1. A tetravalent platinum complex containing posaconazole is characterized by having a structure shown as a general formula I:

wherein the content of the first and second substances,is cisplatin, carboplatin, heptaplatin, nedaplatin, oxaliplatin, lobaplatin, miboplatin, picoplatin, NDDP or

R₃Is hydroxyl, straight chain or branched chain C1-C20 saturated alkyl ester, straight chain or branched chain C1-C20 unsaturated alkyl ester or straight chain or branched chain C1-C20 carbamate;

n is an integer of 0 to 5.

2. The posaconazole-containing tetravalent platinum complex according to claim 1, wherein the posaconazole-containing tetravalent platinum complex has one of the following structures:

3. the preparation method of the posaconazole-containing tetravalent platinum complex according to claim 1 or 2, wherein the method is one of the following methods:

the method comprises the following steps:

adding a divalent platinum anti-tumor drug IV and a hydrogen peroxide solution into a reaction vessel, and controlling the reaction temperature to be 20-60 ℃ for reaction to prepare dihydroxyl substituted tetravalent platinum oxide V;

adding posaconazole II, acid anhydride and a solvent into a reaction container, and reacting at 50-100 ℃ to prepare posaconazole III containing a carboxylic acid side chain;

adding TBTU, triethylamine, a solvent and posaconazole III containing a carboxylic acid side chain into a reaction vessel, replacing air in a system with inert gas, stirring and reacting at room temperature, adding dihydroxyl-substituted tetravalent platinum oxide V into the reaction system, reacting at room temperature for 12-72 hours, carrying out reduced pressure distillation to remove the solvent, and carrying out column chromatography to obtain R₃A tetravalent platinum complex of posaconazole which is a hydroxyl group;

the second method comprises the following steps:

adding solvent, acid anhydride and R in the first method into a reaction vessel₃Substituting air in a system with inert gas, stirring and reacting at room temperature, distilling under reduced pressure to remove solvent, and performing column chromatography to obtain R₃A tetravalent platinum complex of posaconazole being a linear or branched C1-C20 saturated or unsaturated alkyl ester;

the third method comprises the following steps:

adding solvent, isocyanate containing alkyl side chain and R in the first method into a reaction vessel₃Tetravalent platinum complex of posaconazole as hydroxyl group, using an inert compoundReplacing air in the system with sexual gas, stirring at room temperature for reaction, distilling under reduced pressure to remove solvent, and performing column chromatography to obtain R₃A tetravalent platinum complex of posaconazole which is a linear or branched C1-C20 carbamate;

4. the method for preparing a posaconazole-containing tetravalent platinum complex according to claim 3, wherein the inert gas is nitrogen.

5. The preparation method of the posaconazole-containing tetravalent platinum complex according to claim 3, wherein the concentration of the hydrogen peroxide solution is 30%.

6. The preparation method of posaconazole-containing tetravalent platinum complex according to claim 3, wherein the solvent is CH₃CN or DMF.

7. The use of a class of tetravalent platinum complexes containing posaconazole according to claim 1 or 2 for the preparation of antitumor drugs.

8. The use of claim 7, wherein the tumor is human liver cancer HepG2, lung cancer A549, intestinal cancer HCT116, breast cancer MDA-MB-231, or cisplatin-resistant lung adenocarcinoma.

9. Use of a class of tetravalent platinum complexes containing posaconazole according to claim 1 or 2 for the preparation of antifungal agents.

10. The use according to claim 9, wherein the fungus is candida albicans, candida krusei, candida tropicalis, cryptococcus neoformans, candida glabrata or candida parapsilosis.

Background

The platinum antineoplastic drugs are widely used for treating malignant tumors clinically. Currently, the FDA in the united states has approved three platinum drugs on the market, including cisplatin, carboplatin, and oxaliplatin. Cisplatin can be used for treating ovarian cancer, prostatic cancer, testis cancer, lung cancer, nasopharyngeal carcinoma, esophageal carcinoma, malignant lymphoma, head and neck squamous cell carcinoma, thyroid carcinoma, and osteogenic sarcoma. Carboplatin is a second-generation platinum drug, is a broad-spectrum antitumor drug, has no cross drug resistance with other antitumor drugs, has cross drug resistance with cisplatin, and is mainly used for small cell lung cancer, ovarian cancer, testicular tumor, head and neck squamous cell carcinoma and the like. Oxaliplatin is a third-generation platinum drug, has good curative effect on colorectal cancer and ovarian cancer, and has certain curative effect on gastric cancer, non-Hodgkin lymphoma, non-small cell lung cancer and head and neck tumors. The platinum antineoplastic drugs are the most widely used chemotherapeutic drugs for tumor patients in China, but the platinum antineoplastic drugs are easy to generate drug resistance after long-term use and have side effects of renal toxicity, gastrointestinal adverse reactions, blood toxicity and the like.

