CN115894942B - Polycaprolactone-modified hyperbranched comb-type polylysine and its application - Google Patents

Abstract

The invention provides a polycaprolactone-modified hyperbranched comb-type polylysine and its application. The invention uses ε-polylysine as the main chain and reacts with lysine activated ester generation by generation to obtain a hyperbranched comb-type polylysine. Polylysine utilizes the abundant amino groups on its surface to couple with polycaprolactone to obtain an amphiphilic product, namely polycaprolactone-modified hyperbranched comb polylysine; the present invention uses ε-polylysine The acid has the characteristics of multiple amino groups to prepare hyperbranched polylysine, which has a short synthesis route and easy operation; further grafting polycaprolactone to the molecule not only improves the hydrophobicity of the hyperbranched polylysine, but also enhances its Its biocompatibility; the final product, polycaprolactone-grafted hyperbranched comb polylysine, can be adsorbed on the cell membrane surface of negatively charged bacteria and cancer cells through electrostatic interaction, thereby destroying bacteria and cancer cells. effect; in addition, polycaprolactone-grafted hyperbranched comb polylysine has many advantages such as excellent biocompatibility and low hemolysis.

Description

Polycaprolactone-modified hyperbranched comb-type polylysine and its application

Technical field

The invention belongs to the technical field of biomedical polymers, and specifically relates to a polycaprolactone-modified hyperbranched comb-type polylysine and its application, so as to simultaneously achieve efficient antibacterial and anticancer effects.

Background technique

Pathogenic bacteria pose a serious threat to human health. Traditional antibiotics such as penicillin once provided a strong guarantee for humans to resist bacterial infections. However, due to the limitations of its bactericidal mechanism and blind abuse, the increasingly serious problem of bacterial resistance has once again become an urgent problem to be solved. However, the cost of developing new antibiotics is high, the effective period is short, and the economic benefits are low. Therefore, antimicrobial peptides existing in organisms have been considered as powerful substitutes for antibiotics since their discovery.

Antimicrobial peptides are an important component of non-specific immunity of organisms. They are generally short peptides with complex structures and have many advantages such as high thermal stability, good water solubility, and broad antibacterial spectrum. Antimicrobial peptides have cationic and amphipathic structural characteristics. Therefore, most studies believe that antimicrobial peptides mainly achieve antibacterial effects through a membrane destruction mechanism, that is, they are adsorbed to the negatively charged bacterial cell membrane through electrostatic interaction, destroying its integrity and inducing perforation, causing cell content. The substance spills out of the cell causing bacterial death.

Since tumor cell membranes have a higher density of negative charges than normal somatic cells, the anti-tumor properties of antimicrobial peptides have also been confirmed in recent years, such as xenopusin and cecropin. Studies have shown that these natural antimicrobial peptides can both damage membranes and specifically induce tumor cell apoptosis.

However, both the antibacterial and antitumor applications of natural antimicrobial peptides face the same challenges, namely how to reduce biological toxicity and how to still ensure antibacterial and anticancer activity in the body. By simulating the structural characteristics of natural antimicrobial peptides, artificial design and synthesis of antimicrobial peptides is one of the important means to solve the above problems. However, the current clinical application of artificially synthesized antimicrobial peptides also faces the following difficulties: first, they rely on specific amino acid sequence structures, which increases the difficulty of synthesis; second, how to achieve good antibacterial effects and anti-cancer effects at the same time; third, Research on short peptides is progressing slowly, and guidance in new directions is urgently needed.

Contents of the invention

In view of the shortcomings of the existing technology, the purpose of the present invention is to provide a polycaprolactone-modified hyperbranched comb-type polylysine and its application.

