CN103819457B - One class can suppress castration-resistant prostate cancer and the geldanamycin derivant becoming Bone tumour and application thereof - Google Patents

One class can suppress castration-resistant prostate cancer and the geldanamycin derivant becoming Bone tumour and application thereof Download PDF

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CN103819457B
CN103819457B CN201410048892.2A CN201410048892A CN103819457B CN 103819457 B CN103819457 B CN 103819457B CN 201410048892 A CN201410048892 A CN 201410048892A CN 103819457 B CN103819457 B CN 103819457B
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prostate cancer
geldanamycin
prostate
derivant
application
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CN103819457A (en
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王继峰
施国伟
林志远
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FIFTH PEOPLE'S HOSPITAL OF SHANGHAI FUDAN UNIVERSITY
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The present invention relates to one group of geldanamycin derivant; described geldanamycin derivant is: 17 ((1 ((E) 3 (4 hydroxy cinnamate acyl group) piperidines 4 base) methylamino) 17 de-methoxy geldanamycins (3a) and 17 ((1 ((E) 3 Resina Ferulae acylpiperidine 4 base) methylamino) 17 de-methoxy geldanamycins (3b), present invention also offers geldanamycin derivant and the purposes of geldanamycin derivant compositions.17 ((1 replacement cinnamoyl piperidines 4 base) methylamino) 17 de-methoxy geldanamycin derivants of the present invention have good inhibiting effect to human prostate cancer cell line LNCaP, C4 2B, 22RV1, Du 145, the growth of PC3, and have the potentiality of suppression prostate cancer with osseous metastasis.17 ((1 replacement cinnamoyl piperidines 4 base) methylamino) 17 de-methoxy geldanamycin derivants of the present invention have anti-prostate cancer activity, can be used for preparing antiprostate cancer.

Description

One class can suppress castration-resistant prostate cancer and the geldanamycin becoming Bone tumour Derivant and application thereof
Technical field
The present invention relates to organic compound synthesis technical field, specifically, ((1-replaces cinnamoyl about 17-to be one group Phenylpiperidines-4-base) methylamino)-17-AAG and application thereof.
Background technology
Carcinoma of prostate (prostate cancer, PCa) is to betide one of common malignant tumor of male reproductive system, Become in global range the modal cancer of second in male.Androgen removes treatment (androgen deprivation Therapy, ADT) it is the conventional treatments of carcinoma of prostate, but the control of tumor is typically only capable of maintaining 1.5-4, male swashs It is to castration-resistant prostate cancer (CRPC, castration-that element removes a major obstacle for the treatment of carcinoma of prostate Resistant prostate) transformation, this becomes a main cause of prostate cancer related mortality.CRPC sends out Sick rate and main reason is that of mortality rate transfer to skeleton, and Bone tumour is the principal character in carcinoma of prostate late period, more than 80% Patients with prostate cancer Bone tumour can occur, become transitivity castration-resistant prostate cancer (mCRPC).
Geldanamycin (Geldanamycin, GA) as far back as 1970 from streptomyces hygroscopicus (Streptomyces Hygroscopicus) isolated in fermentation liquid, belongs to Geldanamycin.GA and derivant thereof have antibacterial, protozoacide, The biological activitys such as antiinflammatory, antitumor and antiviral.Its antitumor action is one of focus of paying close attention in recent years.But owing to it is water-soluble Property poor, liver toxicity is relatively strong, has had a strong impact on it and has developed as new drug.Through retrieval, utilize and pass through 4-in GA molecule 17-position Aminomethylpiperidine connects the substituent group that introducing is different, while maintaining or increasing its original anti-tumor activity, to reduce its liver poison Patent and the document of property have not been reported.
One group of 17-((1-replaces cinnamoyl piperidin-4-yl) methylamino)-17-de-methoxy involved in the present invention Geldanamycin can suppress castration-resistant prostate cancer and Bone tumour, is expected to become candidate's medicine for the treatment of carcinoma of prostate Thing.
Summary of the invention
It is an object of the invention to for deficiency of the prior art, it is provided that one group of geldanamycin derivant.
Another purpose of the present invention is to provide geldanamycin derivant answering in preparing antiprostate cancer With.
Another the purpose of the present invention is to provide anti-prostate cancer composition of medicine.
Fourth object of the present invention is to provide composition medicine application in preparing antiprostate cancer.