Posaconazole is a derivative of itraconazole, and is a third-generation triazole antifungal drug. Posaconazole can effectively prevent invasive fungal infection, and is suitable for fungemia, respiratory, digestive tract and urinary tract mycosis, peritonitis, meningitis and the like caused by candida and cryptococcus fungi. In addition, recent studies have found that posaconazole inhibits the hedgehog (hh) signaling pathway, blocks tumor neovascularization, and inhibits the progression of various tumors, such as basal cell carcinoma, medulloblastoma. Posaconazole has high clinical safety, low drug-drug interaction and low toxic and side effects. Posaconazole exhibits unique antitumor properties, but its antitumor activity is still low, usually at the level of several tens of micromolar.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides a tetravalent platinum complex containing posaconazole, which has a brand-new framework structure and excellent antitumor and antifungal activities and can be used for preparing antitumor drugs and antifungal drugs.

The invention is realized by the following technical scheme:

a tetravalent platinum complex containing posaconazole has a structure shown as a general formula I:

wherein the content of the first and second substances,is cisplatin, carboplatin, heptaplatin, nedaplatin, oxaliplatin, lobaplatin, miboplatin, picoplatin, NDDP or

R₃Is hydroxyl, straight chain or branched chain C1-C20 saturated alkyl ester, straight chain or branched chain C1-C20 unsaturated alkyl ester or straight chain or branched chain C1-C20 carbamate;

n is an integer of 0 to 5.

Preferably, the structure of the posaconazole-containing tetravalent platinum complex is one of the following structures:

the preparation method of the tetravalent platinum complex containing posaconazole is one of the following methods:

the method comprises the following steps:

adding a divalent platinum anti-tumor drug IV and a hydrogen peroxide solution into a reaction vessel, and controlling the reaction temperature to be 20-60 ℃ for reaction to prepare dihydroxyl substituted tetravalent platinum oxide V;

adding posaconazole II, acid anhydride and a solvent into a reaction container, and reacting at 50-100 ℃ to prepare posaconazole III containing a carboxylic acid side chain;

adding TBTU, triethylamine, a solvent and posaconazole III containing a carboxylic acid side chain into a reaction vessel, replacing air in a system with inert gas, stirring and reacting at room temperature, adding dihydroxyl-substituted tetravalent platinum oxide V into the reaction system, reacting at room temperature for 12-72 hours, carrying out reduced pressure distillation to remove the solvent, and carrying out column chromatography to obtain R₃A tetravalent platinum complex of posaconazole which is a hydroxyl group;

the second method comprises the following steps:

adding solvent, acid anhydride and R in the first method into a reaction vessel₃Substituting air in a system with inert gas, stirring and reacting at room temperature, distilling under reduced pressure to remove solvent, and performing column chromatography to obtain R₃A tetravalent platinum complex of posaconazole being a linear or branched C1-C20 saturated or unsaturated alkyl ester;

the third method comprises the following steps:

adding into a reaction vesselR in solvent, isocyanate containing alkyl side chain and method one₃Substituting air in a system with inert gas, stirring and reacting at room temperature, distilling under reduced pressure to remove solvent, and performing column chromatography to obtain R₃A tetravalent platinum complex of posaconazole which is a linear or branched C1-C20 carbamate;

preferably, the inert gas is nitrogen.

Preferably, the concentration of the hydrogen peroxide solution is 30%.

Preferably, the solvent is CH₃CN or DMF.

The tetravalent platinum complex containing posaconazole is applied to preparation of antitumor drugs.

Preferably, the tumor is human liver cancer HepG2, lung cancer A549, intestinal cancer HCT116, breast cancer MDA-MB-231 or cisplatin-resistant lung adenocarcinoma.

The tetravalent platinum complex containing posaconazole is applied to the preparation of antifungal medicines.

Preferably, the fungus is Candida albicans, Candida krusei, Candida tropicalis, Cryptococcus neoformans, Candida glabrata, or Candida parapsilosis.