In order to achieve the above objectives, the solution of the present invention is:

One of the purposes is to provide a hyperbranched comb polylysine, the structural formula of which is as follows:

Wherein, n represents the degree of polymerization of ε-polylysine, an integer selected from 10-40 (preferably 20-30); m represents the number of iterations, an integer selected from 1-5, and Lys represents the lysine structure Unit, its structural formula is as follows:

The second purpose is to provide a method for preparing the above-mentioned hyperbranched comb polylysine, which includes the following steps:

(1) React lysine with two amino groups protected, a shrinking agent and an activation aid in an organic solvent to obtain a lysine activated ester, whose structural formula is as follows:

Wherein, PG represents an amino protecting group, which is one or more selected from benzyloxycarbonyl, tert-butyloxycarbonyl, and fluorenylmethoxycarbonyl;

(2) Add the lysine activated ester of step (1) to an organic solvent to dissolve, add an aqueous solution of ε-polylysine to react, and obtain hyperbranched comb polylysine after removing the amino protection, where m=1;

(3) Add the lysine activated ester of step (1) to an organic solvent to dissolve, add the hyperbranched comb polylysine of step (2) to react, and obtain hyperbranched comb polylysine after removing the amino protection, wherein m=2;

(4) Add the activated lysine ester of step (1) to an organic solvent to dissolve, add the hyperbranched comb polylysine of step (3) to react, and obtain hyperbranched comb polylysine after removing the amino protection, wherein m=3;

(5) Add the activated lysine ester of step (1) to an organic solvent to dissolve, add the hyperbranched comb polylysine of step (4) to react, and obtain hyperbranched comb polylysine after removing the amino protection, wherein m=4;

(6) Add the activated lysine ester of step (5) to an organic solvent to dissolve, add the hyperbranched comb polylysine of step (5) to react, and obtain hyperbranched comb polylysine after removing the amino protection. where m=5.

Wherein, in step (2) to step (6), the reaction temperature is 0-30°C, and the reaction time is 3-24h.

Preferably, in step (1), the shrinking agent is selected from N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, N,N'-di(2,6 -Diisopropylphenyl)carbodiimide, N,N'-diphenylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride More than one kind.

Preferably, in step (1), the activation assistant is selected from N-hydroxyphthalimide, N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-7-aza One or more types of benzotriazole, 4-N,N-lutidine, 4-pyrrolidinylpyridine, N,N-diisopropylethylamine, and N-methylmorpholine.

Preferably, in steps (1) to (6), the organic solvent is selected from one or more types of tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, and dichloromethane.

The third purpose is to provide a hyperbranched comb-type polylysine modified with polycaprolactone using the above-mentioned hyperbranched comb-type polylysine, and its structural formula is as follows:

Wherein, x represents the degree of polymerization of polycaprolactone, an integer selected from 10-50; a represents the number of ungrafted hyperbranched polylysine units of polycaprolactone, an integer selected from 1-30; b represents the number of polycaprolactone-grafted hyperbranched comb polylysine units, which is an integer selected from 1-30; combined with the structural formula of hyperbranched comb polylysine, then a+b=n;

Linker represents a coupling group, specifically selected from the group consisting of toluene diisocyanate residue, isophorone diisocyanate residue, hexamethylene diisocyanate residue, diphenylmethane diisocyanate residue, and dicyclohexylmethane diisocyanate. More than one of the residues, their structural formulas are as follows:

ran indicates that two structural units are connected in a random copolymerization manner, m indicates the number of iterations, an integer selected from 1-5, Lys indicates the lysine structural unit, and its structural formula is as follows:

The fourth object is to provide a method for preparing the above-mentioned polycaprolactone-modified hyperbranched comb polylysine, which includes the following steps:

(1) Dissolve polycaprolactone in an organic solvent and add it dropwise to the coupling agent to react to obtain a polycaprolactone intermediate solution;

(2) Add the polycaprolactone intermediate solution to the above-mentioned aqueous solution of hyperbranched comb polylysine to react, and then evaporate to dryness to obtain polycaprolactone-modified hyperbranched comb polylysine.

Preferably, in step (1), the organic solvent is selected from one or more types of tetrahydrofuran and dichloromethane.

Preferably, in step (1), the coupling agent is selected from at least one type of toluene diisocyanate, isophorone diisocyanate, diphenylmethane diisocyanate, dicyclohexylmethane diisocyanate, and hexamethylene diisocyanate. .

Preferably, in step (2), the molar ratio of polycaprolactone intermediate solution and hyperbranched comb polylysine is (1-30):1.

