CN109232662B - Compound with anti-tumor effect and preparation method and application thereof - Google Patents

Compound with anti-tumor effect and preparation method and application thereof Download PDF

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CN109232662B
CN109232662B CN201811320096.4A CN201811320096A CN109232662B CN 109232662 B CN109232662 B CN 109232662B CN 201811320096 A CN201811320096 A CN 201811320096A CN 109232662 B CN109232662 B CN 109232662B
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tumor
tumor effect
anthracene
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CN109232662A (en
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李培源
苏炜
霍丽妮
陈睿
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Guangxi University of Chinese Medicine
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
    • C07F15/0073—Rhodium compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Abstract

The invention discloses a compound with an anti-tumor effect, wherein the chemical name of the compound is as follows: monochloro-chloro-mono (9-anthracene-N)4-phenylthiosemicarbazide) pentamethylcyclopentadienylrhodium (III) of the formula:

Description

Compound with anti-tumor effect and preparation method and application thereof
Technical Field
The invention relates to the field of synthetic compounds, in particular to a compound with an anti-tumor effect.
Background
Cancer is one of the most major diseases that endanger human health, and effective treatment means are still lacking to date. Most of the anti-tumor drugs used clinically at present are nucleoside drugs, and the nucleoside drugs have strong toxic and side effects due to the similarity of anti-tumor spectra. On the other hand, some tumor cell lines are easy to generate drug resistance to clinically applied drugs, so that the tumor cell lines are easy to mutate, and the anti-tumor effect of the nucleoside drugs is reduced.
At present, dozens of antitumor drugs applied to clinical chemotherapy or auxiliary medical treatment have better curative effect on partial tumors. In this sense, the development of a novel anti-tumor complex capable of overcoming the drug resistance of tumor cell lines or anti-tumor drugs with broad-spectrum activity, especially the synergistic effect of chemotherapy and phototherapy, is still an important technical difficulty problem which cannot be perfectly solved in the field.
According to related researches, the anti-tumor spectrum and the anti-tumor action mechanism of the metal complex in the compound are obviously different from those of nucleoside drugs, so that the novel metal complex type anti-tumor complex can be prepared, and more and better choices can be provided for treating tumor diseases. Therefore, a new breakthrough direction is brought to the research and development of novel compounds with chemotherapeutic and phototherapy antitumor effects.
Disclosure of Invention
An object of the present invention is to solve at least the above problems and to provide at least the advantages described later.
It is still another object of the present invention to provide compounds having anti-tumor effects, which can be used for preparing drugs for treating prostate cancer, ovarian cancer and hypertension.
To achieve these objects and other advantages in accordance with the present invention, there is provided a compound having an anti-tumor effect, the compound having a chemical name of: monochloro-chloro-mono (9-anthracene-N)4-phenylthiosemicarbazide) pentamethylcyclopentadienylrhodium (III) of the formula:
Figure BDA0001857290990000021
the physical and chemical properties are as follows: red crystals, insoluble in acetone, CHCl3，CH2Cl2And DMSO;
the nuclear magnetic resonance hydrogen spectrum data are as follows:1H NMR(400MHz,DMSO-d6),ppm 9.28(s,1H,NH),9.01(s,1H,NH),8.72(s,1H,-CH＝N),7.45-8.69(m,9H,anthryl-H),6.37-6.52(m,5H,phenyl-H),1.83(s,15H,-CH3)；
the elemental analysis data were: c32H32N3SCl2Rh·1/2CH2Cl2:C,55.22；H,4.70；N,5.94；Found:C,55.24；H,4.71；N,5.92。
The invention also provides a preparation method of the compound with the anti-tumor effect, which comprises the following steps:
s1, dissolving 9-anthracene formaldehyde and 4-phenyl-3-thiosemicarbazide in absolute ethyl alcohol, adding glacial acetic acid, heating for refluxing, cooling and filtering to obtain 9-anthracene-N4-phenylthiosemicarbazide;
s2, mixing 9-anthracene-N4Dissolving phenyl thiosemicarbazide and dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer in ethanol, mixing, and removing the solvent by rotary evaporation to obtain a red solid, namely the compound with the anti-tumor effect.
Preferably, in the preparation method of the compound with the anti-tumor effect, the heating reflux time in S1 is 3-5 h.
Preferably, in the preparation method of the compound with the anti-tumor effect, the mixing temperature in S2 is 15-30 ℃ and the time is 3-6 h.
Preferably, in the preparation method of the compound with the anti-tumor effect, S2 further comprises the step of recrystallizing the obtained red solid in dichloromethane or dichloropentane.
Preferably, in the preparation method of the compound with the anti-tumor effect, the molar volume ratio of the 9-anthracenealdehyde, the 4-phenyl-3-thiosemicarbazide, the absolute ethyl alcohol and the glacial acetic acid in the S1 is 0.05mmol: 0.05-0.1 mmol: 5-10 ml: 0.1-0.3 ml.
Preferably, in the method for preparing the compound with antitumor effect, dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer and 9-anthracene-N are adopted in S24The molar volume ratio of the phenylthiosemicarbazide to the ethanol is 0.05mmol: 0.1-0.15 mmol: 3-6 ml.
In another technical scheme, the invention also provides application of the compound with an anti-tumor effect in preparing a medicament for treating prostatic cancer.