Compared with the prior art, the invention has the following beneficial technical effects:

the complex can fully exert the advantages of both the posaconazole and the tetravalent platinum compound. The unique antitumor mechanism of posaconazole is utilized to play an excellent synergistic antitumor effect with tetravalent platinum. In addition, tumor patients are often hypoimmunity and susceptible to deep fungal infections. The complex still has excellent activity of resisting deep fungal infection while exerting the anti-tumor activity, and exerts excellent treatment effect on fungal infection of tumor patients clinically. The screening of the antitumor activity of the invention discovers that the compounds have the antitumor activityThe tumor activity is obviously better than that of posaconazole and cisplatin and the combination of posaconazole and cisplatin. IC of various tumor cell lines tested as Compounds 4 and 5₅₀The ranges are 1.33 to 6.79. mu.M and 0.81 to 8.66. mu.M, respectively. The antifungal activity screening finds that the compounds have excellent and broad-spectrum antifungal activity, and particularly have excellent antifungal activity on drug-resistant Candida albicans of posaconazole. For example, the minimum inhibitory concentration MIC of the compounds 3-6 and 9 to the posaconazole-resistant Candida albicans 103 is less than or equal to 12.5 mu M, which is obviously superior to that of posaconazole (MIC)>500 μM)。

The synthesis method provided by the invention has the advantages of simple synthesis route, easily obtained synthesis raw materials and easy realization.

The application of the tetravalent platinum complex containing posaconazole in preparing the anti-cancer drugs and the antifungal drugs can provide more choices for clinical treatment.

Detailed Description

The present invention will now be described in further detail with reference to specific examples, which are intended to be illustrative, but not limiting, of the invention.

The first aspect of the invention provides a tetravalent platinum complex containing posaconazole, which has a structure shown as a general formula I:

wherein the content of the first and second substances,is cisplatin, carboplatin, heptaplatin, nedaplatin, oxaliplatin, lobaplatin, miboplatin, picoplatin, NDDP or

R₃Is hydroxyl, straight chain or branched chain C1-C20 saturated alkyl ester, straight chain or branched chain C1-C20 unsaturated alkyl ester or straight chain or branched chain C1-C20 carbamate; n is an integer of 0 to 5.

The structure of the tetravalent platinum complex containing posaconazole is one of the following structures:

the second aspect of the invention provides a preparation method of a tetravalent platinum complex containing posaconazole,

the method comprises the following steps:

adding a divalent platinum anti-tumor drug IV and a hydrogen peroxide solution into a reaction vessel, and controlling the reaction temperature to be 20-60 ℃ for reaction to prepare dihydroxyl substituted tetravalent platinum oxide V;

adding posaconazole II and an anhydride in CH to a reaction vessel₃CN or DMF is used as a solvent, and the posaconazole III containing the carboxylic acid side chain is prepared by reaction at 50-100 ℃;

adding a solvent, TBTU, triethylamine and posaconazole III containing a carboxylic acid side chain into a reaction vessel, replacing air in a system with nitrogen, stirring at room temperature for reaction, adding dihydroxyl-substituted tetravalent platinum oxide V into the reaction system, reacting at room temperature for 12-72 hours, distilling under reduced pressure to remove the solvent, and carrying out column chromatography to obtain R₃A tetravalent platinum complex I-1 of posaconazole which is a hydroxyl group;

the second method comprises the following steps:

adding solvent into a reaction vessel, and adding R in the first method₃Substituting air in a system with nitrogen, stirring and reacting at room temperature, carrying out reduced pressure distillation to remove a solvent DMF, and carrying out column chromatography to obtain R₃Is a tetravalent platinum complex I of posaconazole which is a linear or branched C1-C20 saturated or unsaturated alkyl ester.

The third method comprises the following steps:

adding solvent into a reaction vessel, and adding R in the first method₃Substituting air in a system by hydroxyl tetravalent platinum complex I-1 of posaconazole and isocyanate containing alkyl side chain, stirring and reacting at room temperature, distilling under reduced pressure to remove solvent DMF, and performing column chromatography to obtain R₃A tetravalent platinum complex I of posaconazole which is a linear or branched C1-C20 carbamate;

the solvent is DMF or CH₃CN。

Cisplatin (IV-1) will be exemplified.

Cisplatin (IV-1) reacts with excessive hydrogen peroxide to obtain intermediate oxoplatin (V-1).