The fifth purpose is to provide an application of the above-mentioned polycaprolactone-modified hyperbranched comb polylysine in the preparation of antibacterial and anticancer drugs, which includes the following steps:

(1) Dissolve polycaprolactone-modified hyperbranched comb polylysine in hydrochloride-balanced saline, co-culture the solution with bacteria and cancer cells for a period of time, and calculate the survival of bacteria and cancer cells through stains Rate;

(2) Inject the solution into mice through intraperitoneal injection, and measure the changes in subcutaneous tumor size of mice over time.

Preferably, in step (1), the bacteria are selected from the group consisting of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa.

Preferably, in step (1), the cells are selected from at least one type of mouse colon cancer cells, human lung cancer cells, and human melanoma cells.

Due to the adoption of the above solution, the beneficial effects of the present invention are:

First, the present invention repeatedly grafts lysine to ε-polylysine, that is, using ε-polylysine as the main chain with the characteristics of multiple amino groups, and reacts with lysine activated ester generation by generation, quickly A hyperbranched comb with high degree of branching (each lysine is connected to three lysines), large molecular weight (the molecular weight exceeds 30,000 after three generations of iteration), and rich functional groups (more than 240 amino groups at the back end of three generations of iteration) were prepared. Type polylysine, low manufacturing cost.

Second, the present invention uses polycaprolactone-modified hyperbranched comb-type polylysine. By controlling the feeding ratio, the abundant amino groups on the surface are coupled with polycaprolactone to obtain a series of amphiphilic polycaprolactones. Ester-grafted hyperbranched comb-type polylysine has simple steps and is suitable for large-scale manufacturing. It not only improves the hydrophobicity of hyperbranched polylysine but also enhances its biocompatibility; in addition, polycaprolactone-modified Hyperbranched comb polylysine can be adsorbed on the surface of negatively charged bacterial and cancer cell membranes through electrostatic interaction, thereby achieving the destructive effect on bacteria and cancer cells.

Third, the polycaprolactone-modified hyperbranched comb polylysine of the present invention has excellent antibacterial and anticancer activity, and is effective against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, mouse colon cancer cells, and human Lung cancer cells and human melanoma cells all have excellent killing effects. Polycaprolactone-modified hyperbranched comb-type polylysine achieves antibacterial and anti-cancer effects through the physical method of membrane destruction mechanism, and is less likely to induce drug resistance in bacteria and cancer cells. Through intraperitoneal injection, it can inhibit the growth of tumors in mice, so it has the potential to replace traditional chemotherapy drugs in clinical treatment.

Fourth, the polycaprolactone-modified hyperbranched comb polylysine of the present invention has excellent biocompatibility, low hemolysis rate, and low toxicity to somatic cells.

Description of the drawings

Figure 1 is a schematic diagram of the preparation process of polycaprolactone-modified hyperbranched comb polylysine of the present invention.

Figure 2 is a hydrogen resonance spectrum of the third generation hyperbranched comb polylysine in Example 1 of the present invention.

Figure 3 is a hydrogen resonance spectrum of the third generation hyperbranched comb-type polylysine modified with octacaprolactone in Example 2 of the present invention.

Figure 4 is a graph showing the antibacterial effect test results of the third generation hyperbranched comb-type polylysine modified with octacaprolactone in Example 2 of the present invention.

Figure 5 is a graph showing the hemolytic toxicity results of the third generation hyperbranched comb polylysine modified with octacaprolactone in Example 2 of the present invention.

Figure 6 is a diagram showing the in vitro anti-tumor test results of the third generation hyperbranched comb polylysine modified with octacaprolactone in Example 2 of the present invention.

Detailed ways

The technical solution of the present invention will be further described in detail below with reference to several embodiments. This embodiment is implemented based on the technical solution of the invention and provides detailed implementation modes and specific operating processes. However, the scope of protection of the present invention is not limited to Examples below.

The experimental materials used in the following examples can be purchased from conventional biochemical reagent companies unless otherwise specified.

