CN109021058A - With active ocotillol type sapogenin derivative of tumor drug resistance reversal and its preparation method and application - Google Patents
With active ocotillol type sapogenin derivative of tumor drug resistance reversal and its preparation method and application Download PDFInfo
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- CN109021058A CN109021058A CN201811065082.2A CN201811065082A CN109021058A CN 109021058 A CN109021058 A CN 109021058A CN 201811065082 A CN201811065082 A CN 201811065082A CN 109021058 A CN109021058 A CN 109021058A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention relates to a kind of ocotillol type sapogenin derivatives, contain their pharmaceutical composition and preparation method thereof and its tumor drug resistance reversal purposes.Ocotillol type sapogenin derivative of the invention in the oral cavity epidermis cancer cell line of tumor drug resistance by obtaining as a result, prepared ocotillol type sapogenin derivative all has preferable drug resistance inversion activity, hence it is evident that is better than ocotillol type sapogenin.Meanwhile product of the present invention has good gastrointestinal tract stability, has preferable medicinal application, this is the characteristic that compound disclosed in the prior art does not have.
Description
Technical field
The present invention relates to organic syntheses and field of medicinal chemistry, and in particular to a kind of ocotillol type sapogenin derivative,
Pharmaceutical composition containing them and preparation method thereof and its tumor drug resistance reversal purposes.
Background technique
Oncotherapy is world-famous puzzle, and the appearance of new type antineoplastic medicine makes it have hope, however adjoint tumour medicine
Object multidrug resistance (Multidrug Resistance, MDR) but becomes the biggest obstacle for the treatment of tumour.The generation of tumour MDR,
Cause anti-tumor drug that can not rest in tumour cell, it is made to lose therapeutic effect, tumor patient continuous and effective is caused to treat
Failure, propose stern challenge for oncotherapy now and its drug development.Therefore, exploitation have brand new, low toxicity,
The new compound of efficient MDR Reversal activity is the hot spot of oncotherapy and its drug research.
The features such as Structures of Natural Products type multiplicity, human contact are relatively extensively, toxic side effect is smaller.Ginsenoside is as ginseng
In effective active composition, there is extensive pharmacological activity and biological effect, including it is anti-inflammatory, adjust immune, antibacterial, it is antitumor and
The effect of delay senescence etc..Ocotillol type ginsenoside is as the rare saponin(e of one kind in ginsenoside, most early in ground
It is found in clothing.In recent years, in relation to its different derivative the reperfusion injury that resists myocardial ischemia, in terms of activity also by by
Gradually find.
Summary of the invention
Obtaining one kind in order to solve the above technical problems has the active drug of tumor drug resistance reversal, and the present invention provides one kind
Ocotillol type sapogenin derivative, its pharmaceutically acceptable salt, with good tumor drug resistance reversal activity, the present invention
The preparation method and purposes of the derivative are provided simultaneously.
The technical problem to be solved by the present invention is to find new construction type have fine tumor drug resistance inversion activeization
Conjunction object, and further provide for one kind and how to use treatment gastric cancer, lung cancer, cervical carcinoma, breast cancer or knot with clinical common anti-tumor drug
The pharmaceutical composition of intestinal cancer etc..
In order to solve the above technical problems, the invention provides the following technical scheme:
Lead to ocotillol type sapogenin derivative and its medically acceptable salt shown in formula (I) or (II),
Wherein, R represents (C4-C8) linear or branched alkyl group, R1NHR2、R1O R3、R1(O)CO R3, phenyl, naphthalene, pyridine ring；
R1Represent (C1-C8) straight chained alkyl or oxyethyl chain, CH (NH R2)R4, phenyl, R2N- nafoxidine -2- base；
R2Represent hydrogen, Boc, Fmoc；
R3Represent hydrogen, t-Bu, benzyl；
R4It represents with blocking group and without the amino acid side groups of blocking group, blocking group can be Boc, Fmoc, t-
Bu, benzyl, methyl and (or) ethyl；
It is preferred that part of compounds of the invention are as follows:
- 3 β-N of (20S, 24R)-epoxy-- 12 β of (2-Boc-glycyl)-dammarane, 25-glycol；
- 3 β-N of (20S, 24R)-epoxy-- 12 β of (4-Boc-aminobutanonyl)-dammarane, 25-glycol；
- 3 β-N of (20S, 24R)-epoxy-- 12 β of (6-Boc-aminocaProyl)-dammarane, 25-glycol；
- 12 β of-3 β-N of (20S, 24R)-epoxy-(8-Boc-amino caprylyl)-dammarane, 25-glycol；
- 3 β-N of (20S, 24R)-epoxy-- 12 β of (2-glycyl)-dammarane, 25-glycol；
- 12 β of-3 β-N of (20S, 24R)-epoxy-(8-amino caprylyl)-dammarane, 25-glycol；
- 3 β of (20S, 24R)-epoxy-- 12 β of hexanoyl amino dammarane, 25-glycol；
- 3 β of (20S, 24R)-epoxy-- 12 β of decoyl amino dammarane, 25-glycol；
- 3 β of (20S, 24R)-epoxy-- 12 β of benzamido dammarane, 25-glycol；
- 3 β of (20S, 24R)-epoxy-- 12 β of nicotinoyl amino dammarane, 25-glycol；
- 12 β of-3 β of (20S, 24R)-epoxy-(4-Boc-aminobenzamidoyl) dammarane, 25-glycol；
- 12 β of-3 β of (20S, 24R)-epoxy-(2-(2-hydroxybenzoyl) amino) dammarane, 25-glycol；
- 3 β-N of (20S, 24S)-epoxy-- 12 β of (2-Boc-glycyl)-dammarane, 25-glycol；
- 3 β-N of (20S, 24S)-epoxy-- 12 β of (4-Boc-aminobutanonyl)-dammarane, 25-glycol；
- 3 β-N of (20S, 24S)-epoxy-- 12 β of (6-Boc-aminocaProyl)-dammarane, 25-glycol；
- 12 β of-3 β-N of (20S, 24S)-epoxy-(8-Boc-amino caprylyl)-dammarane, 25-glycol；
- 3 β of (20S, 24S)-epoxy-- 12 β of hexanoyl amino dammarane, 25-glycol；
- 12 β of-3 β of (20S, 24S)-epoxy-(2-(2-hydroxybenzoyl) amino) dammarane, 25-glycol；
- 12 β of-3 β-N of (20S, 24R)-epoxy-(N'- Boc-prolyl)-dammarane, 25-glycol；
- 3 β of (20S, 24R)-epoxy-- 12 β of prolinamidyl dammarane, 25-glycol；
- 12 β of-3 β-N of (20S, 24R)-epoxy-(N'- Boc-lysyl-)-dammarane, 25-glycol；
- 12 β of-3 β-N of (20S, 24R)-epoxy-(N'- Boc-aspartyl)-dammarane, 25-glycol；
- 12 β of-3 β-N of (20S, 24R)-epoxy-(N'- Boc-tyrosyl-)-dammarane, 25-glycol；
- 3 β-N of (20S, 24R)-epoxy-{ 2-[2-(2-Fmoc-amino ethoxy) ethyoxyl] acetyl group }-dammarane-12
β, 25-glycol；
- 3 β-N of (20S, 24S)-epoxy-{ 2-[2-(2-Fmoc-amino ethoxy) ethyoxyl] acetyl group }-dammarane-12
β, 25-glycol；
The optical isomer of the ocotillol type sapogenin derivative and its above compound or its is pharmaceutically acceptable
Solvate.
The present invention leads to formula (I) and (II) ocotillol type sapogenin derivative and its medically acceptable salt, with
Ocotillol type sapogenin is compared, and has better tumor drug resistance reversal effect.As clinical commonly used drug taxol is resistance to tumour
The IC50 of medicine cell strain KBV is 1353.98 ± 303.33nM, and embodiment 3 is to tumor drug resistance cell KBV non-toxic concentrations background
Under, when 10 μM of concentration and taxol share, the IC50 of taxol is 28.29 ± 2.90nM, and reversal index reaches 48 times, is made pair
The tumor drug resistance cell KBV of taxol resistance significantly improves the sensibility of taxol, remains to taxol with extremely low concentration
Good anti-tumor activity is generated to it.