And heating the posaconazole (II) and acid anhydride in acetonitrile or DMF solvent to react to obtain the posaconazole (III) containing the carboxylic acid side chain.

In a DMF solvent, under the action of TBTU and triethylamine, oxygen platinum (V-1) and posaconazole (III) containing carboxylic acid side chain are prepared to obtain R₃The group is the target compound VI of hydroxyl.

The target compound VI reacts with linear or branched saturated or unsaturated C2-C40 acid anhydride to obtain R₃The group is saturated or unsaturated C1-C20 alkyl ester. The target compound VI reacts with linear or branched saturated or unsaturated C1-C20 isocyanate to obtain R₃The group is a saturated or unsaturated C1-C20 carbamate.

With reference to the above synthetic methods, carboplatin, heptaplatin, nedaplatin, oxaliplatin, lobaplatin, miriplatin, picoplatin, NDDP orThe tetravalent platinum complex containing posaconazole can be prepared. For example, oxaliplatin (VIII) is oxidized by hydrogen peroxide to prepare oxaliplatin (IX), and then the oxaliplatin (VIII) reacts with posaconazole containing a carboxylic acid side chain to prepare a target compound X.

The third aspect of the invention provides an application of a tetravalent platinum complex containing posaconazole in preparing antitumor drugs and antifungal drugs.

The tetravalent platinum complex containing posaconazole is preferably a compound 3,4,5 or 9.

The tumor is malignant tumor such as lung cancer, intestinal cancer, breast cancer, liver cancer and cisplatin-resistant lung cancer. The fungi are infections of various fungi such as Candida albicans, Candida krusei, Candida tropicalis, Cryptococcus neoformans, Candida glabrata, Candida parapsilosis, etc.

The present invention will now be described in detail with reference to examples, but the practice of the present invention is not limited thereto. The reagents and starting materials used in the present invention are commercially available or can be prepared according to literature procedures.

The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers.

The compounds referred to in the following examples correspond to the chemical formula I,¹H-NMR、¹³The C-NMR and HRMS data are shown in Table 1, wherein the numbers 1-10 correspond to the compounds 1-10 and the examples 1-10 respectively.

TABLE 1 chemical structural formulas of target compounds 1 to 10,¹H-NMR、¹³C-NMR and HRMS data

Example 1: synthesis of Compound 1

Adding 1.0g of cisplatin, namely the compound IV-1, into 25mL of 30% hydrogen peroxide, reacting for 2h at 60 ℃, filtering, standing the filtrate to obtain yellow needle-shaped solid 0.95g of oxoplatin, namely the compound V-1, wherein the yield is 85%.

Posaconazole, compound II (1.0g,1.43mmol) and succinic anhydride (0.71g,7.1mmol) were reacted in DMF solvent with heating and stirring at 100 ℃ for 12h, and purified by column chromatography (DCM: MeOH ═ 20: 1) to give posaconazole III-1(0.52g, 45%) containing the carboxylic acid side chain.

Posaconazole III-1(50mg,0.0625mmol) containing carboxylic acid side chain, TBTU (30mg,0.0937mmol) and triethylamine (9.5mg,0.0937mmol) were added in succession to 2mL of dry DMF, and after stirring at room temperature for 10min, oxoplatin V-1(21mg,0.0625mmol) was added and stirring at room temperature under nitrogen for 12 h. After the reaction was finished, the solvent was evaporated to dryness, and the residue was purified by silica gel column chromatography (DCM: MeOH ═ 20: 1) to give compound 1 as a brown solid (32mg, yield 46%).

Example 2: synthesis of Compound 2

Compound 1(30mg,0.0269mmol) and acetic anhydride (2.8mg,0.028mmol) were sequentially added to 2mL of DMF and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was evaporated to dryness, and the residue was purified by silica gel column chromatography (DCM: MeOH ═ 20: 1) to give compound 2 (23mg, yield 74%) as a brown solid.

Example 3: synthesis of Compound 3

Refer to example 2. Reaction of compound 1(30mg,0.0269mmol) with n-hexanoic anhydride (6mg,0.028 mmol) in DMF (2mL) gave compound 3 as a brown solid (22mg, 64% yield).

Example 4: synthesis of Compound 4

Refer to example 2. Reaction of compound 1(30mg,0.0269mmol) with n-octanoic anhydride (7.6mg,0.028 mmol) in DMF (2mL) gave compound 4 as a brown solid (20mg, 60% yield).