In another technical scheme, the invention also provides application of the compound with an anti-tumor effect in preparing a medicament for treating ovarian cancer.
In another technical scheme, the invention also provides application of the compound with an anti-tumor effect in preparing a medicament for treating hypertension.
The invention at least comprises the following beneficial effects:
1. experiments prove that the compound with the anti-tumor effect has very good inhibition effect on human prostate cancer PC3 cells and human ovarian cancer SKOV3 cells, and can be used for preparing medicines for treating prostate cancer and ovarian cancer.
2. The compound with the anti-tumor effect has the synergistic effect of chemotherapy and phototherapy, is more targeted for treating cancer cells, and has small toxic and side effects.
3. Experiments prove that the compound with the anti-tumor effect has good inhibitory effect on Angiotensin Converting Enzyme (ACE), and can be used for preparing medicines for treating hypertension.
4. The compound with the anti-tumor effect contains an anthracycline structure, so that good biological activity is brought to the prepared compound; meanwhile, the compound has a large conjugated system, so that the molecular structure of the compound is more stable, and good biological activity and drug effect are maintained.
5. The preparation method is simple, and the composition can be prepared into injections, tablets, pills, capsules, suspending agents or emulsion for use; meanwhile, the invention has the advantage of low cost, reduces the raw material loss and meets the requirement of green chemistry.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Detailed Description
The present invention is further described in detail below with reference to examples so that those skilled in the art can practice the invention with reference to the description. It is to be noted that the experimental methods described in the following embodiments are all conventional methods unless otherwise specified, and the reagents and materials are commercially available unless otherwise specified.
Example 1
A compound having an anti-tumour effect, the compound having the formula:
Figure BDA0001857290990000041
a method for preparing a compound with anti-tumor effect comprises the following steps:
s1, dissolving 9-anthracene formaldehyde and 4-phenyl-3-thiosemicarbazide in absolute ethyl alcohol, adding glacial acetic acid, heating for refluxing, cooling and filtering to obtain 9-anthracene-N4-phenylthiosemicarbazide;
s2, mixing 9-anthracene-N4And (3) dissolving phenylthiosemicarbazide and dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer in ethanol, mixing, and performing rotary evaporation to remove the solvent to obtain a red solid, namely the compound with the anti-tumor effect.
In the preparation method of the compound with the anti-tumor effect, the heating reflux time in S1 is 3 h.
In the preparation method of the compound with the anti-tumor effect, the mixing temperature in S2 is 15 ℃ and the time is 3 hours.
In the preparation method of the compound with the anti-tumor effect, S2 further comprises the step of recrystallizing the obtained red solid in dichloromethane.
In the preparation method of the compound with the anti-tumor effect, the molar volume ratio of the 9-anthracenealdehyde and the 4-phenyl-3-thiosemicarbazide in the S1 to the absolute ethyl alcohol and the glacial acetic acid is 0.05mmol:0.05mmol:5ml:0.1 ml.
In the preparation method of the compound with the anti-tumor effect, dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer and 9-anthracene-N in S24The molar volume ratio of phenylthiosemicarbazide to ethanol was 0.05mmol:0.1mmol:3 ml.
Example 2
A method for preparing a compound with anti-tumor effect comprises the following steps:
s1, dissolving 9-anthracene formaldehyde and 4-phenyl-3-thiosemicarbazide in absolute ethyl alcohol, adding glacial acetic acid, heating for refluxing, cooling and filtering to obtain 9-anthracene-N4-phenylthiosemicarbazide;
s2, mixing 9-anthracene-N4And (3) dissolving phenylthiosemicarbazide and dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer in ethanol, mixing, and performing rotary evaporation to remove the solvent to obtain a red solid, namely the compound with the anti-tumor effect.
In the preparation method of the compound with the anti-tumor effect, the heating reflux time in S1 is 4 h.
In the preparation method of the compound with the anti-tumor effect, the mixing temperature in S2 is 25 ℃ and the time is 4 hours.
In the preparation method of the compound with the anti-tumor effect, S2 further comprises the step of recrystallizing the obtained red solid in dichloromethane.
In the preparation method of the compound with the anti-tumor effect, the molar volume ratio of the 9-anthracenealdehyde and the 4-phenyl-3-thiosemicarbazide in the S1 to the absolute ethyl alcohol and the glacial acetic acid is 0.05mmol to 0.8mmol to 8ml to 0.2 ml.
In the preparation method of the compound with the anti-tumor effect, dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer and 9-anthracene-N in S24The molar volume ratio of phenylthiosemicarbazide to ethanol was 0.05mmol:0.13mmol:5 ml.
Example 3
A method for preparing a compound with anti-tumor effect comprises the following steps:
s1, dissolving 9-anthracene formaldehyde and 4-phenyl-3-thiosemicarbazide in absolute ethyl alcohol, adding glacial acetic acid, heating for refluxing, cooling and filtering to obtain 9-anthracene-N4-phenylthiosemicarbazide;
s2, mixing 9-anthracene-N4And (3) dissolving phenylthiosemicarbazide and dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer in ethanol, mixing, and performing rotary evaporation to remove the solvent to obtain a red solid, namely the compound with the anti-tumor effect.