The present invention leads to formula (I) and (II) ocotillol type sapogenin derivative and its medically acceptable salt purposes, uses
In preparing tumor drug resistance reversal agent and/or pharmaceutical acceptable carrier for treating animal, preferred therapeutic human diseases or illness.
A effective amount of logical formula (I) and (II) ocotillol type sapogenin derivative and its medically acceptable salt and can
It is used to share with clinical antitumor agents with drug carrier, for treating the diseases such as gastric cancer, lung cancer, cervical carcinoma, breast cancer or colon cancer
Disease or illness.
The ocotillol type sapogenin derivative of logical formula (I) and (II) are synthetically prepared according to following reaction route and description,
Using protopanoxadiol as raw material, (20S, 24R)-is prepared in the nucleophilic attack for carrying out double bond epoxidation and intramolecular
Epoxy reaches Ma Wan-3 β, 12 β, 25-triols, 3 hydroxyl oxygen metaplasias up to pure and mild (20S, the 24S)-epoxy of Ma Wan-3 β, 12 β, 25-three
Ketone is produced, then Stereoselective reduction produces amine after oximido, prepares by amide reaction without protecting group and containing protection
The logical formula (I) of base and the derivative of (II), finally the derivative of the logical formula (I) containing protecting group and (II) pass through trifluoroacetic acid or salt
Acid processing prepares the logical formula (I) and (II) derivative of Deprotection.
The compounds of this invention pharmaceutically acceptable salt refers to conventional acid-addition salts, has same as compound
Pharmaceutic efficacy, and with suitable non-toxic organic or inorganic acid at salt.
The invention also discloses a kind of pharmaceutical compositions, contain the compound of the present invention or its pharmaceutically acceptable salt, can
Common pharmaceutical formulation is made to add pharmaceutically acceptable carrier, as tablet, capsule, pulvis, syrup, liquor, suspending agent,
The common excipient substances such as fragrance, sweetener, liquid or solid filler material or diluent can be added in injection.
The administration mode of compound of the present invention clinically can be using modes such as oral, injections.
Dosage used in the compound of the present invention clinic is 0.01mg~1000mg/ days, can also be according to the weight or agent of the state of an illness
The difference of type deviates this range.
Detailed description of the invention
Fig. 1 is embodiment 3 to the influence schematic diagram for inhibiting KBV cell activity in taxol body.
Specific embodiment
The present invention is further elaborated combined with specific embodiments below, but the present invention is not limited to these embodiments.
Embodiment 1
- 3 β-N of (20S, 24R)-epoxy-- 12 β of (2-Boc-glycyl)-dammarane, 25-glycol；
20S-protopanoxadiol (8.000g, 17.36mmol) is dissolved in methylene chloride (160mL), m-CPBA is added
(4.490g, 19.51mmol), is stirred at room temperature 3h.Chloroform dilution plus water washing, saturated common salt water washing, anhydrous sodium sulfate is dry,
Filtering, concentration, column chromatograph to obtain compound as white solid 1 [(20S, 24R)-epoxy Da Ma Wan-3 β, 12 β, 25-triols]
(5.184g, 10.87mmol, 63%) and compound as white solid 2 [(20S, 24S)-epoxy Da Ma Wan-3 β, 12 β, 25-triols]
(3.060g, 6.42mmol, 37%).
Compound 1,1H NMR(400MHz,CDCl3) δ 3.84 (dd, J=8.8,6.8Hz, 1H), 3.51 (td, J=10.5,
4.6Hz, 1H), 3.18 (dt, J=9.9,4.5Hz, 1H), 2.19 (td, J=10.9,3.6Hz, 1H), 1.28 (s, 3H), 1.27
(s,3H),1.14–0.96(m,3H),1.09(s,3H),0.98(s,3H),0.97(s,3H),0.90(s,3H),0.85(s,
3H),0.77(s,3H).
Compound 2,1H NMR(400MHz,CDCl3) δ 5.78 (s, 1H), 3.88 (dd, J=10.7,5.3Hz, 1H), 3.52
(td, J=10.3,4.7Hz, 1H), 3.20 (dd, J=11.3,4.8Hz, 1H), 2.25 (td, J=10.5,4.3Hz, 1H),
1.27(s,3H),1.23(s,3H),1.11(s,3H),1.01(s,3H),0.97(s,3H),0.91(s,3H),0.88(s,3H),
0.78(s,3H).
Compound 1 (821mg, 1.72mmol) is dissolved in methylene chloride (20mL), PCC (chloro-chromic acid pyrrole is added on ice bath
Pyridine salt, 389mg, 1.80mmol), filtering and concentrating after being slowly increased to room temperature and stirring 15 hours, column chromatographs to obtain white solid
It closes object 3 [(20S, 24R)-epoxy Da Ma Wan-12 β, 25-- 3-ketone of glycol] (689mg, 1.45mmol, 84%).1H NMR
(400MHz,CDCl3) δ 3.86 (dd, J=8.8,6.6Hz, 1H), 3.53 (td, J=10.5,4.5Hz, 1H), 2.52 (ddd, J
=15.7,9.6,7.7Hz, 1H), 2.42 (ddd, J=15.7,7.7,4.4Hz, 1H), 2.21 (td, J=10.9,3.7Hz,
1H),1.28(s,3H),1.27(s,3H),1.10(s,3H),1.08(s,3H),1.04(s,3H),1.02(s,3H),0.96(s,
3H),0.91(s,3H)。
Compound 3 (616mg, 1.295mmol) is dissolved in pyridine, at room temperature be added hydroxylamine hydrochloride (722mg,
10.34mmol), it reacts 1 hour for 80 DEG C, is diluted after concentration with ethyl acetate, washed, saturated common salt water washing, anhydrous sodium sulfate
It dries, filters, is concentrated, column chromatographs to obtain compound as white solid 4 [(20S, 24R)-epoxy Da Ma Wan-12 β, 25-glycol-3-
Ketoxime] (590mg, 1.205mmol, 93%).1H NMR(400MHz,CDCl3) δ 5.61 (s, 1H), 3.85 (dd, J=8.9,
6.6Hz, 1H), 3.51 (td, J=10.5,4.6Hz, 1H), 2.99 (ddd, J=15.5,5.9,4.1Hz, 1H), 2.27 (ddd, J
=15.5,11.4,5.9Hz, 1H), 2.19 (td, J=10.1,3.0Hz, 1H), 1.28 (s, 3H), 1.27 (s, 3H), 1.14 (s,
3H),1.10(s,3H),1.05(s,3H),1.01(s,3H),0.96(s,3H),0.88(s,3H).
