CN105985399A - Preparation method and use of (20S, 24R/S)-epoxy-12 beta, 25-hydroxy-dammarane-3 beta-amine derivatives - Google Patents
Preparation method and use of (20S, 24R/S)-epoxy-12 beta, 25-hydroxy-dammarane-3 beta-amine derivatives Download PDFInfo
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Abstract
The invention relates to the field of organic synthesis and pharmaceutical chemistry and concretely relates to dammarane derivatives with novel structures shown in the formulas (I) and (II). The invention also discloses a preparation method of the (20S, 24R/S)-epoxy-12 beta, 25-hydroxy-dammarane-3 beta-amine derivatives, a pharmaceutical composition containing the (20S, 24R/S)-epoxy-12 beta, 25-hydroxy-dammarane-3 beta-amine derivatives and a use of the (20S, 24R/S)-epoxy-12 beta, 25-hydroxy-dammarane-3 beta-amine derivatives in preparation of drugs for reversion of tumor resistance to multiple drugs.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, it is specifically related to (20S, 24R/S)-epoxy-12 β, 25-hydroxyl-dammarane-3 beta-amine derivant, the invention also discloses the preparation method of these dammarane's derivatives, and the pharmaceutical composition containing described compound and application in preparing reverse multiple drug resistance of tumor medicine for the described compound.
Technical background
The human health that appears as of antibiotic and chemotherapeutics is made that huge contribution, but the application with these medicines, chemotherapeutic agent sensitiveness is reduced by pathogen and tumour cell etc., creates resistance phenomenon, the health of the appearance of the Drug-resistant serious threat mankind.Have now been found that, although resistance mechanism has a diversity, but common main cause is some active transporter molecules different for a series of chemical constitutions is pumped out target cell, such as antibiotic, antibacterials, antimalarial and tumor chemotherapeutic drug etc..The overexpression of tumour and bacterial cell Chinese traditional medicine transport protein (efflux pump) is the key factor forming MDR.These multi-efflux pumps are the potential target spots overcoming MDR, and suppression protein called membrane transporters can strengthen the sensitiveness of chemotherapeutics effectively.Wherein, maximum class protein called membrane transporters are abc transport albumen (ATP-binding cassette transporter, ATP combines boxlike albumen) superfamily, known with tumor multi-medicine drug-resistant (multidrug resistance, the member of MDR) relevant abc transport superfamily protein has P-glycoprotein (P-glycoprotein, P-gp), MRP (multidrug resistance-associated protein, and breast cancer Mdr-p (breast cancer resistance protein, BCRP) MRP).At present, the compound in a large amount of natural origins or synthesis source is proven to have the activity of protein called membrane transporters suppression and reverse multidrug resistance.
Document is reported, ginsengenin protopanoxadiol (PPD) and ocotillol type triterpene have effect [the Bioorg Med Chem of the suppression of P-glycoprotein and reverse multiple drug resistance of tumor, 2013,21 (14): 4279-4287.Bioorg Med Chem, 2010,18 (8): 2964-2975.].Present inventor in carrying out structural modification and transformation to protopanoxadiol, obtain novel ocotillol type triterpenoid saponin, further the structural modification, (20S of novel structure of having got back, 24R/S)-epoxy-12 β, 25-hydroxyl-dammarane-3 beta-amine derivant.Pharmacology test proves that these derivatives can reverse the tumor multi-medicine drug-resistant of P-glycoprotein mediation strongly.
Content of the invention
The invention provides and there is the compound shown in formula (I) or (II) or its pharmaceutically acceptable salt.The invention provides the preparation method of a series of compound with logical formula (I) or (II) architectural characteristic.Also include the application in preparing reverse multiple drug resistance of tumor medicine of the compound or its salt of logical formula (I) or (II).
Wherein R represents hydrogen, (C1-C4) straight chained alkyl, acyl group.