For achieving the above object, the present invention adopts the technical scheme that:
One group of geldanamycin derivant, described derivant is one group of monosubstituted geldanamycin derivant in 17-position, its knot Structure formula is as shown in formula I:
Wherein:
R is 4-hydroxyl, 4-methoxyl group, 3,4-dimethoxy and 4-hydroxy-3-methoxy.
Described geldanamycin derivant is: 17-((1-((E)-3-(4-hydroxy cinnamate acyl group) piperidin-4-yl) methylamine Base) ((1-((E)-3-Resina Ferulae acylpiperidine-4-base) methylamino)-17-goes for-17-AAG (3a) and 17- Geldanamycin (3b).
For realizing above-mentioned second purpose, the present invention adopts the technical scheme that: geldanamycin derivant is anti-in preparation Carcinoma of prostate or carcinoma of prostate become the application in Bone tumour disease medicament.
Described geldanamycin derivant is that ((1-((E)-3-Resina Ferulae acylpiperidine-4-base) methylamino)-17-goes 17- Geldanamycin (3b).
Described carcinoma of prostate refers to hormone-independent prostate cancer.
Described carcinoma of prostate refers to hormone-independent prostate cancer.
For realizing above-mentioned 3rd purpose, the present invention adopts the technical scheme that:
A kind of antiprostate cancer compositions, described pharmaceutical composition contains 17-((1-((E)-3-Resina Ferulae acyl group piperazine Pyridine-4-base) methylamino)-17-AAG (3b) and pharmaceutically acceptable carrier.
For realizing above-mentioned 4th purpose, the present invention adopts the technical scheme that:
Compositions is preparing anti-prostate cancer or carcinoma of prostate becomes the application in Bone tumour disease medicament.
Described carcinoma of prostate refers to hormone-independent prostate cancer.
Described carcinoma of prostate refers to hormone-independent prostate cancer.
The preparation of geldanamycin derivant of the present invention can be realized by following universal method.
First 4-aminomethylpiperidine reacts with geldanamycin in chloroform or dichloromethane, obtains intermediate 2, and then 2 Target product 3 (route 1) is generated with substituted styrene acid condensation.
The invention has the advantages that:
1, the invention discloses one group of 17-((1-replaces cinnamoyl piperidin-4-yl) methylamino)-17-de-methoxy lattice That moral mycin.
2, the present invention is to compound 17-((1-((E)-3-Resina Ferulae acylpiperidine-4-base) methylamino)-17-de-methoxy lattice You have excavated new medical application by moral mycin, have opened up a new application.
3, above-claimed cpd safety non-toxic, pharmacological action is strong, imply that good prospect in medicine.
4,17-((1-replaces cinnamoyl piperidin-4-yl) the methylamino)-17-AAG of the present invention Derivant has good inhibiting effect to the growth of human prostate cancer cell line LNCaP, C4-2B, 22RV1, Du-145, PC3, And there is the potentiality of suppression prostate cancer with osseous metastasis, 17-((1-replaces cinnamoyl piperidin-4-yl) methylamine of the present invention Base)-17-AAG derivant have anti-prostate cancer activity, can be used for preparing antiprostate cancer.
Detailed description of the invention
Embodiment 1:17-((1-((E)-3-(4-hydroxy cinnamate acyl group) piperidin-4-yl) methylamino)-17-de-methoxy lattice The synthesis (3a) of your moral mycin