Example 5: synthesis of Compound 5

Refer to example 2. Reaction of compound 1(30mg,0.0269mmol) with hexyl isocyanate (3.5mg,0.028 mmol) in DMF (2mL) gave compound 5 as a brown solid (22mg, 65% yield).

Example 6: synthesis of Compound 6

Refer to example 2. Reaction of compound 1(30mg,0.0269mmol) with n-octyl isocyanate (4.3 mg,0.028mmol) in DMF (2mL) gave compound 6 as a brown solid (24mg, 67% yield).

Example 7: synthesis of Compound 7

Refer to example 2. Reaction of compound 1(30mg,0.0269mmol) with dodecyl isocyanate (5.9 mg,0.028mmol) in DMF (2mL) gave compound 7 as a brown solid (26mg, 72% yield).

Example 8: synthesis of Compound 8

Refer to example 1. The posaconazole and glutaric anhydride react in DMF solvent under heating and stirring to prepare the posaconazole III-2 containing the carboxylic acid side chain. Posaconazole III-2(50 mg,0.0614mmol) containing the carboxylic acid side chain, TBTU (29.5mg,0.0921mmol) and triethylamine (9.3mg,0.0921 mmol) were added successively to 2mL of dry DMF and after stirring at room temperature for 10min, oxoplatin (20.4 mg,0.0625mmol) was added and stirring at room temperature under nitrogen was carried out for 12 h. After the reaction was finished, the solvent was evaporated to dryness, and the residue was purified by silica gel column chromatography (DCM: MeOH ═ 20: 1) to give compound 8 as a brown solid (30mg, yield 43%).

Example 9: synthesis of Compound 9

Refer to example 2. Reaction of compound 8(30mg,0.0265mmol) with acetic anhydride (2.8mg,0.028mmol) in DMF (2mL) gave compound 9 as a pale yellow solid (25mg, 80% yield).

Example 10: synthesis of Compound 10

Refer to example 1. Posaconazole III-1(50mg,0.0625mmol) containing carboxylic acid side chain, TBTU (30mg,0.0937mmol) and triethylamine (9.5mg,0.0937mmol) were added in succession to 2mL of dry DMF, and after stirring at room temperature for 10min, platinum oxide IX (26.8mg,0.0625mmol) was added and stirring at room temperature under nitrogen for 12 h. After the reaction was finished, the solvent was evaporated to dryness, and the residue was purified by silica gel column chromatography (DCM: MeOH ═ 20: 1) to give compound 10 as a pale yellow solid (36mg, yield 47%).

Example 11: antitumor Activity test of Compounds of the present invention

The compound of the present invention is tested for inhibition of tumor cell proliferation by the conventional CKK-8 method.

The cell lines are selected from lung cancer A549, liver cancer HepG2, intestinal cancer HCT116, breast cancer MDA-MB-231 and cis-platinum-resistant lung cancer A549 which are purchased from Shanghai Life sciences institute cell banks.

The culture solution is DMEM + 10% NBS + double antibody.

Preparing a sample solution: test compounds were dissolved in DMSO (Merck) to prepare a 10mM stock solution. The mother liquor was diluted with the medium to give drugs at final concentrations of 100. mu.M, 50. mu.M, 25. mu.M, 12.5. mu.M, 6.25. mu.M, 3.125. mu.M, 1.562. mu.M and 0.781. mu.M, respectively.

The anti-tumor compounds Cisplatin (CDDP), Posaconazole (PSZ) and cisplatin and posaconazole 1:1 were mixed (PSZ + CDDP) to prepare control solutions under the same conditions.

The concentration of each hole of a 96-hole plate is 8 multiplied by 10⁴100 μ L of cell suspension per mL, 8000 cells/well, at 37 deg.C with 5% CO₂In the incubator. After 24 hours, the upper layer of the culture medium was aspirated, and the culture medium containing the sample and the control solution were added thereto at 100. mu.L/well and allowed to act at 37 ℃ for 72 hours. Adding CKK-810 mu L into each well, placing in an incubator, measuring 570nm OD value with MK-2 full-automatic enzyme standard instrument after 1 hour of action, and calculating half inhibitory concentration IC₅₀。

The antitumor activity of some preferred compounds is detailed in table 2, wherein samples 1-10 refer to the tetravalent platinum complex containing posaconazole prepared in the corresponding examples, such as compound 1, which is the compound obtained in example 1, and so on.