Example 1:

The preparation method of the third generation hyperbranched comb polylysine in this embodiment includes the following steps:

(1) Dissolve 34.64g (0.1mol) Boc-Lys(Boc)-OH, 15.45g N,N'-dicyclohexylcarbodiimide and 17.30g N-hydroxysuccinimide in 250mL tetrahydrofuran, at 25 React at ℃ for 24h to obtain lysine activated monomer as follows;

(2) Add 30 mL of deionized water to 12.80 g of ε-polylysine to dissolve, and add the above lysine activated ester solution and mix for 12 hours to obtain the first generation of hyperbranched comb polylysine.

(3) Evaporate tetrahydrofuran to dryness, add 300 mL of trifluoroacetic acid, and react for 12 hours. Adjust the pH of the solution to 10. Weigh half of it and add it to the lysine activated monomer in step (1). Mix and react for 12 hours to obtain the second generation of hyperbranch. Comb type polylysine.

(4) Repeat the above step (3) once to obtain the third generation hyperbranched comb polylysine.

By verifying the product structure through ¹ H-NMR, the third generation hyperbranched comb polylysine can be obtained, as shown in Figure 2. Comparing the characteristic peak area ratio can prove that the third generation hyperbranched comb polylysine successful synthesis.

Example 2:

The preparation method of the third generation hyperbranched comb polylysine modified with octacaprolactone in this embodiment includes the following steps:

(1) Dissolve 10g polycaprolactone with a polymerization degree of 28 in 100 mL tetrahydrofuran, add it dropwise to 20g hexamethylene diisocyanate solution, and react for 12 hours; wash away excess hexamethylene diisocyanate to obtain polycaprolactone Ester intermediate solution;

(2) Add an appropriate amount of the polycaprolactone intermediate solution to the aqueous solution of the third generation hyperbranched comb polylysine (from Example 1) and react for 12 hours. After evaporating to dryness, octacaprolactone modification is obtained. The third generation of hyperbranched comb polylysine.

The product structure was verified through ¹ H-NMR. It can be seen that compared with the hydrogen nuclear magnetic spectrum of the third generation hyperbranched comb polylysine, the peak area of polycaprolactone is obvious, which proves that octacaprolactone Modified third-generation hyperbranched comb polylysine, as shown in Figure 3.

<Experiment 1>

Determination of the minimum inhibitory concentration value of the third generation hyperbranched comb polylysine modified with octacaprolactone.

experimental method:

The micro-broth dilution method was used for determination. First, appropriate LB broth (high-pressure steam sterilization) was added to the 96-well plate, and then the sample solution to be tested (octacaprolactone-modified third-generation hyperbranched comb-type polyethylene glycol) was added. Acid) and control group (PBS buffer) were added to the 96-well plate respectively, diluted using the two-fold dilution method, and finally an equal volume of bacterial solution was inoculated into each well plate to obtain the final drug concentrations of each test group: 500μg/mL, 250μg/mL, 125μg/mL, 62.5μg/mL, 31.25μg/mL, 16μg/mL, 8μg/mL. Incubate at a constant temperature of 37°C for 8 hours. Measure the absorbance values of the sample solution to be tested and the control solution every 2 hours. Based on the absorbance change after 12 hours, determine the minimum inhibitory concentration value of the third generation hyperbranched comb polylysine modified with octacaprolactone. .

Experimental results:

The third-generation hyperbranched comb polylysine modified with octacaprolactone showed excellent antibacterial activity against both Staphylococcus aureus and Escherichia coli, as shown in Figure 4. According to the change in absorbance value after 8 hours, the MIC value of the third-generation hyperbranched comb polylysine modified with octacaprolactone against E. coli was 250g/mL.

<Experiment 2>

Determination of hemolytic toxicity of third-generation hyperbranched comb polylysine modified with octacaprolactone.

experimental method:

Use the two-fold dilution method to dilute the sample solution in half, and then add an equal amount of blood cell PBS suspension to the sample solution to obtain the final drug concentrations of each test group as 4000 μg/mL, 2000 μg/mL, 1000 μg/mL, 500 μg/mL, and 250 μg/mL, 125 μg/mL, and equal amounts of PBS buffer and 0.1% Triton X-100 were added to the blood cell suspension to set up blank and positive control groups respectively. Shake repeatedly and incubate for one hour. After the culture, centrifuge, test the OD ₄₀₅ value of the supernatant of each sample, and calculate the hemolysis percentage in sequence. The calculation formula is as follows:

Experimental results:

The hemolytic toxicity test results are shown in Figure 5. Within the concentration range tested, the hemolysis rate of the third-generation hyperbranched comb polylysine modified with octacaprolactone was ultimately less than 6%, and it has low toxicity to blood cells, so it has good blood compatibility.