By compound 4 (800mg, 1.63mmol), ammonium acetate (315mg, 4.09mmol) and sodium cyanoborohydride (258mg,
It 4.11mmol) is dissolved in isopropanol (45mL), 15% titanium trichloride solution (1.6mL) is slowly added dropwise under ice bath, reacted at room temperature
Night.It after reaction solution is adjusted to pH=10 with sodium hydroxide solution, is extracted with ethyl acetate, organic phase is dry with anhydrous sodium sulfate, mistake
Filter, after concentration, recrystallization acquisition white solid 5 [(20S, 24R)-epoxy Da Ma Wan-12 β, 25-- 3 β of glycol-amine] (545mg,
1.15mmol, 90%).1H NMR (400MHz, CDCl3) δ 3.84 (dd, J=8.4,6.8Hz, 1H), 3.51 (td, J=10.4,
4.3Hz, 1H), 2.85 (dd, J=10.6,5.8Hz, 1H), 2.18 (td, J=10.0,3.4Hz, 1H), 2.09-1.96 (m,
2H),1.27(s,3H),1.26(s,3H),1.13(s,3H),1.09(s,3H),0.98(s,3H),0.95(s,3H),0.89(s,
3H), 0.87 (s, 3H), 0.78 (d, J=9.2Hz, 1H)
Compound 5 (20mg, 0.042mmol) and N-Boc-2- amion acetic acid (11mg, 0.059mmol) are dissolved in anhydrous
In DMF (0.4mL), after argon gas protects lower stirring and dissolving, HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid is added at 0 DEG C
Ester, 24mg, 0.076mmol), triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and
After saturated sodium bicarbonate solution washs, anhydrous sodium sulfate is dry, concentration.Through column chromatograph to obtain target compound (24mg,
90%).1H NMR(400MHz,CDCl3) δ 6.07 (d, J=9.6Hz, 1H), 3.85 (dd, J=8.9,6.6Hz, 1H), 3.78
(dd, J=16.5,5.9Hz, 1H), 3.71 (dd, J=16.5,5.9Hz, 1H), 3.67-3.60 (m, 1H), 3.49 (td, J=
10.5,4.6Hz, 1H), 2.19 (td, J=10.1,3.2Hz, 1H), 1.45 (s, 9H), 1.28 (s, 3H), 1.27 (s, 3H),
1.09(s,3H),0.98(s,3H),0.90(s,3H),0.86(s,3H),0.83(s,3H),0.76(s,3H)。
Embodiment 2
- 3 β-N of (20S, 24R)-epoxy-- 12 β of (4-Boc-aminobutanonyl)-dammarane, 25-glycol；
Compound 5 (20mg, 0.042mmol) and N-Boc-4- aminobutyric acid (12mg, 0.059mmol) are dissolved in anhydrous
In DMF (0.4mL), after argon gas protects lower stirring and dissolving, HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid is added at 0 DEG C
Ester, 24mg, 0.076mmol), triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and
After saturated sodium bicarbonate solution washs, anhydrous sodium sulfate is dry, concentration.Through column chromatograph to obtain target compound (27mg,
97%).1H NMR(400MHz,CDCl3) δ 5.97 (d, J=9.6Hz, 1H), 4.80 (t, J=6.2Hz, 1H), 3.85 (dd, J=
8.7,6.9Hz, 1H), 3.65 (td, J=10.7,5.0Hz, 1H), 3.52 (td, J=10.5,4.6Hz, 1H), 3.23-3.10
(m,2H),2.23-2.16(3H),1.43(s,9H),1.28(s,3H),1.27(s,3H),1.09(s,3H),0.98(s,3H),
0.90(s,3H),0.86(s,3H),0.85(s,3H),0.78(s,3H)。
Embodiment 3
- 3 β-N of (20S, 24R)-epoxy-- 12 β of (6-Boc-aminocaProyl)-dammarane, 25-glycol；
Compound 5 (20mg, 0.042mmol) and N-Boc-6- aminocaproic acid (14mg, 0.059mmol) are dissolved in anhydrous
In DMF (0.4mL), after argon gas protects lower stirring and dissolving, HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid is added at 0 DEG C
Ester, 24mg, 0.076mmol), triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and
After saturated sodium bicarbonate solution washs, anhydrous sodium sulfate is dry, concentration.Through column chromatograph to obtain target compound (26mg,
91%).1H NMR(400MHz,CDCl3) δ 5.44 (d, J=9.6Hz, 1H), 4.63 (s, 1H), 3.85 (dd, J=8.9,
6.6Hz, 1H), 3.66 (ddd, J=11.9,10.1,4.12Hz, 1H), 3.51 (td, J=10.5,4.6Hz, 1H), 3.13-
3.07(m,2H),2.81(s,1H),2.22-2.16(m,3H),1.44(s,9H),1.27(s,3H),1.27(s,3H),1.09
(s,3H),0.98(s,3H),0.90(s,3H),0.86(s,3H),0.84(s,3H),0.76(s,3H)。
Embodiment 4
- 12 β of-3 β-N of (20S, 24R)-epoxy-(8-Boc-amino caprylyl)-dammarane, 25-glycol；
Compound 5 (20mg, 0.042mmol) and N-Boc-8- aminocaprylic acid (15mg, 0.059mmol) are dissolved in anhydrous
In DMF (0.4mL), after argon gas protects lower stirring and dissolving, HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid is added at 0 DEG C
Ester, 24mg, 0.076mmol), triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and
After saturated sodium bicarbonate solution washs, anhydrous sodium sulfate is dry, concentration.Through column chromatograph to obtain target compound (26mg,
91%).1H NMR(400MHz,CDCl3) δ 5.29 (d, J=10.1Hz, 1H), 4.53 (s, 1H), 3.85 (dd, J=8.9,
6.6Hz, 1H), 3.66 (ddd, J=12.3,10.1,4.6Hz, 1H), 3.52 (td, J=10.5,4.6Hz, 1H), 3.09 (dd, J
=7.3,6.4Hz, 2H), 2.22-2.14 (m, 3H), 1.44 (s, 9H), 1.28 (s, 3H), 1.27 (s, 3H), 1.09 (s, 3H),
0.98(s,3H),0.90(s,3H),0.86(s,3H),0.84(s,3H),0.76(s,3H)。
Embodiment 5
- 3 β-N of (20S, 24R)-epoxy-- 12 β of (2-glycyl)-dammarane, 25-glycol；
Embodiment 1 (0.03mmol) is dissolved in anhydrous TFA (trifluoroacetic acid, 0.5mL), after reacting 10min at room temperature
Reaction was completed.It is concentrated to get target compound (0.03mmol).1H NMR(400MHz,CD3OD) δ 3.89 (t, J=7.5Hz,
1H), 3.68 (s, 2H), 3.62 (dd, J=12.6,3.9Hz, 1H), 3.49 (td, J=10.5,4.6Hz, 1H), 2.20 (td, J
=10.9,3.2Hz, 1H), 1.27 (s, 3H), 1.22 (s, 3H), 1.13 (s, 3H), 1.03 (s, 3H), 0.95 (s, 3H), 0.91
(s,3H),0.86(s,3H),0.82(s,3H)。
Embodiment 6
- 12 β of-3 β-N of (20S, 24R)-epoxy-(8-amino caprylyl)-dammarane, 25-glycol；
Embodiment 4 (0.03mmol) is dissolved in anhydrous TFA (trifluoroacetic acid, 0.5mL), after reacting 10min at room temperature
Reaction was completed.It is concentrated to get target compound (0.03mmol).1H NMR(400MHz,CD3OD) δ 3.89 (t, J=7.3Hz,
1H), 3.58 (dd, J=12.3,4.1Hz, 1H), 3.49 (td, J=10.5,4.6Hz, 1H), 2.90 (t, J=7.8Hz, 2H),
2.30-2.17(m,3H),1.27(s,3H),1.22(s,3H),1.13(s,3H),1.02(s,3H),0.94(s,3H),0.91
(s,3H),0.83(s,3H),0.80(s,3H)。
Embodiment 7
- 3 β of (20S, 24R)-epoxy-- 12 β of hexanoyl amino dammarane, 25-glycol；
Compound 5 (20mg, 0.042mmol) and caproic acid (0.059mmol) are dissolved in anhydrous DMF (0.4mL), argon gas is protected
After protecting lower stirring and dissolving, HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester, 24mg, 0.076mmol) is added at 0 DEG C,
Triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and through saturated sodium bicarbonate solution
After washing, anhydrous sodium sulfate is dry, concentration.It chromatographs to obtain target compound (19mg, 78%) through column.1H NMR(400MHz,
CDCl3) δ 5.33 (d, J=10.1Hz, 1H), 3.85 (dd, J=8.7,6.9Hz, 1H), 3.67 (ddd, J=12.3,10.1,
