cytotoxicity IC of complexes 1a, 2a and 3a on cisplatin-sensitive and cisplatin-resistant cancer cells50Value of
Figure 237128DEST_PATH_IMAGE039
TABLE 3 in vitro cytotoxicity IC of complexes 1b-1e, 2b-2c and various substituted Hbt ligands on human cancer and normal cell lines50Value of
Figure 643838DEST_PATH_IMAGE040
Example 6: cellular uptake and nuclear DNA binding of platinum (II) complexes
Example 6 is a non-limiting example of cellular uptake and nuclear DNA binding of platinum (II) complexes in cancer cells. An exemplary human cancer cell line, as described herein, is the colorectal SW480 cancer cell line. Time-dependent cellular uptake of some exemplary platinum (II) complexes was determined by inductively coupled plasma mass spectrometry (ICP-MS). SW480 cells were seeded in 6-well DMEM-containing plates and allowed to incubate in 5 vol% CO2The growth was carried out in an incubator at 37 ℃ for 24 hours. The medium was removed and replaced with medium containing 10 μ M of complex 1 and 2 or oxaliplatin, respectively. Cells were incubated with each complex for 0.5 hours, 1 hour2 hours, 4 hours and 8 hours. At each time point, cells were harvested by trypsinization, followed by resuspension in H2O and sonicated to obtain homogeneous cell lysates. Protein concentration was quantified using the Bradford protein assay and cell lysates were incubated at 68% HNO3Digested at 60 ℃ for 2 hours and subsequently digested overnight at room temperature.
Time-dependent binding of platinum to nuclear DNA was also determined by ICP-MS. SW480 cells were cultured with 10 μ M of complex 1 and 2 or oxaliplatin for 1 hour, 2 hours, 4 hours and 8 hours. At each time interval, cells were harvested by trypsinization, then resuspended in 300 microliters of lysis buffer (100 mM NaCl, 25 mM EDTA, 0.5% (w/v) SDS, 0.1 mg/mL proteinase K and 10 mM Tris-HCl, pH 8.0) and incubated overnight at 50 ℃. To the cell lysate 300. mu.L phenol CHCl was added3Mixture (1: 1, v/v). After vigorous shaking, the solution was centrifuged at 13,000 rpm for 5 minutes. Two layers were formed and the upper layer containing the DNA was transferred to a new tube. mu.g/mL RNase (no DNase) was added to the DNA solution and then incubated at 37 ℃ for 1 hour. Next, 200. mu.l of ammonium acetate (7.5M) was added, followed by 400. mu.l of 100% ethanol, and the mixture was incubated at-80 ℃ for 30 minutes. The DNA was precipitated by centrifugation at 10,000 rpm for 5 minutes, and the DNA precipitate was washed with 70% ethanol and dried by air. The DNA was dissolved in TE buffer (1 mM EDTA and 10 mM Tris-HCl, pH 7.4). The DNA concentration was quantified by measuring the absorbance at 260 nm. DNA in concentrated HNO3Digesting overnight.
Digesting the cell lysate or digested DNA solution in H2Further diluting in O to obtain HNO3Is less than 5%. The platinum content was quantified by ICP-MS by measuring the most abundant isotope of platinum at m/z 195 and corrected against a calibration curve from a series of platinum standard concentrations. Cellular platinum uptake is expressed as ng platinum/mg protein, and binding of platinum to nuclear DNA is expressed as ng platinum/mg DNA.
FIG. 10 shows the intracellular uptake of platinum and Pt-DNA covalent binding fractions after exposure of SW480 cells to complexes 1 and 2. Complexes 1 and 2 accumulated in SW480 cells at higher levels than oxaliplatin, reflecting the favorable cellular uptake efficiency caused by the lipophilic Hbt ligand in these complexes. In the case of complexes 1 and 2, a greater amount of platinum was found to bind to nuclear DNA, which was about 7-fold higher than the clinical oxaliplatin after 8 hours of culture.
Example 7: in vivo tumor growth inhibition by platinum (II) complexes
Example 7 is the in vivo tumor growth inhibitory effect of a non-limiting example of a platinum (II) complex in nude mice bearing HeLa xenografts. Female BALB/cAnN-nu (nude) mice were purchased from Charles River Laboratories (Wilmington, Mass.). Mice were maintained on request of the Laboratory Animal Unit of the University of Hong Kong (HKU) and tested based on guidelines approved by Committee on the Use of Live Animals in Teaching and Research of HKU. To establish tumors, 100 microliters of 2 × 10 in PBS were injected subcutaneously6Individual HeLa cells were injected into the posterior flank of the mice. At a tumor volume of up to about 50 mm3Thereafter, the mice were randomly divided into three groups of four mice each: solvent control, complex 1 (10 mg/kg) and complex 2 (2.5 mg/kg). Complex 1 was reconstituted in PET (60 % polyethylene glycol 400, 30% ethanol and 10% Tween 80) to a final concentration of 20. mu.g/. mu.L, and Complex 2 was reconstituted in PET to a final concentration of 5. mu.g/. mu.L. PBS containing the same amount of PET was also prepared by subsequent dilution of complexes 1 and 2 in PET in PBS. Complexes 1,2 and solvent were injected into mice individually by intraperitoneal injection, twice or three times a week until the mice were sacrificed.
Tumor size was measured two or three times per week and tumor volume (V) was calculated by the following equation:
Figure 486023DEST_PATH_IMAGE041
where a and b are the longest and shortest diameters of the tumor, respectively.
The tumor growth inhibition effect was calculated by the following equation:
Figure 460933DEST_PATH_IMAGE042
wherein
Figure 270626DEST_PATH_IMAGE043
Is the initial tumor size of the 1 or 2 treatment groups, V is the final tumor size of the 1 or 2 treatment groups,
Figure 356393DEST_PATH_IMAGE044
is the initial tumor size of the solvent control group, and
Figure 53085DEST_PATH_IMAGE045
is the final tumor size of the solvent control group.
