CN103145759A - Alizarin molybdenum complex, preparation method, and application thereof in preventing and treating cancers - Google Patents

Alizarin molybdenum complex, preparation method, and application thereof in preventing and treating cancers Download PDF

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CN103145759A
CN103145759A CN2011104023723A CN201110402372A CN103145759A CN 103145759 A CN103145759 A CN 103145759A CN 2011104023723 A CN2011104023723 A CN 2011104023723A CN 201110402372 A CN201110402372 A CN 201110402372A CN 103145759 A CN103145759 A CN 103145759A
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molybdenum
alizarin
organic
salt
solvent
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CN103145759B (en
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鲁晓明
杜世振
冯俊
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Capital Normal University
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Abstract

The invention provides an alizarin molybdenum complex with a molecular chemical formula {[HN(R)3]2[MoO2(C14H6O4)2]}n, wherein R represents a lower alkyl group, and n is an integer equal to or larger than 1. The invention also provides a preparation method of the alizarin molybdenum complex. The alizarin molybdenum complex is easily available in raw materials and low in cost. The alizarin molybdenum complex is precipitated in a crystal form, and has high purity, high yield and good water-solubility and lipid solubility. Experiments demonstrate that the complex can be used as drugs for resisting cancers or tumors or main components of the drugs.

Description

Alizarin molybdenum match and method for making thereof and its application in prevention and treatment cancer
Technical field
The present invention relates to alizarin molybdenum match and preparation method thereof, the application of pharmaceutical composition in the medicine of preparation prevention and treatment cancer and tumor disease that also relates to these compounds and comprise described compound.
Background technology
Molybdenum is the needed micro-bioelement of organism, and scarce molybdenum can cause cancer and tumor incidence to raise.Document announcement is in the district occurred frequently of the cancers such as esophagus cancer, digestive tract cancer, cancer of the stomach, liver cancer, the rectum cancer, lung cancer, mammary cancer, and in resident's serum, urine sample and hair, the content of molybdenum is starkly lower than the low district of sending out.After scarce molybdenum animal and intact animal were accepted the nitroso compound of doses simultaneously, the incidence of the front cancer of the stomach knurl of scarce molybdenum animal was significantly higher than intact animal.
Rose in 1991, begun the research of the anticancer antineoplastic vascular one-tenth of four thio ammonium molybdate, at present, use four thio ammonium molybdate with new vessel as target spot to tumour treat enter the second phase clinical, and reach well anticancer antitumor, extend effect (Quintin, the Celina G.Kleer in patient's life-span, et al.Cancer research 2002,62:4854).But four thio ammonium molybdate is very unstable, and is extremely responsive to light, water and oxygen.Therefore need to be placed in the environment of anhydrous drying, lucifuge, anaerobic, generally be kept in the argon gas of inertia.Within 8 weeks, the four thio ammonium molybdate that is placed in capsule can only keep 90% drug effect.Therefore it is imperative to seek high-efficiency low-toxicity, be better than or be specific to incumbent clinical medicine and have a new type anticancer antitumor drug of certain stability.
Early stage existing two parts of relevant molybdenum matchs cancer therapy drug application invention patent (1. Lu Xiaoming, " molybdenum, tungsten and molybdenum tungsten ligand polymer and method for making thereof and its application in preparation prevention and treatment cancer and tumour medicine " Chinese invention patent, 200410096494.4; 2. Lu Xiaoming, " the octahedra molybdenum tungsten complex of chirality, their synthetic method and the purposes in cancer therapy drug ", Chinese invention patent, 01110359.0), in flow of research, the applicant has found again novel structure uniqueness and has presented the alizarin molybdenum match of excellent antitumor drug effect.