4.12Hz, 1H), 3.52 (td, J=10.4,4.7Hz, 1H), 2.22-2.16 (m, 3H), 2.08-1.83 (m, 5H), 1.71-
1.41(m,12H),1.28(s,3H),1.27(s,3H),1.09(s,3H),0.98(s,3H),0.90(s,3H),0.86(s,
3H),0.84(s,3H),0.76(s,3H)。
Embodiment 8
- 3 β of (20S, 24R)-epoxy-- 12 β of decoyl amino dammarane, 25-glycol；
Compound 5 (20mg, 0.042mmol) and sad (0.059mmol) are dissolved in anhydrous DMF (0.4mL), argon gas is protected
After protecting lower stirring and dissolving, HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester, 24mg, 0.076mmol) is added at 0 DEG C,
Triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and through saturated sodium bicarbonate solution
After washing, anhydrous sodium sulfate is dry, concentration.It chromatographs to obtain target compound (23mg, 90%) through column.1H NMR(400MHz,
CDCl3) δ 5.25 (d, J=10.1Hz, 1H), 3.85 (dd, J=8.9,6.6Hz, 1H), 3.67 (ddd, J=12.3,10.1,
4.1Hz, 1H), 3.52 (td, J=10.3,4.6Hz, 1H), 2.22-2.16 (m, 1H), 2.17 (t, J=7.8Hz, 2H), 2.09-
1.96(m,2H),1.94-1.83(m,3H),1.71-1.41(m,11H),1.28(s,3H),1.27(s,3H),1.09(s,3H),
0.98(s,3H),0.90(s,3H),0.86(s,3H),0.84(s,3H),0.76(s,3H)。
Embodiment 9
- 3 β of (20S, 24R)-epoxy-- 12 β of benzamido dammarane, 25-glycol；
Compound 5 (20mg, 0.042mmol) and benzoic acid (0.059mmol) are dissolved in anhydrous DMF (0.4mL), argon gas
Be added after protecting lower stirring and dissolving, at 0 DEG C HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester, 24mg,
0.076mmol), triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and through saturated carbon
After sour hydrogen sodium solution washing, anhydrous sodium sulfate is dry, concentration.It chromatographs to obtain target compound (23mg, 94%) through column.1H NMR
(400MHz,CDCl3) δ 7.76-7.74 (m, 2H), 7.49 (tt, J=7.3,1.8Hz, 1H), 7.45-7.41 (m, 2H), 5.96
(d, J=9.6Hz, 1H), 3.92-3.83 (m, 2H), 3.54 (td, J=10.5,4.6Hz, 1H), 2.20 (td, J=10.1,
3.0Hz,1H),2.09-1.83(m,5H),1.76-1.44(m,9H),1.28(s,3H),1.27(s,3H),1.10(s,3H),
1.00(s,3H),0.95(s,3H),0.92(s,3H),0.87(s,3H),0.86(s,3H)。
Embodiment 10
- 3 β of (20S, 24R)-epoxy-- 12 β of nicotinoyl amino dammarane, 25-glycol；
Compound 5 (20mg, 0.042mmol) and niacin (0.059mmol) are dissolved in anhydrous DMF (0.4mL), argon gas is protected
After protecting lower stirring and dissolving, HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester, 24mg, 0.076mmol) is added at 0 DEG C,
Triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and through saturated sodium bicarbonate solution
After washing, anhydrous sodium sulfate is dry, concentration.It chromatographs to obtain target compound (20mg, 82%) through column.1H NMR(400MHz,
CDCl3) δ 8.94 (d, J=1.4Hz, 1H), 8.72 (dd, J=4.9,1.5Hz, 1H), 8.10 (dt, J=7.8,1.8Hz, 1H),
7.39 (dd, J=7.8,5.0Hz, 1H), 5.96 (d, J=10.1Hz, 1H), 3.93-3.83 (m, 2H), 3.54 (td, J=
10.5,4.6Hz, 1H), 2.20 (td, J=10.1,3.0Hz, 1H), 2.09-1.83 (m, 5H), 1.78-1.45 (m, 10H),
1.28(s,3H),1.27(s,3H),1.10(s,3H),1.00(s,3H),0.95(s,3H),0.92(s,3H),0.89(s,3H),
0.87(s,3H)。
Embodiment 11
- 12 β of-3 β of (20S, 24R)-epoxy-(4-Boc-aminobenzamidoyl) dammarane, 25-glycol；
Compound 5 (20mg, 0.042mmol) and 4-Boc-aminobenzoic acid (0.059mmol) are dissolved in anhydrous DMF
In (0.4mL), be added after argon gas protects lower stirring and dissolving, at 0 DEG C HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester,
24mg, 0.076mmol), triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and passes through
After saturated sodium bicarbonate solution washing, anhydrous sodium sulfate is dry, concentration.It chromatographs to obtain target compound (22mg, 75%) through column
。1H NMR(400MHz,CDCl3) δ 7.69 (dd, J=6.9,1.8Hz, 2H), 7.43 (d, J=8.7Hz, 2H), 6.82 (s, 1H),
5.88 (d, J=10.1Hz, 1H), 3.90-3.83 (m, 2H), 3.53 (td, J=10.5,4.6Hz, 1H), 2.20 (td, J=
10.1,3.0Hz,1H),2.09-1.83(m,5H),1.52(s,9H),1.28(s,3H),1.27(s,3H),1.10(s,3H),
0.99(s,3H),0.94(s,3H),0.92(s,3H),0.87(s,3H),0.85(s,3H)。
Embodiment 12
- 12 β of-3 β of (20S, 24R)-epoxy-(2-(2-hydroxybenzoyl) amino) dammarane, 25-glycol；
Compound 5 (20mg, 0.042mmol) and 2-hydroxybenzoic acids (0.059mmol) are dissolved in anhydrous DMF (0.4mL)
In, be added after argon gas protects lower stirring and dissolving, at 0 DEG C HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester, 24mg,
0.076mmol), triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and through saturated carbon
After sour hydrogen sodium solution washing, anhydrous sodium sulfate is dry, concentration.It chromatographs to obtain target compound (22mg, 88%) through column.1H NMR
(400MHz,CDCl3) δ 12.39 (s, 1H), 7.38 (td, J=7.8,1.5Hz, 1H), 7.33 (dd, J=8.2,1.4Hz, 1H),
6.98 (dd, J=8.2,0.9Hz, 1H), 6.84 (td, J=7.5,1.2Hz, 1H), 6.15 (d, J=9.6Hz, 1H), 3.90-
3.83 (m, 2H), 3.54 (td, J=10.3,4.9Hz, 1H), 2.20 (td, J=10.1,3.0Hz, 1H), 1.28 (s, 3H),
1.27(s,3H),1.10(s,3H),1.00(s,3H),0.93(s,3H),0.92(s,3H),0.88(s,6H)。
Embodiment 13
- 3 β-N of (20S, 24S)-epoxy-- 12 β of (2-Boc-glycyl)-dammarane, 25-glycol；
Compound 2 (2.500g, 5.24mmol) is dissolved in methylene chloride (52mL), on ice bath be added PCC (1.131g,
5.25mmol), filtering and concentrating after being slowly increased to room temperature and stirring 15 hours, column chromatograph to obtain compound as white solid 6 [(20S,
24S)-epoxy Da Ma Wan-12 β, 25-- 3-ketone of glycol] (2.121g, 4.47mmol, 85%).1H HMR(400MHz,CDCl3)δ
3.88 (dd, J=10.7,5.3Hz, 1H), 3.55 (td, J=10.3,4.6Hz, 1H), 2.56-2.41 (m, 2H), 2.27 (td, J
=10.4,4.3Hz, 1H), 1.28 (s, 3H), 1.24 (s, 3H), 1.11 (s, 3H), 1.08 (s, 3H), 1.05 (s, 3H), 1.05
(s,3H),0.98(s,3H),0.93(s,3H)。
Compound 6 (1.245g, 2.622mmol) is dissolved in pyridine, at room temperature be added hydroxylamine hydrochloride (314mg,
4.52mmol), it reacts 3 hours for 80 DEG C, is diluted after concentration with ethyl acetate, washed, saturated common salt water washing, anhydrous sodium sulfate is dry
It is dry, it filters, concentration, column chromatographs to obtain compound as white solid 7 [(20S, 24S)-epoxy Da Ma Wan-12 β, 25-- 3-ketone of glycol
Oxime] (1.123g, 2.295mmol, 87%).1H HMR(400MHz,CDCl3) δ 5.78 (s, 1H), 3.89 (dd, J=10.7,
5.3Hz, 1H), 3.53 (td, J=10.4,4.7Hz, 1H), 2.98 (ddd, J=15.6,5.7,3.9Hz, 1H), 2.34-2.22