In the preparation method of the compound with the anti-tumor effect, the heating reflux time in S1 is 5 h.
In the preparation method of the compound with the anti-tumor effect, the mixing temperature in S2 is 30 ℃ and the time is 6 hours.
In the preparation method of the compound with the anti-tumor effect, S2 further comprises the step of putting the obtained red solid into dichloropentane for recrystallization.
In the preparation method of the compound with the anti-tumor effect, the molar volume ratio of the 9-anthracenealdehyde and the 4-phenyl-3-thiosemicarbazide in the S1 to the absolute ethyl alcohol and the glacial acetic acid is 0.05mmol:0.1mmol:10ml:0.3 ml.
In the preparation method of the compound with the anti-tumor effect, dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer and 9-anthracene-N in S24The molar volume ratio of phenylthiosemicarbazide to ethanol was 0.05mmol:0.15mmol:6 ml.
In vitro antitumor Activity test
In vitro cytotoxicity assays were performed using the MTT method.
Respectively inoculating human prostatic cancer PC3 cell and human ovarian cancer SKOV3 cell in 10 wt% fetal calf serum and 1% of the special RPMI-1640 culture solution for penicillin-streptomycin antibody, placing at 37 deg.C and 5% CO2And culturing in a culture box with saturated humidity, changing the culture solution once in 1-2 days on average, digesting with trypsin with the mass fraction of 0.25% after the culture box is full of cells, and then carrying out subculture.
Taking cells growing to logarithmic phase in culture solution, preparing into 2 × 10 concentration with culture solution containing 10% embryo bovine serum and 1% double antibody4Per mol of single cell suspension, and inoculated into two plates of sterilized 96-well cell culture plates, 200. mu.L of single cell suspension per well, at 37 ℃ and 5% CO2Culturing for 24h under the condition of saturated humidity; then, the compound having an antitumor effect of example 1 of the present invention was added to the cell suspension as an experimental group; wherein, for the addition of the anti-tumor compound in the experimental group, 7 concentration gradients are set, and each concentration is provided with an illumination group and a non-illumination group. A blank control group and a negative control group were also set, wherein the blank control group contained only a culture solution but no tumor cells, and the negative control group contained only a single cell suspension without the addition of the compound having an antitumor effect of example 1.
The plates were incubated at 37 ℃ with 5% CO2Culturing for 4h under saturated humidity, removing the culture solution, adding new culture solution, irradiating one plate at 400nm wavelength for 30min, and leaving the other plate without irradiation; the plates were then placed in an incubator for 24 h. Adding 10 mu L of CCK-8 solution into each hole, continuously culturing for 3h, placing on a shaker, oscillating at low speed for 5-10 min, and detecting the OD value of each hole by using an enzyme-labeling instrument (the light source is 450nm in wavelength). The results are shown in Table 1.
TABLE 1 half-effective concentration (IC) of compounds with antitumor action on cell lines50)
Cell line PC3 SKOV3
Without illumination 18.6±0.1 14.7±1.1
Illumination of light 7.9±0.7 3.6±0.7
As can be seen from the results in table 1, the compound having an antitumor effect in example 1 was shown to have not only a strong antitumor chemotherapeutic activity but also a strong phototherapeutic activity by in vitro antitumor experiments.
Angiotensin Converting Enzyme (ACE) inhibitory Activity test
Dissolving a substrate hippuric acid-histidine-leucine in 0.1mol/L borate buffer solution (pH 8.3) containing 0.2mol/L NaCl to prepare a hippuric acid-histidine-leucine solution with the concentration of 5.0 mmol/L;
mixing 100. mu.L of the hippuric acid-histidine-leucine solution with 100. mu.L of an aqueous solution containing the anti-tumor compound of example 1 at a concentration of 0.1g/L, adding 150. mu.L of a 0.1U/mL angiotensin-converting enzyme solution (dissolved in 0.1mol/L borate buffer containing 0.2mol/L NaCl substrate at a pH of 8.3), reacting at 37 ℃ for 60min, and adding 250. mu.L of a 1.0mol/L HCl solution to terminate the reaction;
adding 1.5mL of ethyl acetate into the reaction system for extraction, strongly oscillating for 1min, and centrifuging at the rotating speed of 3000r/min for 5 min. Taking 0.5mL of ester layer, adding 1.0mL of acetic anhydride and 2.0mL of 0.5% diaminobenzidine color developing agent, developing color at 40 ℃ for 30min, and measuring the light absorption value at the wavelength of 459 nm;
the inhibition rate was calculated according to the following formula:
ACE inhibition rate [ (a-S)/(a-C) ] × 100%;
wherein A is the absorbance value measured by replacing the inhibitor with water, S is the absorbance value measured by adding the inhibitor, and C is the reference absorbance value by adding ethyl acetate, acetic anhydride and color developing agent.
TABLE 2 ACE inhibitory ratio (%)
Inhibitors ACE inhibitory ratio (%)
Compounds having antitumor Effect in example 1 73.6
From the calculation results, the ACE inhibition rate of the compound with the antitumor effect in example 1 of the present invention is 73.6%, which indicates that the compound has a good therapeutic effect on hypertension.
While embodiments of the invention have been disclosed above, it is not limited to the applications listed in the description and the embodiments, which are fully applicable in all kinds of fields of application of the invention, and further modifications may readily be effected by those skilled in the art, so that the invention is not limited to the specific details without departing from the general concept defined by the claims and the scope of equivalents.