<Experiment 3>

Determination of the in vitro antitumor properties of third-generation hyperbranched comb polylysine modified with octacaprolactone.

(1). Take mouse colon cancer cell CT26 with good logarithmic growth phase and make a cell suspension. A normal control group and 5 experimental groups were established, with 6 replicate holes in each group. Take 100 μL (1 × 10 ³ cells) of cell suspension from each well and inoculate it into a 96-well plate, place it in a 37°C, 5% CO ₂ incubator and culture it for 24 hours before observing.

(2) After the cells adhere to the wall, the third generation hyperbranched comb-type polyurethane modified with octacaprolactone is used according to the concentration gradient of 31 μg/mL, 62.5 μg/mL, 125 μg/mL, 250 μg/mL, and 500 μg/mL. Cells in 5 experimental groups were treated with acid.

(3) After 24h, 48h, and 72h of drug treatment, absorb the supernatant from each well and wash each well twice with cold PBS.

(4) Add 10 μL of CCK-8 solution to each well and continue culturing for 4 hours in a cell culture incubator at 37°C and 5% _CO2 .

(5) Carefully aspirate the supernatant, use a microplate reader to measure the absorbance of each group, and calculate the survival rate of cancer cells after the action of octacaprolactone-modified third-generation hyperbranched comb polylysine on colon cancer cells according to the formula.

Experimental results:

The in vitro anti-tumor performance test results of the third-generation hyperbranched comb polylysine modified with octacaprolactone are shown in Figure 6. Experimental results show that the third-generation hyperbranched comb-type polylysine modified with octacaprolactone has a good inhibitory effect on mouse colon cancer cells and can achieve long-term inhibitory effect. It is treated at a concentration of 125 μg/mL. The survival rate of cancer cells after 72 hours was only 14%.

<Experiment 4>

Determination of the anti-tumor properties of third-generation hyperbranched comb polylysine modified with octacaprolactone in vivo.

(1) Take human lung cancer cells A549 in the logarithmic growth phase, trypsinize the cells, wash them twice with PBS buffer, and after counting the cells, prepare a single cell suspension with an appropriate amount of PBS buffer;

(2) Each nude mouse is injected with cancer cells subcutaneously and raised for 7 days. The establishment of the nude mouse tumor model is determined by confirming the tumor size;

(3) Each nude mouse in the experimental group was injected with 40 mg/kg peptide solution by intraperitoneal injection every two days, and each nude mouse in the control group was injected with an equal amount of PBS buffer every two days;

(4) Record the body weight and tumor volume of nude mice at each injection, and observe the inhibition of tumor growth by the drug.

Experimental results:

The in vitro anti-tumor performance test results of third-generation hyperbranched comb-type polylysine modified with octacaprolactone showed that the tumor volume in the control group grew exponentially and exceeded 500mm ³ after 14 days, while the weight of mice after injection of the drug was zero. There were obvious changes, and the tumor size was only 100mm ³ , indicating its good anti-cancer effect in vivo.

The above description of the embodiments is to facilitate those of ordinary skill in the technical field to understand and use the present invention. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of the present invention.

Claims (12)