In the round-bottomed flask of 50mL, weigh GA (1) (28.0mg, 0.05mmol, 1equiv.) be dissolved to chloroform (5mL) In, it being subsequently adding 4-aminomethylpiperidine (57.1mg, 0.50mmol, 10equiv.), after reactant liquor lucifuge stirring 6h, TLC monitors Reaction process, after reaction terminates, add water 3 times (25mL x 3) of washing, saturated aqueous common salt 3 times (25mL x 3) of washing, anhydrous sulfur Acid sodium is dried, and obtains product 2 after concentration, the most purified, is directly used in next step.Intermediate 2 obtained above is dissolved into DMF (8mL) in, add NHS (6.3mg, 0.055mmol, 1.1equiv.), EDC (10.4mg, 0.055mmol, 1.1equiv.) and 4-hydroxycinnamic acid (8.2mg, 0.050mmol, 1.1equiv.).Reactant liquor at room temperature lucifuge stir, TLC monitoring react into Journey, after completion of the reaction, adds water (30mL), is extracted with ethyl acetate 3 times (25mL x 3), merge organic facies, anhydrous sodium sulfate Being dried, after concentration, crude product silica gel column chromatography (petroleum ether: ethyl acetate=1:1) separates to obtain target compound 3a, solid for purple Body, yield is 28.6%；mp 158-160℃；1H NMR(600MHz,CDCl3) δ 9.14 (s, 1H), 7.59 (d, J=15.1Hz, 1H), 7.38 (d, J=6.2Hz, 2H), 7.28 (s, 1H), 6.93 (d, J=10.8Hz, 1H), 6.85 (d, J=5.2Hz, 2H), 6.71 (d, J=15.1Hz, 1H), 6.57 (t, J=11.1Hz, 1H), 6.35 (s, 1H), 5.92 5.83 (m, 2H), 5.19 (s, 1H), 4.90 (brs, 2H), 4.81 4.74 (m, 1H), 4.31 (d, J=9.3Hz, 1H), 4.21 4.12 (m, 1H), 3.60 3.56(m,1H),3.50–3.46(m,1H),3.46–3.38(m,2H),3.36(s,3H),3.27(s,3H),3.18–3.09(m, 1H),2.78–2.73(m,1H),2.71–2.63(m,2H),2.35(s,1H),2.02(s,3H),1.94–1.84(m,3H), 1.79(s,5H),1.73–1.69(m,2H),1.34–1.26(m,2H),1.00(s,3H),0.96(s,3H).13C NMR (150MHz,CDCl3)δ183.9,180.8,168.4,166.1,158.2,156.2,144.7,143.2,141.4,135.9, 134.9,133.6,132.8,130.8,129.6,127.3,127.0,126.6,115.9,113.8,108.75,108.72, 81.8,81.4,81.1,72.7,57.2,56.8,51.1,45.7,42.2,36.9,35.0,34.4,32.3,30.7,29.7, 28.7,23.0,12.9,12.7,12.5；ESI-MS:m/z811.7[M+Na]+C43H56N4NaO10 calcd.811.9.
Prepare with method:
17-((1-((E)-3-Resina Ferulae acylpiperidine-4-base) methylamino)-17-AAG (3b), purple Color solid, yield is 30.5%；mp 152-153℃；1H NMR(600MHz,CDCl3) δ 9.16 (s, 1H), 7.60 (d, J= 14.9Hz, 1H), 7.30 (s, 1H), 7.10 (d, J=5.4Hz, 1H), 6.99 (s, 1H), 6.95 (d, J=10.6Hz, 1H), 6.91 (d, J=4.4Hz, 1H), 6.72 (d, J=15.3Hz, 1H), 6.58 (t, J=10.8Hz, 1H), 6.34 (s, 1H), 5.93 5.83 (m, 3H), 5.19 (s, 1H), 4.87 (brs, 2H), 4.84 4.76 (m, 1H), 4.31 (d, J=9.0Hz, 1H), 4.24–4.15(m,1H),3.93(s,3H),3.59–3.54(m,1H),3.50–3.38(m,3H),3.36(s,3H),3.27(s, 3H), 3.19 3.09 (m, 1H), 2.77 2.72 (m, 1H), 2.69 (d, J=13.5Hz, 2H), 2.36 (t, J=11.4Hz, 1H),2.02(s,3H),1.94–1.84(m,3H),1.79(s,5H),1.74–1.66(m,2H),1.34–1.26(m,2H), 1.00(s,3H),0.96(s,3H).13C NMR(150MHz,CDCl3)δ183.7,180.8,168.4,165.7,156.0, 147.3,146.7,144.7,143.2,141.4,135.9,134.9,133.7,132.8,127.8,127.0,126.6, 121.9,114.7,114.4,109.8,108.8,108.7,81.7,81.4,81.2,72.6,57.2,56.8,56.0,51.1, 45.7,42.1,37.0,35.0,34.4,32.3,29.7,28.7,23.0,12.8,12.7,12.4；ESI-MS:m/z 841.6 [M+Na]+C43H56N4NaO10 calcd.841.9.
Embodiment 2: geldanamycin derivant extracorporeal anti-tumor cytoactive screening test
Method of testing:
With mtt assay, the anti-tumor activity of various compounds is evaluated.Take the logarithm the cell tryptase enzymic digestion system of trophophase Become single cell suspension.Counting with hemocyte plate and being diluted to cell concentration is 6 × 104Individual/mL, is inoculated in 96 porocyte culture plates In, every hole 80 μ L.Separately set 3 holes acellular, only have same volume culture medium as blank.Continue to cultivate 24h, be subsequently adding The sample that 20 μ L cell culture medium are good.Meanwhile, toward Positive control wells add 20 μ L dilution after cisplatin, negative control hole and Blank control wells adds identical dilution DMSO and 20 μ L culture medium respectively.Continuing to cultivate 72 hours, then to add 10 μ L dense in every hole Degree is 5mg/mL MTT solution, hatches 3 hours for 37 DEG C, and then every hole adds 100 μ L MTT stop buffer (10%SDS-0.01mol/L HCl) dissolve 5 hours.Microplate reader colorimetric determination (measures wavelength 570nm, reference wavelength 655nm).