Claims (10)

1. A compound having an anti-tumor effect, wherein the compound has the structural formula:
Figure FDA0002461958910000011
2. the process for the preparation of compounds with antitumor effect according to claim 1, characterized by comprising the steps of:
s1, dissolving 9-anthracene formaldehyde and 4-phenyl-3-thiosemicarbazide in absolute ethyl alcohol, adding glacial acetic acid, heating for refluxing, cooling and filtering to obtain 9-anthracene formaldehyde condensation-N4-phenylthiosemicarbazide;
s2 preparation of 9-Anthracene carboxaldehyde-N4And (3) dissolving phenylthiosemicarbazide and dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer in ethanol, mixing, and performing rotary evaporation to remove the solvent to obtain a red solid, namely the compound with the anti-tumor effect.
3. The method for preparing a compound having an antitumor effect according to claim 2, wherein the heating reflux time in S1 is 3 to 5 hours.
4. The method for preparing a compound having an antitumor effect according to claim 2, wherein the mixing temperature in S2 is 15 to 30 ℃ for 3 to 6 hours.
5. The method for producing an antitumor compound according to claim 2, wherein S2 further comprises recrystallizing the obtained red solid in methylene chloride or dichloropentane.
6. The method for producing a compound having an antitumor effect according to claim 2, wherein the molar volume ratio of 9-anthracenecarboxaldehyde and 4-phenyl-3-thiosemicarbazide to the absolute ethyl alcohol and the glacial acetic acid in S1 is 0.05mmol:0.05 to 0.1mmol:5 to 10ml:0.1 to 0.3 ml.
7. The process for the preparation of compounds having an antitumor effect according to claim 2, wherein dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, 9-anthracenedial-N-formaldehyde-acetal in S24The molar volume ratio of the phenylthiosemicarbazide to the ethanol is 0.05mmol: 0.1-0.15 mmol: 3-6 ml.
8. Use of a compound with anti-tumor effect according to claim 1 for the preparation of a medicament for the treatment of prostate cancer.
9. Use of an anti-tumor compound according to claim 1 for the preparation of a medicament for the treatment of ovarian cancer.
10. The use of a compound as claimed in claim 1 for the preparation of a medicament for the treatment of hypertension.
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CN105288727B (en) * 2015-11-17 2018-06-29 广西中医药大学 The method that the titania nanotube with antibacterial anticancer is prepared using rhodium complex
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