(m, 2H), 2.06 (td, J=11.1,4.7Hz, 1H), 1.28 (s, 3H), 1.24 (s, 3H), 1.15 (s, 3H), 1.11 (s, 3H),
1.07(s,3H),1.04(s,3H),0.98(s,3H),0.90(s,3H)。
By compound 7 (533mg, 1.09mmol), ammonium acetate (210mg, 2.72mmol) and sodium cyanoborohydride (172mg,
It 2.74mmol) is dissolved in isopropanol (40mL), 15% titanium trichloride solution (1.04mL) is slowly added dropwise under ice bath, reacted at room temperature
Night.It after reaction solution is adjusted to pH=10 with sodium hydroxide solution, is extracted with ethyl acetate, organic phase is dry with anhydrous sodium sulfate, mistake
Filter, after concentration, recrystallization acquisition white solid 8 [(20S, 24S)-epoxy Da Ma Wan-12 β, 25-- 3 β of glycol-amine] (342mg,
0.719mmol, 66%).1H HMR(400MHz,CD3OD) δ 3.81 (dd, J=10.3,4.8Hz, 1H), 3.50 (td, J=
10.3,4.9Hz, 1H), 2.91 (dd, J=10.7,5.7Hz, 1H), 2.22 (td, J=10.1,3.5Hz, 1H), 1.26 (s,
3H),1.17(s,3H),1.10(s,3H),1.06(s,6H),0.94(s,6H),0.89(s,3H)。
Compound 8 (20mg, 0.042mmol) and 2-Boc-amion acetic acid (0.059mmol) are dissolved in anhydrous DMF
In (0.4mL), be added after argon gas protects lower stirring and dissolving, at 0 DEG C HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester,
24mg, 0.076mmol), triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and passes through
After saturated sodium bicarbonate solution washing, anhydrous sodium sulfate is dry, concentration.It chromatographs to obtain target compound (24mg, 90%) through column
。1H NMR(400MHz,CDCl3) δ 6.06 (d, J=9.6Hz, 1H), 5.19 (s, 1H), 3.88 (dd, J=10.7,5.3Hz,
1H), 3.78 (dd, J=16.5,5.9Hz, 1H), 3.72 (dd, J=16.5,5.9Hz, 1H), 3.68-3.61 (m, 1H), 3.53
(td, J=10.3,4.7Hz, 1H), 2.25 (td, J=10.3,4.4Hz, 1H), 1.45 (s, 9H), 1.28 (s, 3H), 1.23 (s,
3H),1.10(s,3H),1.01(s,3H),0.91(s,3H),0.88(s,3H),0.86(s,3H),0.77(s,3H)。
Embodiment 14
- 3 β-N of (20S, 24S)-epoxy-- 12 β of (4-Boc-aminobutanonyl)-dammarane, 25-glycol；
Compound 8 (20mg, 0.042mmol) and 4-Boc-aminobutyric acid (0.059mmol) are dissolved in anhydrous DMF
In (0.4mL), be added after argon gas protects lower stirring and dissolving, at 0 DEG C HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester,
24mg, 0.076mmol), triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and passes through
After saturated sodium bicarbonate solution washing, anhydrous sodium sulfate is dry, concentration.It chromatographs to obtain target compound (23mg, 90%) through column
。1H NMR(400MHz,CDCl3) δ 6.06 (d, J=9.6Hz, 1H), 5.19 (s, 1H), 3.88 (dd, J=10.7,5.3Hz,
1H), 3.78 (dd, J=16.5,5.9Hz, 1H), 3.72 (dd, J=16.5,5.9Hz, 1H), 3.68-3.61 (m, 1H), 3.53
(td, J=10.3,4.7Hz, 1H), 2.25 (td, J=10.3,4.4Hz, 1H), 1.45 (s, 9H), 1.28 (s, 3H), 1.23 (s,
3H),1.10(s,3H),1.01(s,3H),0.91(s,3H),0.88(s,3H),0.86(s,3H),0.77(s,3H)。
Embodiment 15
- 3 β-N of (20S, 24S)-epoxy-- 12 β of (6-Boc-aminocaProyl)-dammarane, 25-glycol；
Compound 8 (20mg, 0.042mmol) and 6-Boc-aminocaproic acid (0.059mmol) are dissolved in anhydrous DMF
In (0.4mL), be added after argon gas protects lower stirring and dissolving, at 0 DEG C HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester,
24mg, 0.076mmol), triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and passes through
After saturated sodium bicarbonate solution washing, anhydrous sodium sulfate is dry, concentration.It chromatographs to obtain target compound (26mg, 90%) through column
。1H NMR(400MHz,CDCl3) δ 5.92 (s, 1H), 5.40 (d, J=9.6Hz, 1H), 4.67 (s, 1H), 3.94 (dd, J=
10.7,5.3Hz, 1H), 3.74 (ddd, J=12.3,10.1,4.6Hz, 1H), 3.61 (td, J=10.4,4.7Hz, 1H),
3.28-2.99 (m, 2H), 2.32 (td, J=10.3,4.3Hz, 1H), 2.25 (t, J=7.5Hz, 2H), 2.21-1.88 (m,
7H),1.88-1.68(m,5H),1.67-1.53(m,8H),1.50(s,9H),1.34(s,3H),1.30(s,3H),1.17(s,
3H),1.08(s,3H),0.98(s,3H),0.94(s,3H),0.93(s,3H),0.83(s,3H)。
Embodiment 16
- 12 β of-3 β-N of (20S, 24S)-epoxy-(8-Boc-amino caprylyl)-dammarane, 25-glycol；
Compound 8 (20mg, 0.042mmol) and 8-Boc-aminocaprylic acid (0.059mmol) are dissolved in anhydrous DMF
In (0.4mL), be added after argon gas protects lower stirring and dissolving, at 0 DEG C HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester,
24mg, 0.076mmol), triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and passes through
After saturated sodium bicarbonate solution washing, anhydrous sodium sulfate is dry, concentration.Through column chromatograph to obtain target compound (30mg,
100%).1H NMR(400MHz,CDCl3) δ 5.31 (d, J=10.1Hz, 1H), 4.54 (s, 1H), 3.88 (dd, J=11.0,
5.5Hz, 1H), 3.67 (ddd, J=12.3,10.1,4.57Hz, 1H), 3.53 (td, J=10.3,4.7Hz, 1H), 3.12-
3.07 (m, 2H), 2.25 (td, J=10.3,4.0Hz, 1H), 2.17 (t, J=7.5Hz, 2H), 1.44 (s, 9H), 1.28 (s,
3H),1.23(s,3H),1.10(s,3H),1.01(s,3H),0.92(s,3H),0.87(s,3H),0.87(s,3H),0.77(s,
3H)。
Embodiment 17
- 3 β of (20S, 24S)-epoxy-- 12 β of hexanoyl amino dammarane, 25-glycol；
Compound 8 (20mg, 0.042mmol) and caproic acid (0.059mmol) are dissolved in anhydrous DMF (0.4mL), argon gas is protected
After protecting lower stirring and dissolving, HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester, 24mg, 0.076mmol) is added at 0 DEG C,
Triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and through saturated sodium bicarbonate solution
After washing, anhydrous sodium sulfate is dry, concentration.It chromatographs to obtain target compound (20mg, 83%) through column.1H NMR(400MHz,
CDCl3) δ 5.31 (d, J=10.1Hz, 1H), 4.54 (s, 1H), 3.88 (dd, J=11.0,5.5Hz, 1H), 3.67 (ddd, J=
12.3,10.1,4.57Hz, 1H), 3.53 (td, J=10.3,4.7Hz, 1H), 3.12-3.07 (m, 2H), 2.25 (td, J=
10.3,4.0Hz, 1H), 2.17 (t, J=7.5Hz, 2H), 1.44 (s, 9H), 1.28 (s, 3H), 1.23 (s, 3H), 1.10 (s,
3H),1.01(s,3H),0.92(s,3H),0.87(s,3H),0.87(s,3H),0.77(s,3H)。
Embodiment 18
- 12 β of-3 β of (20S, 24S)-epoxy-(2-(2-hydroxybenzoyl) amino) dammarane, 25-glycol；
Compound 8 (20mg, 0.042mmol) and 2-hydroxybenzoic acids (0.059mmol) are dissolved in anhydrous DMF (0.4mL)
In, be added after argon gas protects lower stirring and dissolving, at 0 DEG C HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester, 24mg,
0.076mmol), triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and through saturated carbon
After sour hydrogen sodium solution washing, anhydrous sodium sulfate is dry, concentration.It chromatographs to obtain target compound (23mg, 92%) through column.1H NMR