The suppression ratio of cell proliferation is calculated as follows:
IC50Represent that sample is concentration when 50% to the suppression ratio of cell.
Test material:
Human prostata cancer LNCap, C4-2B (independent prostate cancer cells strain), 22RV1 are (before hormonal dependent Row adenocarcinoma cell strain), Du-145, PC3 (independent prostate cancer cells strain) and Human normal hepatocyte HL7702, people are just Often prostate epithelial cell RWPE-1, people's normal umbilical vein epithelial cell HUVEC cell, cell strain used derives from ATCC.
Test result: be shown in Table 1.
The table 1:GA derivant 3b activity to 8 strain cells
As can be seen from Table 1, compound 3b shows stronger inhibitory activity to 5 strain prostate cancer tumor cells, right The activity of androgen-independent prostate cancer cell lines in vitro Du-145 is the strongest.The compound 3b IC to conventional prostate gland cancer cell50All Below 1 μM, and umbilical vein epithelial cell HUVEC normal to people, normal prostatic epithelium cell RWPE-1 and people's normal hepatocytes The toxicity of cell HL7702 is less.
In sum, have significant inhibitory action, particularly androgen to prostate cancer tumor cells non-for compound 3b Dependency prostate gland cancer cell Du-145 has stronger biological activity, and thin to the umbilical vein epithelium in Normal human tissue source Born of the same parents and Human normal hepatocyte toxicity are little, have preferable druggability.
Embodiment 3: geldanamycin derivant 3b induced androgen dependent/non-dependent prostate gland cancer cell Du-145 apoptosis Detection
Method of testing:
With Annexin V-FITC/PI double dye method detection 3b apoptosis-induced effect to Du-145 cell.Take the logarithm growth The cell tryptase enzymic digestion of phase is made single cell suspension and is inoculated in 6 porocyte culture plates, 3 × 105, every hole cell.Continue training Support 24h, change fresh culture, and add the sample 3b of the variable concentrations good with cell culture medium.Continue to cultivate 24 little Time, then with the collected by trypsinisation cell (including suspension cell in culture fluid) without EDTA, 1000r/min is centrifuged 5min, Remove supernatant, then with cold PBS washed cell twice (1000r/min, centrifugal 5min), with 400ul 1X Binding Buffer suspension cell, concentration is about 1 × 106 cell/ml, is then adding 5ul Annexin in cell suspending liquid V-FITC, hatches under the conditions of 2-8 DEG C of lucifuge after mixing gently 15 minutes, mixes gently in 2-8 DEG C after adding 10ul PI afterwards Hatch under the conditions of lucifuge 5 minutes, in 1 hour, use flow cytomery.
Test material:
Annexin V-FITC/PI cell apoptosis detection kit, purchased from BD Pharmingen (USA)；Human prostate Cancer Du-145 is purchased from ATCC.
Test result: geldanamycin derivant 3b can the Du-145 of induced androgen dependent/non-dependent prostate gland cancer cell Apoptosis.
Embodiment 4: the inhibitory action that osteoblast is activated by osteoblast differentiation experimental analysis compound 3b
Method of testing:
Under RAW 264.7 cell dissociation that will be grown in the MEM culture medium containing 10%FBS and 1% non essential amino acid Come, be placed in incubator, place 2min, allow differentiated cell be sunken to bottom, by unprecipitated for upper strata cell according to 1 × 104 Individual cell per well is inoculated in 24 orifice plates, after 2hr, adds recombined human RANKL (the receptor activator of of 100ng/mL NF-κ B ligand) albumen, then it is not added with or adds the compound 3b of variable concentrations being then incubated for 5 days, the apocyte of differentiation Observe with MGG dyeing.
Test material:
RAW 264.7 cell is purchased from ATCC；Recombined human RANKL albumen is purchased from R&D.
Test result: geldanamycin derivant 3b can suppress RAW264.7 cell to be divided into apocyte,
There are the potentiality of suppression prostate cancer with osseous metastasis.