The preferred following arbitrary compound of the present invention or its pharmaceutically acceptable salt:
(20S, 24S)-epoxy dammarane-12 β, 25-glycol-3 β-amine；
(20S, 24R)-epoxy dammarane-12 β, 25-glycol-3 β-amine；
(20S, 24S)-epoxy-3 β-methylamino dammarane-12 β, 25-glycol；
(20S, 24R)-epoxy-3 β-methylamino dammarane-12 β, 25-glycol；
(20S, 24S)-epoxy-3 β-acetamido dammarane-12 β, 25-glycol；
(20S, 24R)-epoxy-3 β-acetamido dammarane-12 β, 25-glycol；
Logical formula (I) and (II) compound can be according to following reaction scheme and description preparations:
With protopanoxadiol as raw material, 3,12 hydroxyls are protected in acetylation, carry out epoxidation and intramolecular affine attack, and deacetylation obtains (20S, 24R/S)-epoxy dammarane-3 beta, 12 β, 25-triol；3 are oxidized to ketone, become oxime, amination；It is alkylated and is acylated and prepare formula (I) and (II) derivative.
The compounds of this invention pharmaceutically acceptable salt, it is characterised in that: referring to the acid-addition salts of routine, it has the pharmaceutic efficacy as compound, and the salt becoming with suitable non-toxic organic acid or inorganic acid.
The invention also discloses a kind of pharmaceutical composition, compound containing the present invention or its pharmaceutically acceptable salt, pharmaceutically acceptable carrier can be added and make common pharmaceutical formulation, such as tablet, capsule, pulvis, syrup, liquor, suspending agent, injection, the excipient substance that spices, sweetener, liquid or solid inserts or diluent etc. are conventional can be added.
Compound of the present invention administering mode clinically can use the modes such as oral, injection.
The clinical dosage used of the compound of the present invention is 0.01mg～1000mg/ days, it is possible to weight or the difference of formulation according to the state of an illness deviate this scope.
The pharmacological results of of the present invention part of compounds is presented herein below, and in test, embodiment be shown in compound used therefor code name.
Laboratory apparatus:
Microwell plate
Trace adjustable pipette
OPSYS microplate reader (DYNEX Technology, Inc., Chantilly, VA).
Liquid scintillation analyzer (Packard Instrument Company, Inc (Downers Grove, IL))
Reagent material:
Paclitaxel, vincristine, cisplatin, verapamil,
Dulbecco ' s modified Eagle ' s medium (DMEM), fetal bovine serum (FBS), DMSO
Cell line:
SW620, SW620/Ad300
HEK293/pcDNA3.1, HEK/ABCB1,
Experimental technique:
1. cell dissociation, to count, make concentration be 5 × 104The cell suspension of individual/mL, in 96 orifice plates, every hole adds 100ul cell suspension (every hole 5 × 103Individual cell)；
2. 96 orifice plates are placed in 37 DEG C, 5%CO2Incubator is cultivated 24 hours；
3. with complete medium dilution medicine to desired concn, the corresponding pastille culture medium of every hole addition 100 μ L, set up negative control group, Vehicle controls group, positive controls simultaneously；
4. 96 orifice plates are placed in 37 DEG C, 5%CO2Incubator is cultivated 72 hours；
5. 96 orifice plates are carried out MTT dyeing, λ=570nm, measure OD value.
1) every hole adds 20 μ L MTT (5mg/mL), continues to cultivate 4 hours at incubator；
2) discarding culture medium, every hole adds 150 μ L DMSO to dissolve, and shaking table mixes for 10 minutes gently；λ=570nm,
ELIASA reads the OD value in every hole, calculates inhibiting rate and IC50Value.Drug-resistant intensity (Resistance Fold) is with medicine
The IC to normal sensitive cancer cell for the thing50Value is divided by the IC on MDR cell50Value is weighed.
Experimental result is shown in Tables 1 and 2:
The reversal to the MDR that P-glycoprotein mediates for ORA and OSA in table 1. P-glycoprotein process LAN tumour cell.
Table 2. ORA and OSA in transfectional cell to the reversal to the MDR that P-glycoprotein mediates.
Detailed description of the invention
Below in conjunction with instantiation, the present invention is further elaborated, but the present invention is not limited to these embodiments.
