CN103202825A - Application of curcumin analogue - Google Patents
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- CN103202825A CN103202825A CN 201310056835 CN201310056835A CN103202825A CN 103202825 A CN103202825 A CN 103202825A CN 201310056835 CN201310056835 CN 201310056835 CN 201310056835 A CN201310056835 A CN 201310056835A CN 103202825 A CN103202825 A CN 103202825A
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Abstract
The invention relates to application of a curcumin analogue, and usage of the curcumin analogue as a medicine for inhibiting activity of human type III 17beta-hydroxysteroid dehydrogenase. When used as a medicine, the compound provided by the invention can be used directly in a bulk form, and can also be used in a form of a pharmaceutical composition. The pharmaceutical composition contains 0.1%-99% of the compound provided by the invention, and the balance of a pharmaceutically acceptable carrier or excipient having no toxicity or inertness to human and animal; and the medicinal carrier or excipient is one or more selected from solid, semi-solid, a liquid diluent, a filler and a pharmaceutical product. The medicine provided by the invention can be applied in form of unit weight service amount by a variety of drug delivery ways, such as oral, sublingual, rectal, vein or transdermal, but preferably oral administration.
Description
Technical field
The present invention relates to a kind of application of curcumin analogue, belong to medical technical field.
Background technology
(Prostate cancer PCa) is the modal malignant tumor of male reproductive system to carcinoma of prostate, and morbidity increased with the age.It is reported to be only second to pulmonary carcinoma, is second of male cancer death.Owing to China's aged tendency of population, the carcinoma of prostate sickness rate is remarkable ascendant trend (Sun Yinghao, Chinese magazine of urology surgery, 2004,25,2) in recent years.The cause of disease of carcinoma of prostate is relevant with androgen, early stage prostatic cell and prostate gland cancer cell growth have the biological characteristics that androgen relies on, androgenic effect is by androgen receptor (androgen receptor, AR) mediate, so the phase carcinoma of prostate is called androgen-dependent carcinoma of prostate (androgen-dependent prostate cancer, ADPC) (Fang Xiaoliang, international urinary system magazine, 2009,29,500).But this treatment has certain effect duration for some patient.The verified many patient experiences of the fact from the androgen-dependent to the androgen independence (androgen independent prostate cancer, AIPC) this transition process, and it is no longer valid to the androgen antagonist treatment, final cancer patient is died from the androgen independence carcinoma of prostate and is shifted (Fizazi K, et al. Clin Cancer Res, 2002,8,775).However, reducing androgenic level or suppress androgenic activity, still is very important strategy in carcinoma of prostate early prevention and treatment and the treatment.Cell in the prostata tissue has nothing in common with each other to the dependency of hormone, and cancerous cell depends on androgen mostly, and the androgen level descends in body, and cancerous cell has lost this environment of androgen, cancerous cell namely can be dead, and this is the core place of endocrine therapy carcinoma of prostate.Androgen in the human serum is mainly derived from testis and adrenal gland, and testis can produce most of androgen, and behind the male castration, the adrenal gland still can produce a certain amount of androgen, and these androgenic existence influence the effect of operative treatment carcinoma of prostate.Therefore capable male castration in 1945 adds bilateral and adrenalectomizes, to eliminate testis and adrenal androgen simultaneously, i.e. so-called full blocking-up androgen treatment carcinoma of prostate, but often suffer from the complication such as pigmentation, anemia of hyperpyrexia, hypotension, Addison's disease, curative effect is not very desirable (CHARLES HUGGINS, M.D, WILLIAM WALLACE SCOTT, M.D AND Annals of Surgery, 1945,12,1031; Holley is new, Chinese tumor magazine, 2005,25,496).Nineteen eighty-three Labrie etc. adopts luteinizing hormone releasing hormone analog (LHRHa) and androgen antagonist medicine treatment carcinoma of prostate simultaneously, the androgen of not only using the medicine castration but also producing with androgen antagonist medicine blocking-up adrenal gland, curative effect obviously is better than single endocrine medicine (Labrie F that plants, et al. J Steroid Biochem, 1983,19,999).Orchiectomy, these therapies of LHRH inhibitor have the side effect such as quality of life decline, hyposexuality and bone density reduction that make the patient.