Embodiment 5: the injection formula for the treatment of carcinoma of prostate and effect detection
Treatment carcinoma of prostate injection formula is shown in Table 2.
Table 2: treatment carcinoma of prostate injection formula
Preparation method:
PEG400 water for injection is diluted, adds 3b (17-((1-((E)-3-Resina Ferulae acylpiperidine-4-base) first Amido)-17-AAG) stirring and dissolving.Add dimethyl sulfoxide and benzyl alcohol, make all to dissolve, filter, Embedding, 100 DEG C of sterilizings 30 minutes, active component content is 10mg/mL.
Method of testing:
This experiment chooses the nude mice (about 18～20 grams, male) of 6～8 weeks as experimental subject, is divided into two groups, often organizes 10 Only.Du-145 cell is seeded to nude mice oxter and buttocks, and the size of monitoring inoculation tumor mass, when length to certain level gives chemical combination Thing is treated, agents useful for same formula according to shown in table 2, the pharmaceutical preparation of every injected in mice 10mg/kg.Quiet by tail every 2 days Arteries and veins is administered once, and is administered 5 times altogether.The period fast size of results of regular determination tumor mass is until experiment terminates.
Test material:
BALB/c nude mice (SPF level), is purchased from Beijing Vital River Experimental Animals Technology Co., Ltd.
Test result:
The injection of the treatment carcinoma of prostate of geldanamycin derivant 3b preparation can effectively suppress Du-145 cell Xenograft tumor.
Being shown by above-described embodiment, 17-((1-replaces cinnamoyl piperidin-4-yl) the methylamino)-17-of the present invention is nor- The growth of human prostate cancer cell line LNCaP, C4-2B, 22RV1, Du-145, PC3 is had by epoxide geldanamycin derivant Good inhibiting effect, and there are the potentiality of suppression prostate cancer with osseous metastasis, thus proving, ((1-replaces the 17-of the present invention Cinnamoyl piperidin-4-yl) methylamino)-17-AAG derivant have anti-prostate cancer activity, can use In preparing antiprostate cancer.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art Member, on the premise of without departing from the inventive method, it is also possible to makes some improvement and supplements, and these improve and supplement and also should be regarded as Protection scope of the present invention.

Claims (8)

1. one group of geldanamycin derivant, it is characterised in that: described derivant is that one group of monosubstituted geldanamycin in 17-position spreads out Biology, its general structure as shown in the formula (I):
Wherein:
R is 4-hydroxyl, 4-methoxyl group, 3,4-dimethoxy and 4-hydroxy-3-methoxy；
The described monosubstituted geldanamycin derivant in 17-position is 17-((1-((E)-3-Resina Ferulae acylpiperidine-4-base) methylamine Base)-17-AAG (3b).
Geldanamycin derivant the most according to claim 1 is preparing anti-prostate cancer or carcinoma of prostate becomes Bone tumour disease Application in medicine.
Application the most according to claim 2, it is characterised in that: described carcinoma of prostate refers to hormonal independent prostate Cancer.
Application the most according to claim 3, it is characterised in that: described carcinoma of prostate refers to hormone-independent prostate Cancer.
5. an antiprostate cancer compositions, it is characterised in that: described pharmaceutical composition contains 17-((1-((E)-3-Ah Wei acylpiperidine-4-base) methylamino)-17-AAG (3b) and pharmaceutically acceptable carrier.
Compositions the most according to claim 5 is preparing anti-prostate cancer or carcinoma of prostate becomes in Bone tumour disease medicament Application.
Application the most according to claim 6, it is characterised in that: described carcinoma of prostate refers to hormonal independent prostate Cancer.
Application the most according to claim 7, it is characterised in that: described carcinoma of prostate refers to hormone-independent prostate Cancer.
CN201410048892.2A 2014-02-12 2014-02-12 One class can suppress castration-resistant prostate cancer and the geldanamycin derivant becoming Bone tumour and application thereof Active CN103819457B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101220068A (en) * 2008-01-18 2008-07-16 中国医学科学院医药生物技术研究所 A set of geldanamycin derivant and method for preparing the same
CN102115460A (en) * 2010-01-05 2011-07-06 杭州华东医药集团生物工程研究所有限公司 Geldanamycin derivative and preparation method and application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101220068A (en) * 2008-01-18 2008-07-16 中国医学科学院医药生物技术研究所 A set of geldanamycin derivant and method for preparing the same
CN102115460A (en) * 2010-01-05 2011-07-06 杭州华东医药集团生物工程研究所有限公司 Geldanamycin derivative and preparation method and application thereof

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