Embodiment 1
(20S, 24S)-epoxy dammarane-12 β, 25-glycol-3 β-amine (OSA)
It is dissolved in 20 (S)-protopanoxadiols (500mg, 1.08mmol) in anhydrous pyridine (3mL), add DMAP (20mg, 0.16mmol), it is slowly added dropwise acetic anhydride (0.42mL, 4.43mmol) after stirring, 12h is stirred at room temperature.Ethyl acetate (20mL) dilutes, and 10% hydrochloric acid is washed till acidity, washing, and saturated aqueous common salt washs, anhydrous sodium sulfate is dried, and filters, and concentrates, column chromatography (petroleum ether: ethyl acetate=10: 1), obtains white solid 1 (508mg, 85%).
By 1 (208mg obtained above, it 0.38mmol) is dissolved in anhydrous methylene chloride (6mL), it is slowly added dropwise metachloroperbenzoic acid (185mg under cryosel bath precooling, 75%, dichloromethane (5mL) solution 0.16mmol), dropping is warmed to room temperature stirring reaction 2h after finishing half an hour.Add isopropanol (0.1mL), after continuing stirring one hour, separatory extraction after adding saturated sodium bicarbonate solution to stir one hour, organic phase is washed by saturated sodium thiosulfate solution, water, saturated aqueous common salt successively, and anhydrous sodium sulfate is dried, and filters, concentrate, column chromatography (petroleum ether: ethyl acetate=8: 1), obtains white solid 2 (132mg, 62%).
2 (132mg, 0.24mmol) obtained above are dissolved in DMSO (8mL) and H2In O (2mL), add potassium hydroxide (85mg, 1.52mmol), 135 DEG C of stirring reaction 2h.After reactant liquor is cooled to room temperature, adding appropriate water, a large amount of white solids separate out, suction filtration, is dried, column chromatography (petroleum ether: ethyl acetate=2: 1-1: 1), obtain compound as white solid 3 [(20S, 24S)-epoxy dammarane-3 beta, 12 β, 25-triol] (50mg, 43.3%) and white compound 4 [(20R, 24S)-epoxy dammarane-3 beta, 12 β, 25-triol].
Compound 3:1H NMR(CDCl3, 300MHz) and δ 3.87 (dd, J=10.2Hz, 5.1Hz, 1H), 3.52 (td, J=10.2Hz, 4.8Hz, 1H), 3.19 (dd, J=10.8Hz, 5.4Hz, 1H), 2.25 (td, J=10.5Hz, 4.2Hz, 1H), 1.27 (s, 3H), 1.23 (s, 3H), 1.10 (s, 3H), 1.01 (s, 3H), 0.97 (s, 3H), 0.91 (s, 3H), 0.88 (s, 3H), 0.78 (s, 3H)；MS (ESI) m/z:477.3 [M+H]+。
Compound 4:1H NMR(CDCl3, 300MHz) and δ 3.84 (dd, J=8.4Hz, 6.6Hz, 1H), 3.52 (td, J=10.5Hz, 4.8Hz, 1H), 3.19 (dd, J=10.8Hz, 5.1Hz, 1H), 2.19 (td, J=10.8Hz, 3.6Hz, 1H), 1.28 (s, 3H), 1.27 (s, 3H), 1.10 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H), 0.90 (s, 3H), 0.86 (s, 3H), 0.78 (s, 3H)；MS (ESI) m/z:477.3 [M+H]+。
Compound 3 (40mg, 0.08mmol) is dissolved in anhydrous methylene chloride (3mL), adds PCC (pyridinium chloro-chromate, 36mg, 0.17mmol), be stirred at room temperature 3 hours.Decompression removes solvent, acetic acid ethyl dissolution, extraction, organic layer is washed, saturated common salt is washed, and anhydrous sodium sulfate is dried, and filters, concentrate, column chromatography (petroleum ether: ethyl acetate=10: 1), obtains white solid 5 (20S, 24S)-epoxy dammarane-12 β, 25-glycol-3-ketone (23mg, 58%).1H NMR(CDCl3, 500MHz) and δ 3.88 (dd, J=10.5Hz, 5.0Hz, 1H), 3.55 (td, J=10.0Hz, 4.5Hz, 1H), 2.49-2.54 (m, 1H), 2.45 (ddd, J=11.0Hz, 8.0Hz, 3.5Hz, 1H), 2.24-2.29 (td, J=10.5Hz, 4.5Hz, 1H), 1.28 (s, 3H), 1.23 (s, 3H), 1.11 (s, 3H), 1.08 (s, 3H), 1.053 (s, 3H), 1.046 (s, 3H), 0.96 (s, 3H), 0.93 (s, 3H)；MS (ESI) m/z:475.3 [M+H]+。