The mechanism of this cancer transition process is a lot of from the androgen-dependent to the androgen independence, but to be the androgen independence cancerous cell self produced some androgen synzyme for one of them, comprising HSD17B3(human III type 17beta-hydroxysteroid dehydrogenase), this enzyme can utilize adrenal dehydroepiandros-sterone (DHEA), and the generation testosterone, thereby the propagation of irritation cancer cell and growth (Marchais-Oberwinkler, et al. J Steroid Biochem Mol Biol, 2011,125,1).
Suppress androgenic activity and can pass through the antagonism androgen receptor, also can disturb the key enzyme of the biosynthetic one or more steps of androgen.HSD17B3 is the biosynthetic key enzyme of androgen, and can transform androstenedione is testosterone.Thereby reduce the synthetic of testosterone by the activity that suppresses HSD17B3, can treat androgen dependent form and some independent form carcinoma of prostate effectively.Simultaneously, the HSD17B3 inhibitor has same curative effect to benign prostatic hyperplasia, also can use (Joanna M. Daya, et al. Molecular and Cellular Endocrinology, 2009,301,251) as contraceptive.
Curcumin (Curcumin) is a kind of xanthein that obtains that extracts from the Rhizoma Curcumae Longae rhizome, is a kind of acid aldehydes matter, and main chain is unsaturated aliphatic and aromatic group.The pharmacodynamic study result shows that curcumin and derivant thereof have significant antioxidation, antiinflammatory, antitumor and angiogenesis inhibitor isoreactivity (Chinese patent 200410013118.4; 200580042393.1; 200610163262.5; 200610102338.3; 200810222060.2; 200810072457.8).At present, curcumin also can be treated carcinoma of prostate (Sundram V etc., PLoS One, 2012,7, e35368; Shehzad A etc., Future Oncol., 2012,8,179), and safety is very high.Human trial is the result show, (Villegas, I et al. Mol. Nutr. Food Res. 2008,52,1040) even reach the dosage of 8 g/kg, still do not have side effects.In addition, conceived rat test result is shown that a large amount of oral curcumins can't obviously increase the probability (Sharma, R. A, et al. Clin. Cancer Res. 2001,7,1452) that stillborn fetus and miscarriage occur.
Although curcumin has the effect of potential treatment carcinoma of prostate, yet its bioavailability is low, the absorption of human body extreme difference, thereby has greatly limited application (Ni X, the et al. Oncol Rep. 2012,28,85 of its treatment carcinoma of prostate; Yallapu MM, et al. Curr Drug Metab, 2012,13,120), for this reason, need the better curcumin derivate of inhibition HSD17B3 enzymatic activity of exploitation, for the medicine of developing prevention and treatment androgen-dependent disorders provides experiment and clinical basis in the future.
The application that the analog of mono carbonyl structure of curcumin that contains Ketohexamethylene is used for the treatment of inflammation or tumor is disclosed in the patent of invention description of application publication number CN 102381951 A, but the tumor of the sort of type of its unexposed concrete treatment.
The application that the analog of mono carbonyl structure of curcumin that contains Ketocyclopentane is used for the treatment of inflammation or tumor is disclosed in the patent of invention description of application publication number CN 102432447 A, but the tumor of the sort of type of its unexposed concrete treatment.
Application in the medicine that a kind of analog of mono carbonyl structure of curcumin is ready for use on treatment inflammation or tumor is disclosed in the patent of invention description of Granted publication CN 101003470 B, but the tumor of the sort of type of its unexposed concrete treatment.