TABLE 2 half inhibitory concentration IC of partial compounds of the invention on tumor cells₅₀(Unit: μ M)

N.d. representative of no test

The results show that the compound of the invention generally shows broad-spectrum and excellent anti-tumor activity, and can be used for treating liver cancer HepG2, lung cancer A549, intestinal cancer HCT116 and breast cancer MDA-MB-231 produced excellent proliferation inhibition. The antitumor activity of part of compounds is stronger than that of cisplatin. For example, the compound 4 shows the optimal anti-tumor activity on the whole, and has half inhibition concentration IC on lung cancer A549, liver cancer HepG2, intestinal cancer HCT116 and breast cancer MDA-MB-231₅₀Are below 4. mu.M. In addition, part of the high-activity compounds still show excellent antitumor activity on cisplatin-resistant A549 tumor cells. IC of compounds 5,6 and 7, for example, cisplatin-resistant Lung cancer A549₅₀Less than 5 mu M, obviously better than cisplatin (IC)₅₀31.47 μ M). In addition, the antitumor activity of the compound is superior to that of the combination of posaconazole and cisplatin. Therefore, the compound provided by the invention has a brand-new framework structure and excellent anti-tumor activity, and can be used for developing anti-tumor drugs.

Example 12: antifungal Activity test of Compounds of the present invention

(I) in vitro antifungal Activity screening

Seven common human pathogenic fungi are selected as test bacteria. 1) Candida albicans (Candida albicans, Standard strain SC 5314); 2) candida albicans posaconazole resistant strain (Candida albicans 103); 3) candida krusei (Candida krusei); 4) candida tropicalis (Candida tropicalis); 5) cryptococcus neoformans (Cryptococcus neoformans, standard strain 32609); 6) candida glabrata (Candida glabrata); 7) candida parapsilosis (Candida parapsilosis). The positive control drug is selected from Posaconazole (PSZ, Posaconazole), Cisplatin (CDDP, Cisplatin) and a 1:1 mixture of Posaconazole and Cisplatin (PSZ + CDDP).

Preparing a bacterial suspension: the strain was cultured in YEPD liquid medium at 35 ℃ for 16 hours, activated twice, counted on a hemacytometer plate, and adjusted to 10% concentration in RPM1640 liquid medium^-3-5×10^-3one/mL.

Preparing a liquid medicine: the drugs were made into 10mM DMSO drug stock.

Inoculation: no. 1 hole of a 96-well plate is added with RPM 1640100 mu L to be used as a blank control, No. 2 hole is added with 200 mu L of bacterial suspension and No. 2-11 holes of liquid medicine for dilution in a multiple ratio, the concentration of the medicine in each hole is 100,50,25, 12.5,6.25,3.125,1.563,0.782,0.391 and 0.196 mu M, and the bacterial suspension level is 100 mu L. No. 12 well was filled with 100. mu.L of bacterial suspension, and no liquid medicine was added as a positive control. For Candida albicans (Candida albicans, Standard strain SC5314), the initial concentration of posaconazole and the combination of posaconazole and cisplatin was 25. mu.M.

Culturing and detecting: after the candida is cultured for 24 hours, determining the result; the results were determined after 72h incubation of Cryptococcus neoformans. Setting the Optical Density (OD) value of the positive control hole as 100%, and setting the lowest drug concentration with optical density value lower than that of the positive control hole by more than 80% as the Minimum Inhibitory Concentration (MIC)₈₀)。

The results of the antifungal activity test are shown in Table 3.

TABLE 3 in vitro antifungal Activity (MIC, μ M) of Compounds^a

^aC. alb., candida albicans; c.kru., candida krusei; tro, candida tropicalis; neo, cryptococcus neoformans; gla., candida glabrata; par, candida parapsilosis; PSZ, posaconazole; CDDP, cisplatin.

As shown in Table 3, the compounds have excellent and broad-spectrum antifungal activity, and particularly have excellent antifungal activity on drug-resistant Candida albicans of posaconazole. For example, the minimum inhibitory concentration MIC of the compounds 3-6 and 9 to the posaconazole-resistant Candida albicans strain 103 is less than or equal to 12.5 mu M, and is obviously superior to that of posaconazole (MIC is more than 500 mu M).

In conclusion, the tetravalent platinum complex containing the posaconazole unit can be applied to the research and development of antitumor drugs and antifungal drugs, and has potential application value for tumor patients and the prevention and treatment of fungal infection of the tumor patients.