Being dissolved in compound 5 (80mg, 0.17mmo1) in anhydrous pyridine, adding hydroxylamine hydrochloride (28mg, 0.39mmo1) under room temperature, 60 DEG C are reacted three hours.Diluted ethyl acetate, 10% hydrochloric acid is washed till acidity, washing, and saturated aqueous common salt washs, anhydrous sodium sulfate is dried, filter, concentrate, column chromatography (petroleum ether: ethyl acetate=1: 1), obtain white solid 7 (20S, 24S)-epoxy dammarane-12 β, 25-glycol-3-ketoxime (70mg, 85%).1H NMR(CDCl3, 300MHz) and δ 3.88 (dd, J=10.2Hz, 4.9Hz, 1H), 3.52 (td, J=10.4Hz, 5.5Hz, 1H), 2.93-3.03 (m, 1H), 2.21-3.35 (m, 2H), 1.96-2.09 (m, 2H), 1.28 (s, 3H), 1.24 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.06 (s, 3H), 1.04 (s, 3H), 0.98 (s, 3H), 0.90 (s, 3H)；MS (ESI) m/z:490.3 [M+H]+。
By compound 7 (310mg, 0.63mmol) with ammonium acetate (500mg, it 6.3mmol) is dissolved in methyl alcohol (50mL), sodium cyanoborohydride (400mg is added under room temperature, 6.3mmol), it is slowly dropped into the hydrochloric acid solution (2.6mL, 15-20%in HCl) of titanium trichloride under cryosel bath, drip and finish, room temperature reaction 5 hours.The NaOH solution of reactant liquor 2N is adjusted to pH=10.Water layer is extracted by dichloromethane and ethyl acetate successively, and organic phase anhydrous sodium sulfate is dried, and filters, and concentrates, column chromatography (dichloromethane: methyl alcohol=20: 1), obtains white solid OSA (220mg, 71%).1H NMR(CDCl3, 300MHz) and δ 3.87 (dd, J=10.2Hz, 5.0Hz, 1H), 3.52 (td, J=9.8Hz, 4.0Hz, 1H), 2.62 (dd, J=10.2Hz, 4.9Hz, 1H), 2.24 (td, J=9.8 Hz, 5.8Hz, 1H), 1.27 (s, 3H), 1.23 (s, 3H), 1.10 (s, 3H), 1.04 (s, 3H), 1.01 (s, 3H), 0.91 (s, 6H), 0.88 (s, 3H), 0.85 (s, 3H)；13C NMR(CDCl3, 75MHz) and δ 87.4,87.1,70.4,70.1,60.4,56.4,52.1,50.2,48.9,48.8,39.7,38.8,37.3,37.1,34.7,32.2,31.6,29.7,28.9,28.5,28.0,25.1,24.2,18.4,17.8,16.0,15.5；ESI-MSm/z476.4[M+H]+；HR-MS (ESI) m/z:calculated forcalculated for C30H54NO3[M+H]+: 476.4098, found:476.4094.
Embodiment 2
(20S, 24R)-epoxy dammarane-12 β, 25-glycol-3 β-amine (ORA)
With reference to (20S, 24S)-epoxy dammarane-12 β, 25-glycol-3-amine (OSA) synthetic method, by compound 4, through compound 6,8 obtain white solid ORA (120mg, 73%).1H NMR(CDCl3, 300MHz) and δ 3.84 (dd, J=13.7Hz, 7.0Hz, 1H), 3.50 (td, J=10.4Hz, 4.6Hz, 1H), 2.35 (dd, J=11.5Hz, 4.4Hz, 1H), 2.18 (td, J=10.9Hz, 3.5Hz, 1H), 1.28 (s, 3H), 1.26 (s, 3H), 1.09 (s, 3H), 0.98 (s, 3H), 0.94 (s, 3H), 0.90 (s, 3H), 0.83 (s, 6H), 0.74 (s, 3H).13C NMR(CDCl3, 75MHz) and δ 86.5,85.4,80.0,70.1,59.7,56.6,52.0,50.6,49.4,47.9,39.6,39.5,38.1,37.3,34.8,32.6,31.2,28.6,28.3,27.9,27.6,26.1,25.0,18.6,18.1,16.2,15.5,15.4；ESI-MS m/z476.4[M+H]+；HR-MS (ESI) m/z:calculated for C30H54NO3[M+H]+: 476.4098, found:476.4091.