Summary of the invention
The objective of the invention is to overcome above shortcomings in the prior art, and the application of a kind of curcumin analogue of absorption easily of a kind of bioavailability height, human body is provided.
The present invention addresses the above problem the technical scheme that adopts: the application of this curcumin analogue, its special character is: one of formula I, formula II, formula III, formula IV, formula V, the described chemical compound of formula VI or its compositions are used as suppressing human III type 17beta-hydroxysteroid dehydrogenase active medicine
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Among the present invention, one of formula I, formula II, formula III, formula IV, formula V, the described chemical compound of formula VI or its compositions are as the drug use that prevents and/or treats of androgen-dependent disorders.
Among the present invention, described androgen-dependent disorders includes but not limited to: human androgen-dependent carcinoma of prostate, benign prostate hyperplasia, acne, sebaceous adenitis, hirsutism, androgenetic alopecia, sexual precosity, adrenal hyperplasia and polycystic ovarian syndrome.
Among the present invention, one of formula I, formula II, formula III, formula IV, formula V, the described chemical compound of formula VI or its compositions are used as contraceptive.
Among the present invention, the described chemical compound of formula I is called YHX01, and the described chemical compound of formula II is called YHX02, and the described chemical compound of formula III is called YHX03, and the described chemical compound of formula IV is called YHX04, and the described chemical compound of formula V is called YHX05, and the described chemical compound of formula VI is called YHX06.
Early stage prostatic cell and prostate gland cancer cell growth have the biological characteristics that androgen relies on, and suppress androgenic activity and can pass through the antagonism androgen receptor, also can disturb the key enzyme of the biosynthetic one or more steps of androgen.And the HSD17B3 enzyme biosynthetic key enzyme that is androgen, the activity that suppresses the HSD17B3 enzyme can reduce the synthetic of testosterone, treats androgen dependent prostate cancer effectively.The growth of later stage prostatic cell and prostate gland cancer cell has the ind biological characteristics of androgen, because this moment, prostate gland cancer cell produced the HSD17B3 enzyme and the synthetic testosterone of dehydroepiandros-sterone that utilizes the adrenal gland to produce.Suppressing androgenic activity can be by disturbing the key enzyme HSD17B3 of the biosynthetic one or more steps of androgen.Simultaneously, the HSD17B3 enzyme inhibitor has same curative effect to benign prostatic hyperplasia, also can be used as contraceptive and uses.Human trial is the result show, even HSD17B3 enzyme inhibitor curcumin reaches the dosage of 8g/kg, still do not have side effects.In addition, conceived rat test result is shown that a large amount of oral HSD17B3 enzyme inhibitor curcumins can't obviously increase the probability that stillborn fetus and miscarriage occur.Curcumin analogue among the present invention has the activity that suppresses people's testis HSD17B3 enzyme, and its IC50 is significantly higher than 67.3 μ M of curcumin at 0.1-2.7 μ M.In these 6 candidate compounds (YHX01, YHX02, YHX03, YHX04, YHX05, YHX06), the chemical compound of preferably using as curative with YHX02, YHX04, YHX05.YHX05 the best.
When The compounds of this invention is used as medicine, can adopt formation in bulk directly to use, also can adopt the form of pharmaceutical composition to use.And this pharmaceutical composition contains the 0.1%-99% The compounds of this invention, and all the other are acceptable on the materia medica, pharmaceutically suitable carrier or the excipient of and inertia nontoxic to humans and animals.Pharmaceutically suitable carrier or excipient are one or more solids, semisolid, liquid diluent, filler and pharmaceutical preparation.Medicine of the present invention is used with the form of per weight volume of services, can be through various ways, for example oral, rectum Sublingual, vein or transdermal administration, but preferred oral administration.
The specific embodiment
The present invention is described in further detail below by embodiment, and following examples are explanation of the invention and the present invention is not limited to following examples.
Embodiment 1.
6 kinds of curcumin analogues suppress the detection of HSD17B3 in rat and the people's testis microsome.
