CN108101925A - A kind of plectranthin type diterpene split melphalan derivative and its preparation method and application - Google Patents
A kind of plectranthin type diterpene split melphalan derivative and its preparation method and application Download PDFInfo
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- CN108101925A CN108101925A CN201810047598.8A CN201810047598A CN108101925A CN 108101925 A CN108101925 A CN 108101925A CN 201810047598 A CN201810047598 A CN 201810047598A CN 108101925 A CN108101925 A CN 108101925A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/18—Bridged systems
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- C07—ORGANIC CHEMISTRY
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
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Abstract
The present invention relates to natural drug and medicinal chemistry arts, are related to a kind of plectranthin type diterpene split melphalan derivative and its preparation method and application.More particularly to these in 14 OH of plectranthin type diterpene mother nucleus structure or 6,14 OH the sites preparation method for being introduced into DNA alkylating agent melphalan derivatives and its application in antitumor drug is prepared.Plectranthin type diterpene split melphalan derivative of the present invention and its pharmaceutically acceptable salt structure as shown in general formula I or II, wherein, n is as described in claims and specification.
Description
Technical field
The present invention relates to natural drug and medicinal chemistry arts, are related to a kind of plectranthin type diterpene split melphalan and derive
Object and its preparation method and application, and in particular to the derivative that the 14-OH or 6,14-OH of plectranthin are modified is related to this
Plectranthin derivative substituted a bit in 14-OH or 6,14-OH sites by DNA alkylating agent melphalan derivatives and preparation method thereof
With the application in antitumor drug is prepared.
Background technology
1958, Takshashi etc. obtained enmein from rabdosia japonica (Rabdosia japonica) for the first time,
Natsume in 1966 etc. determines the stereochemical structure of enmein, from that time, a series of plectranthin with X-ray diffraction method
Type diterpene-kind compound is separated.Plectranthin (enmein) is divided from Labiatae Rabdosia (Rabdosia) plant
A kind of kauran diterpene class (ent-kaurane diterpenoid) natural organic-compound separated out, with anti-cell
The effects that multiplication, the synthesis for inhibiting cancer cell DNA, RNA and protein, inducing cell tune are died, anti-mutation and beta-receptor block.
Chlormethine series pharmaceuticals, also referred to as DNA alkylating agents, belong to cytotoxic drug, mechanism of action is to be formed in vivo
The height reactive intermediate of electron deficient or other compounds with active electrophilic groups, and then occur with large biological molecule
Covalent Irreversible binding makes DNA molecular loss of activity or is broken.This kind of drug is clinically widely used, but it
Toxic side effect is bigger, specificity is lacked to cytosis, and with the generation of tumor drug resistance in recent years, therapeutic effect is not
Therefore ideal, is chemically modified chlormethine series pharmaceuticals, improving its curative effect has critically important value.
The content of the invention
The technical problems to be solved by the invention are to find the good plectranthin type diterpene split melphalan of antitumor activity
Derivative, and further provide for including the pharmaceutical composition of the derivative, the derivative or its composition are with antitumor
Activity.
In order to solve the above technical problems, the present invention provides following technical solution：
The present invention provides the plectranthin type diterpene split melphalan derivative shown in general formula I or II and its pharmaceutically may be used
The salt of receiving：
Wherein, n is the integer of 1-12.
Preferably, n is the integer of 1-6.
It is highly preferred that n is 2.
The derivative of general formula I or II of the present invention can be prepared with following method：
Oridonin 1 reacts in water with sodium metaperiodate, obtains plectranthin type derivative 2, adds in acetone, with fine jade
This reagent reacting obtains oxidation plectranthin type derivative 3.
Melphalan methyl esters 5 is obtained by the reaction in the heating of melphalan 4 and methanol, then 5 under conditions of DMAP catalysis with succinic acid
Anhydride reactant obtains melphalan methyl esters carboxylic acid derivates 6.
Plectranthin type derivative 2 or oxidation plectranthin type derivative 3 exist with melphalan methyl esters carboxylic acid derivates 6
It is reacted at room temperature under the conditions of EDCI/DMAP, respectively obtains target compound 7 or 8.