As shown in figures 10 and 11, treatment of mice with 10 mg/kg of complex 1 or 2.5 mg/kg of complex 2 twice or three times a week significantly inhibited tumor growth after 10 days (p-value < 0.05). Both complexes 1 and 2 reduced tumor volume by more than 60%. Notably, no death or weight loss was detected in the treated groups.
It is to be understood that the disclosed methods and complexes are not limited to the particular methodology, protocols, and reagents described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the methods and complexes described herein. Such equivalents are intended to be encompassed by the following claims.
While the present invention is described herein with reference to illustrative embodiments for particular applications, it should be understood that the invention is not limited thereto. Those having ordinary skill in the art and access to the teachings provided herein will recognize additional modifications, applications, and embodiments within the scope thereof and additional fields in which the invention would be of significant utility. It is therefore intended by the appended claims to cover any and all such applications, modifications and embodiments within the scope of the present invention.
Various terms have been defined above. To the extent a term used in a claim is not defined above, it should be given the broadest definition persons in the pertinent art have given that term as reflected in at least one printed publication or issued patent.
As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, if the terms "include," have, "" contain, "or variants thereof are used in the detailed description and/or claims, such terms are intended to be inclusive in a manner similar to the term" comprise. The transitional terms/phrases (and any grammatical variants thereof) "include," consist essentially of, "and" consist of.
As used herein, the use of the singular includes the plural unless specifically stated otherwise. The use of "or" means "and/or" unless stated otherwise. As used herein, the use of the term "including" as well as other forms is non-limiting.
As used herein, "optional" or "optionally" means that the subsequently described event or circumstance is present or absent, and that the description includes instances where the event or circumstance is present or instances where it is not present. For example, an optional component in a system means that the component may or may not be present in the system.
All patents, patent applications, provisional applications, and publications mentioned or cited herein are hereby incorporated by reference in their entirety, including all figures and tables, so long as they are not inconsistent with the explicit teachings of this specification.
Reference to the literature
Benedetti, B.T. et al (2011) "Effects of non-volatile coatings-proteins interactions on a coating effect" use of fluorescent compositions as probes for a coating method "Molecular Pharmaceutics 8(3): 940-948.
ChanS.L. -F.et al (2011), "Iron-Ligand Coordination in derived radial cyclicizations: Synthesis of benzos [ b ]]thiophenes by a One-pot Reaction of Iron 1,3-Diketone Complexes with 2-Thiosalicylic Acids." Chemistry – A European Journal 17(17): 4709-4714.
Che, C.M. et al (1999) "platinum (II) complexes of dipyridylphenylazine as reactants for DNA and potential cytoxic agents against cells lines"Chemistry-A European Journal 5(11): 3350-3356.
Legin, A. et al (2014) "NanoSIMS combined with fluorine as a tool for particulate imaging of isopropyl labelled membrane-based anticancerogen drivers"Chemical Science 5(8): 3135-3143.
Liu, H, Q, et al (1996). "cyclotellated platinum (II) complexes as fluorescent switches for calf-thymus DNA.Chemical Communications(9): 1039-1040.
Ma, D.L. and C.M. Che (2003), "A biofunctional platinum (II) complex able of interaction and hydrogen-binding interactions with DNA binding partners and cytoxicity"Chemistry 9(24): 6133-6144.
Ma, D.L. et al (2005) "Water soluble fluorescent molecules complexes with glycosylated and arylarylarylacetate ligands, fluorescent molecules and cytotoxins"Chemical Communication(37): 4675-4677.
Wedlock, L.E. et al (2013). "NanoSIMS multi-element imaging interpretation and nuclear targeting for a high-charged polymeric membrane compound".Chemical Communications 49(62): 6944-6946.
Zou, T. et al (2014). "luminesent cyclic interactive DNA and RNA with double-stranded DNA and RNA"Angewandte Chemie International Edition 53(38): 10119-10123.

Claims (6)

1. A platinum (II) complex comprising:
Figure 19262DEST_PATH_IMAGE001
wherein:
R1and R2Independently selected from the group consisting of amines, optionally substituted amines, -NH3And optionally substituted heterocyclic amines; or a pair of R1And R2Linked together to form a bidentate ligand containing a nitrogen atom;
R3selected from optionally substituted alkyl and optionally substituted aryl;
R4、R5、R6and R7Independently selected from H, halogen and optionally substituted alkyl;
y is a sulfur atom;
z is a carbon atom; and
x is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
2. The platinum (II) complex of claim 1, comprising:
Figure 817454DEST_PATH_IMAGE002
Figure 157300DEST_PATH_IMAGE003
Figure 91757DEST_PATH_IMAGE004
Figure 350700DEST_PATH_IMAGE005
wherein
X is selected from the group consisting of fluoride, chloride, bromide, iodide, triflate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
3. The platinum (II) complex according to claim 1, wherein said bidentate ligand containing a nitrogen atom comprises a bidentate ligand containing a 10-to 64-membered heterocyclic molecule, consisting of carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein such heterocyclic molecule contains at least one nitrogen atom.
4. Use of a platinum (II) complex as defined in any preceding claim in the manufacture of a medicament for treating a subject having cancer.
5. An in vitro method for monitoring cells in vitro for the purpose of non-disease diagnosis and treatment, comprising:
applying at least one platinum (II) complex according to any one of the preceding claims 1 to 3; and
detecting a fluorescent signal of the platinum (II) complex.
6. Use of a platinum (II) complex as defined in any one of the preceding claims 1 to 3 for the manufacture of a compound for use in a method of monitoring cells.
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