HSD17B3 be a kind of be the reductase of coenzyme with NADPH, mainly in the microsome of tissues such as testis, express.
The preparation of microsomal protein: adult rat testis and people's testis microsome are by Ge RS, and et al reported method is prepared [Ge RS, et al.Endocrinology, 1997,138:435-42].
The activity of adult rat and people's testis microsomal protein HSD17B3 detects: the activity of adult rat and people's testis microsomal protein HSD17B3 detects presses Ge RS, et al reported method is carried out [Hu G, et al. J Steroid Biochem Mol Biol. 2009; 115:14-9].Utilizing [3H]-androstenedione is substrate, detects the amount that testosterone generates, and characterizes the HSD17B3 activity.Add 200nM[3H in the active detector tube of each HSD17B3]-androstenedione (this concentration in the androstenedione testis within the concentration range) and 50mg microsomal protein and 0.2 mM NADPH, cultivate 1.5-2hr after, with the termination of 2ml ice ether.Then, with the steroidal in the organic solvent extraction Incubating Solution, in the stream of nitrogen gas after the drying, with chloroform/methanol (97:3, v/v) be mobile phase, separate steroidal by thin layer chromatography, [3H] but-radioactivity of androstenedione and [3H] testosterone detects (System AR2000, Bioscan Inc. by scanning radiometer, Washington, DC, USA), the conversion ratio between androstenedione and the testosterone is calculated by their radioactive standard numbers own to be determined.This experiment with DMSO in contrast.
Experimental result is as shown in table 1, and 6 kinds of curcumin analogues all are better than curcumin (IC to the inhibition ability of people's testis HSD17B3 enzyme
50=67.3 μ M), its IC
50Be 0.1 μ M-2.7 μ M.Therefore be preferred for treating the chemical compound employing YHX02 of knot carcinoma of prostate, YHX03, YHX05 is best with YHX05.
Table 1 curcumin analogue is to the inhibitory action of people and rat testicle microsome HSD17B3 enzymatic activity
| Chemical compound | Rat testicle | People's testis |
| YHX01 | （IC 50=3.3μM） a | 39% b |
| YHX02 | 15% | (IC 50=2.4 μM) |
| YHX03 | (IC 50=8.5μM) | (IC 50=2.7 μM) |
| YHX04 | 33% | 48% |
| YHX05 | (IC 50=1.8μM) | (IC 50=0.1μM) |
| YHX06 | 34% | 38% |
| Curcumin | (IC 50=2.3μM) | (IC 50=67.3μM) |
a?(IC
50,?μΜ)；
b% suppressed when compound concentration was 100 μ M.
Embodiment 2.
6 kinds of curcumin analogues suppress the detection of HSD17B3 in the rat testicle Interstitial cell.
HSD17B3 be a kind of be the reductase of coenzyme with NADPH, mainly in interstitial cell, express.The HSD17B3 activity measurement need not to add NADPH in the interstitial cell.Measure chemical compound with complete interstitial cell, the reflection chemical compound is to the penetrance of cell.
The separation of adult rat interstitial cell: 6 SD rat testicles of 90 ages in days are used for the separation of adult rat interstitial cell.Separation method is pressed Salva, and et al reported method is prepared [Salva, A.; Klinefelter, G. R.; Hardy, M. P. J. Androl. 2001,22,665].The purity of interstitial cell is pressed Payne, and et al reported method is assessed the 3b-steroid dehydrogenase with histochemical stain, and interstitial cell purity is 95%.