Summary of the invention
Given this, the object of the present invention is to provide a class molybdenum match, i.e. alizarin molybdenum match and method for making thereof and its application in the preparation anticancer, antitumor medicament.
For achieving the above object, the present invention adopts following technical scheme:
The invention provides a class alizarin molybdenum match, its molecular chemistry formula is:
{[HN(R) 3] 2[MoO 2(C 14H 6O 4) 2]} n
Wherein, R is low alkyl group, and n is 1 or greater than 1 integer.
Described low alkyl group is methyl, ethyl or propyl group, is preferably ethyl.
The present invention also provides the preparation method of described alizarin molybdenum match, is in the mixed phase of water, organic phase or water and organic phase, and molybdenum salt, alizarin and organic amine reaction are consisted of title complex of the present invention.
Concrete, Complex synthesis method of the present invention comprises:
1. under normal temperature, alizarin, molybdenum salt and organic amine are placed at are positioned in solvent on magnetic stirrer, stir;
2. with reacted solution filter, then mother liquor is placed in container, slowly adds after the organic solvents such as the ether of arbitrary volume ratio or sherwood oil standing;
3. crystallize outs in containers after two weeks.
Wherein, water is water solvent; Organic phase is organic solvent as the alcohols such as methyl alcohol, ethanol, Virahol, acetonitrile, acetone, DMF etc.; Mixed phase is the mixture of water and organic phase; Molybdenum salt is inorganic salt or organic salt and the hydrate thereof of the inorganic salt of monokaryon molybdenum or inorganic salt hydrate, multinuclear molybdenum; Organic amine is Trimethylamine 99, triethylamine or tripropyl amine or other low-grade alkylamine.
Preferably, described molybdenum salt is ammonium molybdate, Sodium orthomolybdate, potassium molybdate, calcium molybdate, molybdic oxide, moly-sulfide, ammonium molybdate, ammonium thiomolybdate, positive tetrabutyl ammonium octamolybdate, the positive tetrabutyl six ammonium molybdates, just tetrabutyl Ammonium Heptamolybdate, two ammonium molybdate, six carbonyls close molybdenum or molybdenum tetrachloride or their hydrate.More preferably six carbonyls close molybdenum or molybdenum tetrachloride or mixture both.
Described solvent is selected from the mixed organic solvents of one or more arbitrary proportions in described organic solvent.Preferably, described solvent is the mixed solvent of methyl alcohol and DMF arbitrary proportion.
Title complex of the present invention confirms by experiment, can be used as anticancer and antitumor drug or chief component, so the present invention also provides the application of described title complex in the medicine of the generation for preparing prevention and inhibition cancer and tumour and growth.
Beneficial effect of the present invention is as follows: front two parts of existing patents of the applicant that compares, the part of title complex of the present invention is defined as the monokaryon molybdenum match of alizarin and organic amine.Synthesizing of title complex medicine of the present invention, raw material is easy to get, and cost is low, and product is separated out with crystalline form, and purity is large, and productive rate is high; The title complex of the present invention of gained can stable existence under state of nature; The title complex of the present invention of gained has good water-soluble and fat-soluble; The title complex of the present invention of gained has presented good restraining effect to A-549 (lung cancer), Bel-7402 (liver cancer), HCT (adenocarcinoma of colon), HL-60 (leukemia), BGC-823 (cancer of the stomach), KB (nasopharyngeal carcinoma).
Description of drawings
Fig. 1 is the infrared spectrum of title complex of the present invention.
Fig. 2 is the molecular structure of title complex of the present invention.
Fig. 3 is the meso Molecular Graphs of title complex of the present invention.