(400MHz,CDCl3) δ 12.39 (s, 1H), 7.39 (t, J=8.5Hz, 1H), 7.33 (d, J=7.7Hz, 1H), 6.99 (d, J=
8.2Hz, 1H), 6.85 (t, J=7.4Hz, 1H), 6.16 (d, J=9.9Hz, 1H), 3.91-3.85 (m, 2H), 3.56 (td, J=
10.2,4.8Hz, 1H), 2.27 (td, J=10.2,4.2Hz, 1H), 1.28 (s, 3H), 1.24 (s, 3H), 1.11 (s, 3H),
1.03(s,3H),0.94(s,3H),0.93(s,3H),0.92(s,3H),0.89(s,3H)。
Embodiment 19
- 12 β of-3 β-N of (20S, 24R)-epoxy-(N'- Boc-prolyl)-dammarane, 25-glycol；
Compound 5 (20mg, 0.042mmol) and N-Boc-proline (0.059mmol) are dissolved in anhydrous DMF (0.4mL)
In, be added after argon gas protects lower stirring and dissolving, at 0 DEG C HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester, 24mg,
0.076mmol), triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and through saturated carbon
After sour hydrogen sodium solution washing, anhydrous sodium sulfate is dry, concentration.Through column chromatograph to obtain target compound (25mg, 0.037mmol,
88%).1H NMR(400MHz,CDCl3) δ 4.31-4.26 (m, 1H), 3.85 (dd, J=8.7,6.9Hz, 1H), 3.68-3.56
(m, 1H), 3.52 (td, J=10.5,4.6Hz, 1H), 3.46-3.32 (m, 2H), 2.19 (td, J=10.1,3.0Hz, 1H),
2.08-1.83(m,6H),1.46(s,9H),1.27(s,3H),1.27(s,3H),1.09(s,3H),0.98(s,3H),0.90
(s,3H),0.88(s,3H),0.84(s,3H),0.76(s,3H)。
Embodiment 20
- 3 β of (20S, 24R)-epoxy-- 12 β of prolinamidyl dammarane, 25-glycol；
Embodiment 18 (0.03mmol) is dissolved in anhydrous TFA (trifluoroacetic acid, 0.5mL), after reacting 10min at room temperature
Reaction was completed.It is concentrated to get target compound (0.03mmol).1H NMR(400MHz,CD3OD) δ 4.26 (dd, J=8.2,
6.4Hz, 1H), 3.89 (t, J=7.3Hz, 1H), 3.63 (dd, J=12.8,4.1Hz, 1H), 3.49 (td, J=10.5,
4.6Hz, 1H), 3.42-3.32 (m, 2H), 2.47-2.40 (m, 1H), 2.20 (td, J=10.1,3.0Hz, 1H), 1.27 (s,
3H),1.22(s,3H),1.13(s,3H),1.03(s,3H),0.95(s,3H),0.92(s,3H),0.83(s,6H)。
Embodiment 21
- 12 β of-3 β-N of (20S, 24R)-epoxy-(N'- Boc-lysyl-)-dammarane, 25-glycol；
Compound 5 (20mg, 0.042mmol) and N-Boc-lysine (0.059mmol) are dissolved in anhydrous DMF (0.4mL)
In, be added after argon gas protects lower stirring and dissolving, at 0 DEG C HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester, 24mg,
0.076mmol), triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and through saturated carbon
After sour hydrogen sodium solution washing, anhydrous sodium sulfate is dry, concentration.Through column chromatograph to obtain target compound (30mg, 0.037mmol,
89%).1H NMR(400MHz,CDCl3) δ 6.08 (d, J=9.6Hz, 1H), 5.22 (s, 1H), 4.64 (s, 1H), 3.99 (dd, J
=12.6,7.5Hz, 1H), 3.84 (dd, J=8.5,6.6Hz, 1H), 3.61 (td, J=10.6,4.7Hz, 1H), 3.51 (td, J
=10.5,4.6Hz, 1H), 3.14-3.07 (m, 2H), 2.22-2.16 (m, 1H), 2.08-1.80 (m, 6H), 1.44 (s, 18H),
1.27(s,3H),1.27(s,3H),1.09(s,3H),0.98(s,3H),0.90(s,3H),0.85(s,3H),0.84(s,3H),
0.75(s,3H)。
Embodiment 22
- 12 β of-3 β-N of (20S, 24R)-epoxy-(N'- Boc-aspartyl)-dammarane, 25-glycol；
Compound 5 (20mg, 0.042mmol) and N-Boc-aspartic acid (0.059mmol) are dissolved in anhydrous DMF
In (0.4mL), be added after argon gas protects lower stirring and dissolving, at 0 DEG C HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester,
24mg, 0.076mmol), triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and passes through
After saturated sodium bicarbonate solution washing, anhydrous sodium sulfate is dry, concentration.Through column chromatograph to obtain target compound (25mg,
0.033mmol, 80%).1H NMR(400MHz,CDCl3) δ 6.46 (d, J=9.6Hz, 1H), 5.73 (d, J=6.9Hz, 1H),
4.43-4.38 (m, 1H), 3.84 (dd, J=8.9,6.6Hz, 1H), 3.58 (ddd, J=11.4,10.1,5.0Hz, 1H), 3.51
(td, J=10.5,4.6Hz, 1H), 2.85 (dd, J=17.0,4.7Hz, 1H), 2.61 (dd, J=16.9,6.9Hz, 1H),
2.19 (td, J=10.1,3.2Hz, 1H), 2.11-1.82 (m, 5H), 1.45 (s, 9H), 1.44 (s, 9H), 1.27 (s, 3H),
1.27(s,3H),1.09(s,3H),0.97(s,3H),0.90(s,3H),0.84(s,3H),0.83(s,3H),0.76(s,3H)。
Embodiment 23
- 12 β of-3 β-N of (20S, 24R)-epoxy-(N'- Boc-tyrosyl-)-dammarane, 25-glycol；
Compound 5 (20mg, 0.042mmol) and N-Boc-tyrosine (0.059mmol) are dissolved in anhydrous DMF (0.4mL)
In, be added after argon gas protects lower stirring and dissolving, at 0 DEG C HBTU (O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester, 24mg,
0.076mmol), triethylamine (20 μ L), reaction was completed after reaction 10min at room temperature.It is extracted with ethyl acetate, and through saturated carbon
After sour hydrogen sodium solution washing, anhydrous sodium sulfate is dry, concentration.Through column chromatograph to obtain target compound (28mg, 0.035mmol,
84%).1H NMR(400MHz,CDCl3) δ 7.11 (d, J=8.2Hz, 2H), 6.91 (d, J=8.7Hz, 2H), 5.77 (d, J=
9.6Hz, 1H), 5.01 (s, 1H), 4.27 (q, J=7.2Hz, 1H), 3.84 (dd, J=8.7,6.4Hz, 1H), 3.60-3.47
(m, 2H), 3.08 (dd, J=13.7,5.9Hz, 1H), 2.99 (dd, J=14.2,7.8Hz, 1H), 2.19 (td, J=10.1,
3.0Hz,1H),2.10-1.82(m,5H),1.68-1.63(m,2H),1.42(s,9H),1.32(s,9H),1.27(s,3H),
1.27(s,3H),1.09(s,3H),0.96(s,3H),0.89(s,3H),0.78(s,3H),0.70(s,3H),0.55(s,3H)。
Embodiment 24
- 3 β-N of (20S, 24R)-epoxy-{ 2-[2-(2-Fmoc-amino ethoxy) ethyoxyl] acetyl group }-dammarane-12
β, 25-glycol；
By compound 5 (42mg, 0.088mmol) and 2-[2-(2-Fmoc-amino ethoxy) ethyoxyl] acetic acid (48mg,
It 0.124mmol) is dissolved in anhydrous DMF (0.8mL), after argon gas protects lower stirring and dissolving, HBTU (three nitrogen of O- benzo is added at 0 DEG C
Azoles-tetramethylurea hexafluorophosphoric acid ester, 51mg, 0.158mmol), triethylamine (50 μ L) terminates instead after reacting 10min at room temperature
It answers.It is extracted with ethyl acetate, and after saturated sodium bicarbonate solution washs, anhydrous sodium sulfate is dry, concentration.It chromatographs to obtain through column
Target compound (52mg, 0.062mmol, 70%).1H NMR(400MHz,CDCl3) δ 7.76 (d, J=7.3Hz, 2H), 7.60
(d, J=7.3Hz, 2H), 7.40 (td, J=7.5Hz, 2H), 7.31 (td, J=7.3,0.9Hz, 2H), 6.56 (d, J=
10.1Hz, 1H), 5.22 (s, 1H), 4.40 (d, J=6.9Hz, 2H), 4.22 (t, J=6.9Hz, 1H), 4.03 (d, J=
10.1Hz, 1H), 4.00 (d, J=10.1Hz, 1H), 3.84 (dd, J=8.7,6.9Hz, 1H), 3.72-3.56 (m, 6H), 3.51
(td, J=10.5,4.6Hz, 1H), 3.42-3.38 (m, 2H), 2.18 (td, J=9.9,2.9Hz, 1H), 2.11-1.82 (m,
5H),1.71-1.39(m,10H),1.28(s,3H),1.26(s,3H),1.09(s,3H),0.96(s,3H),0.88(s,3H),
0.87(s,3H),0.83(s,3H),0.78(s,3H)。