The activity of adult rat interstitial cell HSD17B3 detects: the activity of rat testicle Interstitial cell HSD17B3 detects and presses Ge RS, and et al reported method is carried out [Ge RS, et al. Endocrinology, 1997,139 (9): 3787-95].Utilizing [3H]-androstenedione is substrate, detects the amount that testosterone generates, and characterizes the HSD17B3 activity.Add 200nM[3H in the active detector tube of each HSD17B3]-androstenedione (this concentration in the androstenedione testis within the concentration range) and 0.05 μ 10
6Cell behind the cultivation 1.5-2hr, stops with 2ml ice ether.Then, with the steroidal in the organic solvent extraction Incubating Solution, in the stream of nitrogen gas after the drying, with chloroform/methanol (97:3, v/v) be mobile phase, separate steroidal by thin layer chromatography, [3H] but-radioactivity of androstenedione and [3H] testosterone detects (System AR2000, Bioscan Inc. by scanning radiometer, Washington, DC, USA), the conversion ratio between androstenedione and the testosterone is calculated by their radioactive standard numbers own to be determined.
Experimental result is as shown in table 2, and 6 kinds of curcumin analogues are different with effect in the microsome to the inhibition ability of people's interstitial cell HSD17B3 enzyme.
Table 2 curcumin analogue is to the inhibitory action of rat testicle Interstitial cell HSD17B3 enzymatic activity.
| Chemical compound | The rat testicle Interstitial cell |
| YHX01 | （IC 50=0.1μM） a |
| YHX02 | Unrestraint b |
| YHX03 | 20% c |
| YHX04 | 30% |
| YHX05 | (IC 50=100μM) |
| YHX06 | 13% |
| Curcumin | (IC 50=9.0μM) |
(IC
50,?μΜ)；
bUnrestraint;
c% suppressed when compound concentration was 100 μ M.
Embodiment 3.
Testosterone is synthetic in the curcumin analogue inhibition rat testicle Interstitial cell.
Interstitial cell is synthetic testosterone under LH stimulates.
Synthetic and the measurement of the testosterone of adult rat interstitial cell: 0.1 * 10
6Interstitial cell and variable concentrations chemical compound and 100ng/ml LH cultivate 3hr, and testosterone exempts to measure with putting in the culture fluid.Testosterone exempts to measure by Salva et al method [Salva, A. with putting; Klinefelter, G. R.; Hardy, M. P. J. Androl. 2001,22,665].
The influence that curcumin stimulates testosterone (T) to produce to LH.
Adult interstitial cell.Cultivate the curcumin 0.1x10 of variable concentrations
6Grow up interstitial cell in the presence of 100ng/ milliliter LH and lipoprotein 18 hours.On average ± SE(SEM), N=8, and " * * * " expression showing property level compares with control value＜and 0.001.
10 μ M curcumins suppress rat testicle Interstitial cell testosterone and generate.
Above content described in this description only is to example explanation of the present invention.Those skilled in the art can make various modifications or replenish or adopt similar mode to substitute described specific embodiment; only otherwise depart from the content of description of the present invention or surmount the defined scope of these claims, all should belong to protection scope of the present invention.
Claims (4)
1. the application of a curcumin analogue is characterized in that: one of formula I, formula II, formula III, formula IV, formula V, the described chemical compound of formula VI or its compositions are used as suppressing human III type 17beta-hydroxysteroid dehydrogenase active medicine,
（Ⅰ）
（Ⅱ）
（Ⅲ）
（Ⅳ）
（Ⅴ）
（Ⅵ）
。
2. the application of curcumin analogue according to claim 1 is characterized in that: one of formula I, formula II, formula III, formula IV, formula V, the described chemical compound of formula VI or its compositions are as the drug use that prevents and/or treats of androgen-dependent disorders.
3. the application of curcumin analogue according to claim 2 is characterized in that: described androgen-dependent disorders includes but not limited to: human androgen-dependent carcinoma of prostate, benign prostate hyperplasia, acne, sebaceous adenitis, hirsutism, androgenetic alopecia, sexual precosity, adrenal hyperplasia and polycystic ovarian syndrome.
4. the application of curcumin analogue according to claim 1 is characterized in that: one of formula I, formula II, formula III, formula IV, formula V, the described chemical compound of formula VI or its compositions are used as contraceptive.
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