It is beautiful comprising the plectranthin type diterpene split shown in general formula I or II the present invention also provides a kind of pharmaceutical composition
Method logical sequence derivative and its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
Plectranthin type diterpene split melphalan derivative and its pharmaceutically acceptable shown in the general formula I or II of the present invention
Salt or pharmaceutical composition clinically acceptable pharmaceutical preparation can be made with pharmaceutically acceptable carrier, such as tablet, glue
Wafer, granule etc..
The plectranthin type diterpene split melphalan derivative and its pharmaceutically acceptable salt of the present invention is to prolong life grass
Plain type forskolin is guide, using principle of hybridization, selects the preferable melphalan derivative of activity, is passed through linking group
It is connected on the 14-OH or 6,14-OH of its molecular structure, it is beautiful to have designed and synthesized the plectranthin type diterpene split that general formula is I
Method logical sequence derivative.Compound and its pharmaceutical composition and preparation after split have preferable pharmaceutical active.
Specific embodiment
Embodiment 1
Plectranthin type intermediate 2 (56mg, 0.16mmol) is taken, is dissolved in dichloromethane (5ml), sequentially adds melphalan
Methyl esters butyric acid (154mg, 0.37mmol), EDCI (94mg, 0.50mmol), DMAP (8mg, 0.07mmol), are stirred at room temperature reaction,
TCL monitors reaction process, terminates reaction afterwards for 24 hours.Reaction solution is poured into 10ml mixture of ice and water, dichloromethane extraction (30ml
× 3), saturated common salt aqueous solution washs, and anhydrous sodium sulfate drying recycles dichloromethane, crude product 7 obtained, through silicagel column (dichloro
Methane:Methanol=200:1), separate, obtain brown oil, yield 14%.HRMS(ESI,M+H)m/z calcd for
C56H70Cl4N4O14:1163.3643,found:1163.3792.1H NMR(CDCl3,400M Hz),δ(ppm):6.98(4H,
Dd, J=8.7,2.5Hz, Ar-H), 6.63 (4H, dd, J=8.7,3.3Hz, Ar-H), 6.22 (1H, s, 6-CH), 6.15 (1H,
S, 14-CH), 6.02 (1H, d, J=7.6Hz, NH) 5.96 (1H, d, J=7.6Hz, NH), 5.73 (1H, s, 17-CH2),5.60
(1H,s,17-CH2), the 4.76 (- CH of 2H, dd, J=7.8,5.6Hz, 5'-CH, 5 "), 4.56 (1H, dd, J=10.8,5.3Hz,
1-CH), 4.11,3.96 (each 1H, d, J=9.4Hz, 20-CH2),3.72(3H,s,18”-CH3),3.74(3H,s,18'-
CH3), 3.62,3.71 (each 8H, t, J=6.4Hz, 13', 14'-CH2,15',16'-CH2,13”,14”-CH2,15”,16”-
CH2), 3.19 (1H, d, J=10.0Hz, 13-CH), 3.01 (4H, m, 6'-CH2,6”-CH2),2.62(2H,m,2”-CH2),
2.53(2H,m,3”-CH2),2.53(2H,m,2'-CH2),2.39(2H,m,3'-CH2),1.06(3H,s,19-CH3),1.01
(3H,s,19-CH3).13C NMR(CDCl3,100M Hz),δ(ppm):197.76,172.16,172.00,171.88,
171.27,170.79,170.41,166.98,147.51,145.10,144.96,130.64,130.56,124.98,120.95,
120.53,112.37,112.28,101.94,101.74,77.23,76.12,75.74,75.16,74.12,73.89,60.17,
59.88,53.81,53.65,53.57,53.48,53.27,52.34,52.26,49.83,49.46,48.46,48.00,
40.54,40.37,37.03,36.91,36.60,32.84,31.38,30.55,30.18,30.02,29.74,29.56,
29.31,23.18,23.08,22.95,19.69.