Embodiment 25
- 3 β-N of (20S, 24S)-epoxy-{ 2-[2-(2-Fmoc-amino ethoxy) ethyoxyl] acetyl group }-dammarane-12
β, 25-glycol；
By compound 8 (30mg, 0.063mmol) and 2-[2-(2-Fmoc-amino ethoxy) ethyoxyl] acetic acid (34mg,
It 0.088mmol) is dissolved in anhydrous DMF (0.6mL), after argon gas protects lower stirring and dissolving, HBTU (three nitrogen of O- benzo is added at 0 DEG C
Azoles-tetramethylurea hexafluorophosphoric acid ester, 36mg, 0.113mmol), triethylamine (20 μ L) terminates instead after reacting 10min at room temperature
It answers.It is extracted with ethyl acetate, and after saturated sodium bicarbonate solution washs, anhydrous sodium sulfate is dry, concentration.It chromatographs to obtain through column
Target compound (34mg, 0.040mmol, 64%).1H NMR(400MHz,CDCl3) δ 7.77 (d, J=7.3Hz, 2H), 7.60
(d, J=7.3Hz, 2H), 7.40 (t, J=7.3Hz, 2H), 7.31 (t, J=7.3Hz, 2H), 6.55 (d, J=10.1Hz, 1H),
5.73 (s, 1H), 5.20 (s, 1H), 4.40 (d, J=6.9Hz, 2H), 4.22 (t, J=6.6Hz, 1H), 4.01 (s, 2H), 3.87
(dd, J=10.7,5.3Hz, 1H), 3.73-3.49 (m, 8H), 3.44-3.38 (m, 2H), 2.25 (td, J=10.3,4.3Hz,
1H),2.10-1.65(m,10H),1.27(s,3H),1.23(s,3H),1.10(s,3H),0.99(s,3H),0.90(s,3H),
0.88(s,3H),0.87(s,3H),0.79(s,3H)。
Pharmacological testing proves that ocotillol type sapogenin derivative of the invention has tumor drug resistance reversal activity, is used for
MDR reversal agents are prepared, are shared with common anti-tumor drug, good anti-tumor activity is played.
Here is the pharmacology test and data of part of compounds of the present invention.
Instrument and equipment:
Super-clean bench
Autoclave sterilizer
Carbon dioxide incubator
Microplate reader
Assay balance
Refrigerator
Liquid-transfering gun
Tissue Culture Dish
96 orifice plates
Filter
Cell strain and reagent:
Dimethyl sulfoxide (DMSO)
Methyl thiazoly tetrazolium assay (MTT)
Complete medium
Oral cavity epidermoid carcinoma cell KBV
Pancreatin digestive juice (0.25% trypsase+0.02%EDTA)
Ocotillol type sapogenin and its derivative DMSO dissolve configuration raw medicine liquid
Experimental method:
One: drug screening:
Mtt assay, also known as MTT colorimetric method are a kind of methods for detecting cell survival and growth.Its principle is in living cells mitochondria
Succinate dehydrogenase exogenous MTT can be reduced to water-insoluble bluish violet crystallization first a ceremonial jade-ladle, used in libation (Formazan), in cell
Middle deposition, and in dead cell be not in this phenomenon.The crystallization of first a ceremonial jade-ladle, used in libation is soluble in DMSO, is existed with enzyme-linked immunosorbent assay instrument
Absorbance is measured under 570nm wavelength, within the scope of certain cell number, absorbance value is directly proportional to viable count, thus reversed
Reflect living cells quantity.
1, plating cells: KBV persister cell is presented by research institute of Chinese Academy of Medical Sciences teacher Chen Xiaoguang seminar friendship.It takes
In logarithmic growth phase growth, adherent KBV cell in good condition, single cell suspension is digested to pancreatin.Cell count
After be diluted to 3~4 × 104A/mL is simultaneously inoculated in 96 orifice plates with the volume in 100 holes μ L/, in 37 DEG C, 5%CO2It is quiet in incubator
Set culture.
2, cell administration: after plating cells are adherent for 24 hours, 10 μM of different compounds is separately added into and combine the taxol of 100nM
And coordinative solvent control culture, 3 parallel holes of every group of setting.After dosing, 96 orifice plates are placed in incubator, stationary culture
72h。
3, MTT is detected: after giving corresponding drug culture cell 72h, the MTT solution that addition concentration is 5mg/mL, and every 20 μ L of hole,
37 DEG C of incubators are incubated for 2h, discard the culture medium containing MTT.Every hole is added 150 μ L DMSO and dissolves first a ceremonial jade-ladle, used in libation, oscillation mix after in
The absorbance value that each hole is measured at 570nm, using the tumour cell group handled added with DMSO as control group, and use Verapamil as
Positive control calculates the inhibiting rate for acquiring compound.
Inhibiting rate (%)=(control group mean OD value-administration group mean OD value)/control cell mean * 100%
Two: mtt assay detection compound to antitumor drug paclitaxel tumor drug resistance cell strain KBV cell Reversal activity
After the KBV cell tryptase enzymic digestion of logarithmic growth phase, 96 orifice plates are inoculated in by 3000-4000/hole.Plating cells are for 24 hours
Afterwards, be separately added into 5 μM, 10 μM of untested compound taxol and the coordinative solvent control culture of various concentration is given in combination.72h
After abandon supernatant, every hole, which is added, contains 20 μ L MTT, continues to cultivate 2h, 150 μ L DMSO are added after abandoning supernatant, are placed in microoscillator
Upper oscillation measures absorbance value (OD) at 570nM after mixing, and the tumour cell handled using solvent control is control group, calculatingization
Object is closed to the inhibiting rate of tumour cell, and calculates and acquires IC50 and compound reversal index.
IC50 when IC50/ shares reversal agent when reversal index=anti-tumor drug is applied alone
Three: embodiment 3 has drug resistance inversion activity in nude mouse
KBV cell is collected under aseptic condition, cell counter counts, and every nude mice inoculates 5 × 10 in right side6A KBV is thin
Born of the same parents.It is long to 100~300mm to tumor mass3Afterwards, control group, taxol (30mg/kg) group, embodiment 3 (10mg/kg) are randomly divided into
3 combination therapy group of group, taxol and embodiment.Compound is administered once a day by the way of stomach-filling, taxol intraperitoneal injection,
Biweekly.Record the weight of animals and knurl product.
Calculate gross tumor volume: volume (V)=a × b2/ 2 (a: major diameter, b: minor axis), do the growth curve chart of tumour.After two weeks, it moves
Object is euthanized and shells tumor, weighs knurl weight and calculates inhibition rate of tumor growth (%).