1. A hyperbranched comb polylysine modified with polycaprolactone using hyperbranched comb polylysine, characterized in that its structural formula is as follows: Wherein, x represents the degree of polymerization of polycaprolactone, an integer selected from 10-50; a represents the number of ungrafted hyperbranched polylysine units of polycaprolactone, an integer selected from 1-30; b represents the number of polycaprolactone-grafted hyperbranched comb polylysine units, an integer selected from 1-30; Linker represents the coupling group; ran indicates that two structural units are connected in a random copolymerization manner, m indicates the number of iterations, and is an integer selected from 1-5; The preparation method of the polycaprolactone-modified hyperbranched comb polylysine includes the following steps: (1) Dissolve polycaprolactone in an organic solvent and add it dropwise to the coupling agent to react to obtain a polycaprolactone intermediate solution; (2) Add the polycaprolactone intermediate solution to an aqueous solution of hyperbranched comb polylysine for reaction, and then evaporate to dryness to obtain polycaprolactone-modified hyperbranched comb polylysine; The structural formula of the hyperbranched comb polylysine is as follows: Among them, n represents the degree of polymerization of ε-polylysine, an integer selected from 10-40; m represents the number of iterations, an integer selected from 1-5, Lys represents the lysine structural unit, and its structural formula is as follows: 2. The polycaprolactone-modified hyperbranched comb polylysine according to claim 1, characterized in that: the preparation method of the hyperbranched comb polylysine includes the following steps: (1) React lysine with two amino groups protected, a shrinking agent and an activation aid in an organic solvent to obtain a lysine activated ester, whose structural formula is as follows: Among them, PG represents an amino protecting group, selected from benzyloxycarbonyl, tert-butyloxycarbonyl, and fluorenylmethoxycarbonyl; (2) The lysine activated ester is dissolved in an organic solvent, and an aqueous solution of ε-polylysine is added to react. After removing the amino protection, the hyperbranched comb polylysine is obtained successively. 3. The polycaprolactone-modified hyperbranched comb polylysine according to claim 2, characterized in that: in step (1), the shrinking agent is selected from N, N'-diisopropyl carbon Diimide, N,N'-dicyclohexylcarbodiimide, N,N'-bis(2,6-diisopropylphenyl)carbodiimide, N,N'-diphenylcarbodiimide One or more of imine and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride. 4. The polycaprolactone-modified hyperbranched comb polylysine according to claim 2, characterized in that: in step (1), the activation auxiliary agent is selected from N-hydroxyphthalimide. Amine, N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-7-azabenzotriazole, 4-N,N-dimethylpyridine, 4-pyrrolidinylpyridine , N,N-diisopropylethylamine, or more than one of N-methylmorpholine. 5. The polycaprolactone-modified hyperbranched comb polylysine according to claim 2, characterized in that: in step (1) and step (2), the organic solvent is selected from the group consisting of tetrahydrofuran, dimethyl One or more of sulfoxide, N,N-dimethylformamide and methylene chloride. 6. The polycaprolactone-modified hyperbranched comb polylysine according to claim 1, characterized in that: the coupling group is selected from the group consisting of toluene diisocyanate residues and isophorone diisocyanate residues. group, diphenylmethane diisocyanate residue, dicyclohexylmethane diisocyanate residue, and hexamethylene diisocyanate residue. 7. The polycaprolactone-modified hyperbranched comb polylysine according to claim 6, characterized in that: The structural formulas of the toluene diisocyanate residue, isophorone diisocyanate residue, hexamethylene diisocyanate residue, diphenylmethane diisocyanate residue, and dicyclohexylmethane diisocyanate residue are as follows: 8. A method for preparing polycaprolactone-modified hyperbranched comb polylysine as claimed in claim 1, characterized in that: it includes the following steps: (1) Dissolve polycaprolactone in an organic solvent and add it dropwise to the coupling agent to react to obtain a polycaprolactone intermediate solution; (2) Add the polycaprolactone intermediate solution to the aqueous solution of hyperbranched comb polylysine as claimed in claim 1 for reaction, and then evaporate to dryness to obtain polycaprolactone-modified hyperbranched comb polylysine. Lysine. 9. The preparation method according to claim 8, characterized in that: in step (1), the organic solvent is selected from one or more types of tetrahydrofuran and dichloromethane. 10. The preparation method according to claim 8, characterized in that: in step (1), the coupling agent is selected from toluene diisocyanate, isophorone diisocyanate, diphenylmethane diisocyanate, dicyclohexyl One or more of methane diisocyanate and hexamethylene diisocyanate. 11. The preparation method according to claim 8, characterized in that: in step (2), the molar ratio of the polycaprolactone intermediate solution and the hyperbranched comb polylysine is (1-30) :1. 12. Application of the polycaprolactone-modified hyperbranched comb polylysine according to claim 1 in the preparation of antibacterial and anticancer drugs.