Embodiment 2
Compound 8 is prepared into reference to the synthetic method of embodiment 1.Brown oil, yield 35%.HR-MS(ESI,M+H)m/
z:calcd for C38H46Cl2N2O10:783.2640,found:783.2422.1H NMR(CDCl3,400M Hz),δ(ppm):
6.97,6.63 (each 2H, d, J=8.6Hz, Ar-H), 6.25 (1H, d, J=1.2Hz, 14-CH), 6.02 (1H, d, J=
7.6Hz,6-OH),5.70(1H,s,17-CH2),5.64(1H,s,17-CH2), 4.74 (1H, dt, J=7.8,5.7Hz, 5'-
), CH 4.58 (1H, dd, J=11.5,5.7Hz, 1-CH), 4.34,4.03 (each 1H, d, J=10.2Hz, 20-CH2),3.73
(3H,s,18'-CH3), 3.63,3.71 (each 4H, t, J=6.2Hz, 13', 14'-CH2,15',16'-CH2),3.22(1H,
D, J=8.6Hz, 13-CH), 2.63 (2H, m, 2'-CH2),2.51(2H,m,3'-CH2),2.38(1H,m,6'-CH2),2.08
(1H,m,6'-CH2),1.21(3H,s,18-CH3),1.06(3H,s,19-CH3).13C NMR(CDCl3,100M Hz),δ
(ppm):197.17,175.21,172.28,171.98,170.63,166.32,146.93,145.03,130.53(×2),
124.84,121.65,112.32(×2),77.24,74.47,73.53,71.32,59.45,53.60,53.42,52.27,
50.77,47.43,45.95,40.38(×2),40.16,36.62,36.37,33.04,32.25,30.43,29.51,29.44,
23.62,23.02,19.17.
Pharmacological testing
Experimental facilities and reagent
Experimental method
Cell inhibitory activity experimental method
Cell is in 37 DEG C, 5%CO2Cellar culture in the incubator of saturated humidity.Culture solution is containing 10% heat inactivation tire ox
The RPMI1640 cell culture mediums of serum, penicillin 100U/mL and streptomysin 100U/mL.48h replaces culture solution, cell attachment
Afterwards, passed on 0.25% Trypsin Induced.Experiment is in exponential phase with cell, and trypan exclusion stain shows that cell is lived
Power>95%.
It takes in exponential phase one bottle of cell in good condition, adds in digestive juice (0.125% trypsase+0.01%
EDTA) digest, count 2~4 × 104Cell suspension inoculation is made on 96 orifice plates in cell/mL, and constant temperature CO is put in 100 μ L/ holes2Training
When culture 24 is small in foster case.Liquid is changed, adds in test medicine, 100 μ L/ holes, when culture 72 is small.CCK-8 is added in 96 orifice plates, 50
μ L/ holes, be incubated in incubator 4 it is small when.Supernatant is sucked, adds DMSO, 200 μ L/ holes are shaken 10 minutes on plate shaker.It is tested
Object investigates 3 concentration (0.25 μM, 0.5 μM, 1 μM), with enzyme linked immunological monitor in the extinction that wavelength is the every hole of measure at 450nm
Degree, calculates the cell inhibitory rate under each concentration respectively.
Inhibiting rate computational methods：
Susceptibility hole is with respect to the absolute absolute OD values of OD values ﹣ blank control wells in OD values=susceptibility hole
Experimental result
1 embodiment of table is to the IC of 4 kinds of human cancer cell's strains and a kind of normal human cells' antiproliferative activity50It is worth (μM)
Pharmacological testing proves, target compound of the invention there is better antitumor action and to normal cell and
The selectivity of tumour cell can be used for further preparing antitumor drug.
Claims (10)
1. plectranthin type diterpene split melphalan derivative and its pharmaceutically acceptable salt shown in general formula I or II：
Wherein, n is the integer of 1-12.
2. plectranthin type diterpene split melphalan derivative shown in general formula I or II described in claim 1 and its pharmaceutically
Acceptable salt：
Wherein, n is the integer of 1-6.