Embodiment 3
(20S, 24S)-epoxy-3 β-methylamino dammarane-12 β, 25-glycol
By (20S, 24S)-epoxy dammarane-12 β, 25-glycol-3-amine (OSA, 200mg, 0.42mmol) with Anhydrous potassium carbonate (60mg, 0.42mmol) add in anhydrous tetrahydro furan (8mL), be subsequently adding iodomethane (60mg, 0.42mmol).N2The lower room temperature reaction of protection 5 hours.Diluted ethyl acetate, washing, saturated common salt washing, anhydrous sodium sulfate is dried, and column chromatography obtains faint yellow product (155mg, 75%).1H NMR(CDCl3, 300MHz) and δ 3.86 (dd, J=10.2Hz, 5.0Hz, 1H), 3.51 (td, J=9.8Hz, 4.0Hz, 1H), 3.16 (s, 3H), 2.54 (m, 1H), 2.22 (td, J=9.8Hz, 5.8Hz, 1H), 1.26 (s, 3H), 1.21 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H), 0.89 (s, 6H), 0.88 (s, 3H), 0.85 (s, 3H)；ESI-MS m/z 490.4[M+H]+。
Embodiment 4
(20S, 24R)-epoxy-3 β-methylamino-dammarane-12 β, 25-glycol
With reference to the synthetic method of embodiment 3, by (20S, 24R)-epoxy dammarane-12 β, 25-glycol-3 β-amine (ORA) obtains white solid (120mg, 73%).1H NMR(CDCl3, 300MHz) and δ 3.85 (dd, J=13.7Hz, 7.0Hz, 1H), 3.49 (td, J=10.4Hz, 4.6Hz, 1H), 3.15 (s, 3H), 2.33 (m, 1H), 2.16 (td, J=10.9Hz, 3.5Hz, 1H), 1.27 (s, 3H), 1.25 (s, 3H), 1.09 (s, 3H), 0.99 (s, 3H), 0.95 (s, 3H), 0.90 (s, 3H), 0.84 (s, 6H), 0.75 (s, 3H)；ESI-MS m/z 490.4[M+H]+。
Embodiment 5
(20S, 24S)-epoxy-3 β-acetamido dammarane-12 β, 25-glycol
By (20S, 24S)-epoxy dammarane-12 β, 25-glycol-3-amine (OSA, 200mg, it 0.42mmol) is dissolved in anhydrous methylene chloride (8mL) with the DMAP of catalytic amount, be subsequently adding acetic anhydride (0.06mL, 0.65mmol).Room temperature reaction 5 hours.Dchloromethane, washing, saturated common salt washing, anhydrous sodium sulfate is dried, and column chromatography obtains white solid (155mg, 75%).1H NMR(CDCl3, 300MHz) and δ 3.88 (dd, J=10.2Hz, 5.0Hz, 1H), 3.53 (td, J=9.8Hz, 4.0Hz, 1H), 3.41 (m, 1H), 2.23 (td, J=9.8Hz, 5.8Hz, 1H), 2.00 (s, 3H), 1.27 (s, 3H), 1.23 (s, 3H), 1.11 (s, 3H), 1.02 (s, 3H), 1.01 (s, 3H), 0.90 (s, 6H), 0.88 (s, 3H), 0.85 (s, 3H)；ESI-MS m/z 518.4[M+H]+。
Embodiment 6
(20S, 24R)-epoxy-3 β-acetamido dammarane-12 β, 25-glycol
With reference to the synthetic method of embodiment 5, by (20S, 24R)-epoxy dammarane-12 β, 25-glycol-3 β-amine (ORA) obtains white solid (100mg, 85%).1H NMR(CDCl3, 300MHz) and δ 3.84 (dd, J=13.7Hz, 7.0Hz, 1H), 3.48 (td, J=10.4Hz, 4.6Hz, 1H), 3.45 (m, 1H), 2.14 (td, J=10.9Hz, 3.5Hz, 1H), 1.99 (s, 3H), 1.25 (s, 6H), 1.07 (s, 3H), 0.98 (s, 3H), 0.93 (s, 3H), 0.88 (s, 3H), 0.82 (s, 6H), 0.73 (s, 3H)；ESI-MS m/z 518.4[M+H]+。
Claims (4)
1. lead to compound or pharmaceutically acceptable salt thereof shown in formula (I) or (II):
Wherein R represents hydrogen, (C1-C4) straight chained alkyl, acyl group.