Experimental result:
By being obtained in the oral cavity epidermis cancer cell line (KBV cell) of tumor drug resistance as a result, prepared ocotillol type
Sapogenin derivative all has preferable drug resistance inversion activity, hence it is evident that is better than ocotillol type sapogenin 1 and 2, as shown in table 1.
And compared compared to positive control medicine Verapamil, under 5 and 10 μM of concentration embodiment 1,2,3,4,6,7,8,9,10,
11,12,13,15,16,18,19,20,21,22,23,24,25 better enhancing antitumor drug paclitaxel is shown to swollen
The cytotoxicity of oncocyte.
In addition, product of the present invention has good gastrointestinal tract stability, there is preferable medicinal application, this is existing skill
The characteristic that compound disclosed in art does not have.For example, choosing representative embodiment 3 and taxol combination to the half of KBV cell
Number inhibiting rates research, be shown in Table 2, as a result its under 5 and 10 μM of concentration, the IC50 of taxol is respectively 48.41 ± 3.16 Hes
28.29±2.90nM.Reversal index respectively reaches 28 and 48 times.The esterification derivative of natural products is modified, often after oral administration,
It is digested in small intestine by esterase, to lose activity.The drug of our Patent designs is found in nude mouse xenograft tumor model
(referring to Fig. 1) takes orally representative drugs embodiment 3 in KBV heteroplastic transplantation tumor model to the internal anti-tumor activity of taxol
There is apparent enhancing, show significant drug resistance inversion activity, this illustrates that our drug is stablized with preferable gastrointestinal tract
Property, tumor locus can be arrived, drug resistance inversion activity is generated.
The influence of 1 ocotillol type sapogenin of table and its derivative in KBV cell to taxol cytotoxicity
2 embodiment of table, 3 drug resistance inversion determination of activity
Above description is only the preferred embodiment of the application and the explanation to institute's application technology principle.
It will be appreciated by those skilled in the art that invention scope involved in the application, however it is not limited to above-mentioned technical characteristic
Specific combination made of technical solution, while should also cover in the case where not departing from the inventive concept, by above-mentioned technology
Feature or its equivalent feature carry out any combination and other technical solutions for being formed.Such as features described above and disclosed herein
But the technical solution that is not limited to there is the technical characteristic of similar functions to be replaced mutually and be formed.
Claims (5)
1. ocotillol type sapogenin derivative and its medically acceptable salt shown in logical formula (I) or (II),
Wherein, R represents (C4-C8) linear or branched alkyl group, R1NHR2、R1OR3、R1(O)COR3, phenyl, naphthalene, pyridine ring；
R1Represent (C1-C8) straight chained alkyl or oxyethyl chain, CH (NHR2)R4, phenyl, R2N- nafoxidine -2- base；
R2Represent hydrogen, Boc, Fmoc；
R3Represent hydrogen, t-Bu, benzyl；
R4It represents with blocking group and without the amino acid side groups of blocking group, blocking group Boc, Fmoc, t-Bu, benzyl
Base, methyl or ethyl.
2. ocotillol type sapogenin derivative shown in logical formula (I) according to claim 1 or (II) and its medically may be used
The salt of receiving, which is characterized in that
- 3 β-N of (20S, 24R)-epoxy-- 12 β of (2-Boc-glycyl)-dammarane, 25-glycol；
- 3 β-N of (20S, 24R)-epoxy-- 12 β of (4-Boc-aminobutanonyl)-dammarane, 25-glycol；
- 3 β-N of (20S, 24R)-epoxy-- 12 β of (6-Boc-aminocaProyl)-dammarane, 25-glycol；
- 12 β of-3 β-N of (20S, 24R)-epoxy-(8-Boc-amino caprylyl)-dammarane, 25-glycol；
- 3 β-N of (20S, 24R)-epoxy-- 12 β of (2-glycyl)-dammarane, 25-glycol；
- 12 β of-3 β-N of (20S, 24R)-epoxy-(8-amino caprylyl)-dammarane, 25-glycol；
- 3 β of (20S, 24R)-epoxy-- 12 β of hexanoyl amino dammarane, 25-glycol；
- 3 β of (20S, 24R)-epoxy-- 12 β of decoyl amino dammarane, 25-glycol；
- 3 β of (20S, 24R)-epoxy-- 12 β of benzamido dammarane, 25-glycol；
- 3 β of (20S, 24R)-epoxy-- 12 β of nicotinoyl amino dammarane, 25-glycol；
- 12 β of-3 β of (20S, 24R)-epoxy-(4-Boc-aminobenzamidoyl) dammarane, 25-glycol；
- 12 β of-3 β of (20S, 24R)-epoxy-(2-(2-hydroxybenzoyl) amino) dammarane, 25-glycol；
- 3 β-N of (20S, 24S)-epoxy-- 12 β of (2-Boc-glycyl)-dammarane, 25-glycol；
- 3 β-N of (20S, 24S)-epoxy-- 12 β of (4-Boc-aminobutanonyl)-dammarane, 25-glycol；
- 3 β-N of (20S, 24S)-epoxy-- 12 β of (6-Boc-aminocaProyl)-dammarane, 25-glycol；
- 12 β of-3 β-N of (20S, 24S)-epoxy-(8-Boc-amino caprylyl)-dammarane, 25-glycol；
- 3 β of (20S, 24S)-epoxy-- 12 β of hexanoyl amino dammarane, 25-glycol；
- 12 β of-3 β of (20S, 24S)-epoxy-(2-(2-hydroxybenzoyl) amino) dammarane, 25-glycol；
- 12 β of-3 β-N of (20S, 24R)-epoxy-(N'- Boc-prolyl)-dammarane, 25-glycol；
- 3 β of (20S, 24R)-epoxy-- 12 β of prolinamidyl dammarane, 25-glycol；
- 12 β of-3 β-N of (20S, 24R)-epoxy-(N'- Boc-lysyl-)-dammarane, 25-glycol；
- 12 β of-3 β-N of (20S, 24R)-epoxy-(N'- Boc-aspartyl)-dammarane, 25-glycol；
- 12 β of-3 β-N of (20S, 24R)-epoxy-(N'- Boc-tyrosyl-)-dammarane, 25-glycol；
- 12 β of-3 β-N of (20S, 24R)-epoxy-{ 2-[2-(2-Fmoc-amino ethoxy) ethyoxyl] acetyl group }-dammarane,
25-glycol；
- 12 β of-3 β-N of (20S, 24S)-epoxy-{ 2-[2-(2-Fmoc-amino ethoxy) ethyoxyl] acetyl group }-dammarane,
25-glycol.
3. ocotillol type sapogenin derivative shown in logical formula (I) of any of claims 1 or 2 or (II) and its medically may be used
The salt of receiving prepares the application of tumor drug resistance reversal agent.
4. ocotillol type sapogenin derivative shown in logical formula (I) according to claim 3 or (II) and its medically may be used
The salt of receiving prepares the application of tumor drug resistance reversal agent, which is characterized in that
A effective amount of logical formula (I) and (II) ocotillol type sapogenin derivative and its medically acceptable salt and with clinic
Anti-tumor drug shares.
5. ocotillol type sapogenin derivative shown in logical formula (I) of any of claims 1 or 2 or (II) and its medically may be used
The preparation method of the salt of receiving, it is characterised in that include the following steps:
Using protopanoxadiol as raw material, (20S, 24R)-epoxy is prepared in the nucleophilic attack for carrying out double bond epoxidation and intramolecular
Ma Wan-3 β is reached up to pure and mild (20S, the 24S)-epoxy of Ma Wan-3 β, 12 β, 25-three, 12 β, 25-triols, 3 hydroxyl oxygen metaplasias produce ketone,
Then Stereoselective reduction produces amine after oximido, is prepared by amide reaction logical without protecting group and containing protecting group
The derivative of formula (I) and (II), finally the derivative of the logical formula (I) containing protecting group and (II) pass through trifluoroacetic acid or HCl treatment
Prepare the logical formula (I) and (II) derivative of Deprotection.
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