Fig. 4 is the structure cell accumulation graph of title complex of the present invention.
Embodiment
Following embodiment is intended to further set forth the present invention, but should be clear and definite be, the scope that the present invention is not limited to describe in detail below.
Embodiment 1
1 mole of alizarin, 0.5 mole of six carbonyl are closed molybdenum, 0.5 mole of molybdenum tetrachloride and 4 milliliters of triethylamines put into and fill the 50ml round-bottomed flask that the 15ml anhydrous methanol closes 15 milliliters of DMF, be placed on magnetic stirrer and stir, form dark red solution.After 96 hours, filter, mother liquor is placed in long test tube, slowly add ether to two times of At The Heights of filtrate along test tube wall, standing, approximately separate out red random crystal Z1 after two weeks.
Ultimate analysis value (%) is (being theoretical value in bracket): C:59.58% (59.41%); H:5.59% (5.48%); N:3.57% (3.46%).The infrared analysis of title complex 1 shows, in IR (KBr compressing tablet) spectrum (seeing Fig. 1), and ν s(N-H) 3447 m, ν s(C-H) 2975 m, ν s(C=C) 1534 m, 1450 s, ν s(C=O) 1653 s, ν s(C-O) 1251 s, ν s(Mo=O) 898 m, ν s(Mo-O) 835 mTitle complex 1HNMR (in CDCl 3Solution), δ 8.31,2H (t, Ar C13H), δ 7.82,4H (m, Ar C11, C12H), δ 7.71,2H (dd, Ar C10H), δ 7.53,2H (dd, Ar C6H), δ 7.25,2H (dd, Ar C5H), δ 3.07,12H (q, CH 2), δ 1.21,18H (t, CH 3).
Crystal analysis to title complex shows, in each structural unit, center Mo atom is octahedral coordination of distortion.The complex structure unit is [MoO 2(C 14H 6O 4) 2] 2-Negatively charged ion (seeing Fig. 2), two protonated triethylamine positively charged ion [(HNCH 2CH 3) 3] +Mo (VI) O with described hexa-coordinate on document 6Different is [1-3], center Mo atom is with octahedral structure and the coordination of two bidentate ligand alizarins of distortion, and the bond distance of molybdenum and oxygen exists
Figure BDA0000116547860000041
In scope.Two chirality [MoO 2(C 14H 6O 4) 2] 2-Mode with mapping is each other arranged, and forms mesomeride (seeing Fig. 3).See Fig. 4 along the structure cell accumulation that c-axis is piled up.
The in-vitro screening of the anticancer drug effect of title complex:
The cell experiment of title complex Z1
Select the adherent tumour cell of logarithmic phase: A-549 (lung cancer), Bel-7402 (liver cancer), HCT (adenocarcinoma of colon), HL-60 (leukemia), BGC-823 (cancer of the stomach), KB (nasopharyngeal carcinoma) with after trysinization, be made into the cell suspension of 5000/mL with the RPM11640 nutrient solution of 10% calf serum, be seeded in 96 well culture plates, every hole inoculation 100 μ L, 37 ℃, 5%CO 2Cultivate 24h.
Experimental group: add embodiment 1 gained sample solution 10 μ L (namely use physiological saline solution embodiment 1 gained complex crystal Z1, concentration is 5 μ g/mL), every hole final volume is 200 μ L, supplies with RPMI-1640.37 ℃, 5%CO 2Cultivate 3d.
Abandon supernatant liquor after cultivating 3d, every hole adds the serum-free medium of the 100 freshly prepared 0.5mg/mL MTT of μ L (tetrazolium bromide), 37 ℃ are continued to cultivate 4h, carefully abandon supernatant, and add 200 μ L DMSO dissolving MTT formazon to precipitate, with miniature ultrasonic vibrator mixing, measure the optical density value at wavelength 544nm place on microplate reader.Calculate the growth of tumour cell inhibiting rate according to following formula:
Growth of tumour cell inhibiting rate (%)=(OD Contrast-OD Experiment)/(OD Contrast-OD Blank) * 100%
Result shows, embodiment 1 gained title complex Z1 all has good growth-inhibiting effect to kinds of tumor cells, is respectively:
Be 65.22% to A-549 (lung cancer) inhibitory rate of cell growth;
Be 65.16% to Bel-7402 (liver cancer) inhibitory rate of cell growth;
Be 62.66% to HCT (adenocarcinoma of colon) inhibitory rate of cell growth;
Be 65.16% to HL-60 (leukemia) inhibitory rate of cell growth;
Be 63.63% to BGC-823 (cancer of the stomach) inhibitory rate of cell growth;
Be 60.89% to KB (nasopharyngeal carcinoma) inhibitory rate of cell growth;
Conclusion: this explanation, title complex Z1 of the present invention can be for the preparation of the medicine of prevention and treatment cancer.