2. the compound or pharmaceutically acceptable salt thereof of claim 1, Qi Zhongyou:
(20S, 24S)-epoxy dammarane-12 β, 25-glycol-3 β-amine；
(20S, 24R)-epoxy dammarane-12 β, 25-glycol-3 β-amine；
(20S, 24S)-epoxy-3 β-methylamino dammarane-12 β, 25-glycol；
(20S, 24R)-epoxy-3 β-methylamino dammarane-12 β, 25-glycol；
(20S, 24S)-epoxy-3 β-acetamido dammarane-12 β, 25-glycol；
(20S, 24R)-epoxy-3 β-acetamido dammarane-12 β, 25-glycol.
3. for treating a pharmaceutical composition for human diseases or illness, the compound containing claim 1 or its pharmaceutically acceptable salt and carrier.
4. the compound or pharmaceutically acceptable salt thereof of claim 1, or the application that the pharmaceutical composition described in claim 3 is in preparing reverse multiple drug resistance of tumor medicine.
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| CN106749494A (en) * | 2017-02-06 | 2017-05-31 | 烟台大学 | α hederagenin derivatives with tumor drug resistance reversal activity and its production and use |
| CN109021058A (en) * | 2018-09-12 | 2018-12-18 | 烟台大学 | With active ocotillol type sapogenin derivative of tumor drug resistance reversal and its preparation method and application |
| CN115181154A (en) * | 2022-07-01 | 2022-10-14 | 烟台大学 | Pyxinol amide derivative, preparation method thereof and application thereof in field of medicines |
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| CN103059088A (en) * | 2013-01-16 | 2013-04-24 | 烟台大学 | Dammarane saponin derivatives with novel structure as well as preparation method and anti-microbial application thereof |
| CN103965281A (en) * | 2013-01-31 | 2014-08-06 | 上海中药创新研究中心 | Protopanaxadiol derivative, preparation method and application thereof |
| CN104586860A (en) * | 2013-11-01 | 2015-05-06 | 中国科学院上海药物研究所 | Use of dammarane-type triterpene derivatives |
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| CN103059088A (en) * | 2013-01-16 | 2013-04-24 | 烟台大学 | Dammarane saponin derivatives with novel structure as well as preparation method and anti-microbial application thereof |
| CN103965281A (en) * | 2013-01-31 | 2014-08-06 | 上海中药创新研究中心 | Protopanaxadiol derivative, preparation method and application thereof |
| CN104586860A (en) * | 2013-11-01 | 2015-05-06 | 中国科学院上海药物研究所 | Use of dammarane-type triterpene derivatives |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749494A (en) * | 2017-02-06 | 2017-05-31 | 烟台大学 | α hederagenin derivatives with tumor drug resistance reversal activity and its production and use |
| CN106749494B (en) * | 2017-02-06 | 2019-03-12 | 烟台大学 | With the active α of tumor drug resistance reversal-hederagenin derivative and its preparation method and application |
| CN109021058A (en) * | 2018-09-12 | 2018-12-18 | 烟台大学 | With active ocotillol type sapogenin derivative of tumor drug resistance reversal and its preparation method and application |
| CN115181154A (en) * | 2022-07-01 | 2022-10-14 | 烟台大学 | Pyxinol amide derivative, preparation method thereof and application thereof in field of medicines |
| CN115181154B (en) * | 2022-07-01 | 2024-04-30 | 烟台大学 | Pyxinol amide derivative, preparation method thereof and application thereof in pharmaceutical field |
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