3. plectranthin type diterpene split melphalan derivative and its pharmacy shown in the general formula I or II described in claim 1 or 2
Upper acceptable salt：
Wherein, n 2, i.e.,
4. a kind of pharmaceutical composition, wherein the institutes of general formula I or II described in the claim 1-3 any one containing therapeutically effective amount
The plectranthin type diterpene split melphalan derivative and its pharmaceutically acceptable salt and pharmaceutically acceptable carrier shown.
5. a kind of pharmaceutical preparation includes the plectranthin type diterpene shown in the general formula I or II described in claim 1-3 any one
Composition described in split melphalan derivative and its pharmaceutically acceptable salt or claim 4.
6. plectranthin type diterpene split melphalan derivative and its pharmacy shown in general formula I or II as described in claim 1
The preparation method of upper acceptable salt, it is characterised in that：
Oridonin 1 is in NaIO3/H2Obtain plectranthin type derivative 2 under the conditions of O, product again with Jones reagent in acetone
Oxidation plectranthin type derivative 3 is obtained by the reaction；
Melphalan methyl esters 5 is obtained by the reaction with methanol heating in melphalan 4, and then 5 is anti-with succinic anhydride under conditions of DMAP catalysis
Deserved melphalan methyl esters carboxylic acid derivates 6；
Plectranthin type derivative 2 or oxidation plectranthin type derivative 3 and melphalan methyl esters carboxylic acid derivates 6 are in EDCI/
Room temperature reaction respectively obtains target compound 7 or 8 under the conditions of DMAP；
7. the plectranthin type diterpene split melphalan derivative shown in the general formula I or II described in claim 1-3 any one
And its application of the pharmaceutically acceptable salt in the drug for preparing treatment tumor disease.
8. application of the pharmaceutical composition in the drug for preparing treatment tumor disease described in claim 4.
9. application of the pharmaceutical preparation in the drug for preparing treatment tumor disease described in claim 5.
10. the application as described in claim 7 or 8 or 9, which is characterized in that the tumour is prostate cancer, liver cancer or white blood
Disease.
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| CN109134490A (en) * | 2018-09-18 | 2019-01-04 | 沈阳药科大学 | Plectranthin type diterpene hydrogen sulfide donor derivative and its preparation method and application |
| CN109134487A (en) * | 2018-08-10 | 2019-01-04 | 沈阳药科大学 | Compound and its preparation method and application of the one kind containing benzoic acid nitrogen mustard segment |
| CN109336901A (en) * | 2018-09-18 | 2019-02-15 | 沈阳药科大学 | 6,14- split hydrogen sulfide donor derivatives of plectranthin type diterpene |
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Patent Citations (3)
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| CN105524061A (en) * | 2015-12-15 | 2016-04-27 | 中国人民解放军第二军医大学 | Multi-targeted antitumor active evodiamine derivative and preparation and application thereof |
| CN105622607A (en) * | 2016-01-12 | 2016-06-01 | 沈阳药科大学 | Furazan NO donor type evodiamine derivatives with anti-tumor activity |
| CN105859741A (en) * | 2016-05-06 | 2016-08-17 | 沈阳药科大学 | Enmein-like ent-kaurane derivatives and preparation method and application thereof |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109134487A (en) * | 2018-08-10 | 2019-01-04 | 沈阳药科大学 | Compound and its preparation method and application of the one kind containing benzoic acid nitrogen mustard segment |
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| CN109134490A (en) * | 2018-09-18 | 2019-01-04 | 沈阳药科大学 | Plectranthin type diterpene hydrogen sulfide donor derivative and its preparation method and application |
| CN109336901A (en) * | 2018-09-18 | 2019-02-15 | 沈阳药科大学 | 6,14- split hydrogen sulfide donor derivatives of plectranthin type diterpene |
| CN109134490B (en) * | 2018-09-18 | 2019-08-30 | 沈阳药科大学 | Plectranthin type diterpene hydrogen sulfide donor derivative and its preparation method and application |
| CN109336901B (en) * | 2018-09-18 | 2020-03-17 | 沈阳药科大学 | Plectranthin type diterpene 6, 14-position split hydrogen sulfide donor derivative |
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