Claims (10)

1. a class alizarin molybdenum match, its molecular chemistry formula is:
{[HN(R) 3] 2[MoO 2(C 14H 6O 4) 2]} n
Wherein, R is low alkyl group, and n is 1 or greater than 1 integer.
2. alizarin molybdenum match according to claim 1, wherein said low alkyl group is methyl, ethyl or propyl group.
3. alizarin molybdenum match according to claim 2, its molecular chemistry formula is { [HN (CH 2CH 3) 3] 2[MoO 2(C 14H 6O 4) 2] n, n is 1 or greater than 1 integer.
4. the method for preparing the described alizarin molybdenum match of claim 1 is in the mixed phase of water, organic phase or water and organic phase, and molybdenum salt, alizarin and organic amine reaction are consisted of title complex of the present invention.
5. method according to claim 4, comprise the steps:
1) under normal temperature, alizarin, molybdenum salt and organic amine are placed at are positioned in solvent on magnetic stirrer, stir;
2) with reacted solution filter, then mother liquor is placed in container, slowly adds after the organic solvents such as the ether of arbitrary volume ratio or sherwood oil standing;
3) the interior crystallize out of container after two weeks.
6. according to claim 4 or 5 described methods, wherein, water is water solvent; Organic phase is organic solvent as the alcohols such as methyl alcohol, ethanol, Virahol, acetonitrile, acetone, DMF etc.; Mixed phase is the mixture of water and organic phase; Molybdenum salt is inorganic salt or organic salt and the hydrate thereof of the inorganic salt of monokaryon molybdenum or inorganic salt hydrate, multinuclear molybdenum; Organic amine is Trimethylamine 99, triethylamine or tripropyl amine or other low-grade alkylamine.
7. method according to claim 6, wherein, described molybdenum salt is ammonium molybdate, Sodium orthomolybdate, potassium molybdate, calcium molybdate, molybdic oxide, moly-sulfide, ammonium molybdate, ammonium thiomolybdate, positive tetrabutyl ammonium octamolybdate, the positive tetrabutyl six ammonium molybdates, just tetrabutyl Ammonium Heptamolybdate, two ammonium molybdate, six carbonyls close molybdenum or molybdenum tetrachloride or their hydrate.
8. method according to claim 7, wherein, described molybdenum salt is selected from six carbonyls and closes molybdenum or molybdenum tetrachloride or mixture both.
9. method according to claim 6, wherein, described solvent is selected from the mixed organic solvents of one or more arbitrary proportions in organic solvent, for example the mixed solvent of methyl alcohol and DMF arbitrary proportion.
10. the application of the described title complex of claim 1-3 any one in the medicine of the generation for preparing prevention and inhibition cancer and tumour and growth.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1321644A (en) * 2001-04-06 2001-11-14 鲁晓明 Chiral octahedral Mo-W complexes, their synthesis method and application for preparing anticancer medicine
CN1634944A (en) * 2004-12-02 2005-07-06 首都师范大学 Molybdenum, wolfram, molybdenum and wolfram complex, method for making and use in preparing anticancer, antitumor medicament
US20080311189A1 (en) * 2004-03-18 2008-12-18 Matos Marta R P Norton Compositions Comprising Organometallic Molybdenum Compounds For Treating Cancer
CN101486733A (en) * 2009-03-09 2009-07-22 华南师范大学 Oxygen-containing bridge dinuclear molybdenum cluster compound, and preparation and use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1321644A (en) * 2001-04-06 2001-11-14 鲁晓明 Chiral octahedral Mo-W complexes, their synthesis method and application for preparing anticancer medicine
US20080311189A1 (en) * 2004-03-18 2008-12-18 Matos Marta R P Norton Compositions Comprising Organometallic Molybdenum Compounds For Treating Cancer
CN1634944A (en) * 2004-12-02 2005-07-06 首都师范大学 Molybdenum, wolfram, molybdenum and wolfram complex, method for making and use in preparing anticancer, antitumor medicament
CN101486733A (en) * 2009-03-09 2009-07-22 华南师范大学 Oxygen-containing bridge dinuclear molybdenum cluster compound, and preparation and use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
邓元等，: "含钼化合物及其配合物的抗癌抗肿瘤活性", 《化学通报》 *

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