CN103242336A - Gambogic acid-type derivative and preparation and application thereof - Google Patents
Gambogic acid-type derivative and preparation and application thereof Download PDFInfo
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Abstract
The invention relates to a gambogic acid-type derivative and preparation and application thereof. The derivative is shown as formula I, formula II and formula III, wherein R1 is H or nitrogen heterocyclic ring or -(CH2)mR3, m is 1-8, R3 is nitrogen heterocyclic ring or NR4R5, R4 and R5 are respectively selected from H and C1-8 linear-chain or branch alkyl groups, or the R4 and R5 form a loop, R2 is a H, alicyclic or nitrogen heterocyclic ring, and X is O or NH independently or forms the nitrogen heterocyclic ring together with R1. The preparing method comprises the step of enabling the gambogic acid catalyzed and rearranged under medium-strong protonic acid to react with R1XH or salt compound thereof. The gambogic acid-type derivative disclosed by the invention has broad-spectrum antitumor activity, has obvious grow inhibiting effect on multiple solid tumors, can form salt compound to greatly improve water-solubility, is stable in chemical structure and is expected to be developed as an innovative antitumor medicine.
Description
Technical field
The invention belongs to field of antineoplastic medicaments, particularly a kind of gambogic acid derivative and preparation and application.
Background technology
Gamboge (Gamboge) is the guttiferae plant, the secreted dry resin of gamboge (Garcinia hanburyi), represent composition and be morellic acid (Gambogic acid, GA), xanthone compounds such as allogambogic acid, neogambogic acid.Wherein, GA is the antitumor topmost bioactive ingredients of gamboge.GA is the kill tumor cell optionally, and to the normal hemopoietic system of body and not influence of immunity system, studies have shown that GA and derivative thereof are agonist and the apoptotic inductors of caspase.GA has broad spectrum anticancer, can suppress propagation and the cell death inducing of kinds of tumor cells such as cancer of the stomach, lung cancer, colorectal carcinoma, cervical cancer, mammary cancer, has the obvious in-vitro anti-tumor activity, and is low to toxicity such as marrow, liver, kidneys.
Because morellic acid and derivative thereof have remarkable antitumor effect, Chinese scholars have been carried out various chemically modifieds to the region of interest of morellic acid, San Diego, USA Marxim institute of materia medica (US2003078292, WO0044216) has carried out partly modifying to the morellic acid structure, mainly concentrate on C-30, C-8, C-6, C-12, C-9,10 positions; The Xu Lifeng of Liaoning Lifeng Technology and Development Co., Ltd. (200710157223.9,200910166738.4) is to C-30, C-6, the C-9 of morellic acid, and 10 have carried out various modifications, have synthesized a lot of Cambogic acid glycoside derivates and analogue; Pharmaceutical chemistry teaching and research room of China Medicine University opens especially that winter study group (20061088251.5,200610088252.X, 201110347886.3) has carried out deriving to the side chain of morellic acid and the xanthone ring structure of morellic acid has been carried out complete synthesis, studies its structure activity relationship.
Summary of the invention
Technical problem to be solved by this invention provides a kind of gambogic acid derivative and preparation and application, and this gambogic acid derivative has the anti-tumor activity of wide spectrum, and to the effect that multiple solid tumor has significant inhibition to grow, its preparation method is simple.
Gambogic acid derivative of the present invention, this derivative is shown in general formula I, II or III:
Wherein, R
1For hydrogen or nitrogen heterocyclic ring or-(CH
2)
mR
3, wherein m is 1-8, R
3Can be saturated or undersaturated nitrogen heterocyclic ring or NR
4R
5Described R
4, R
5Independently be selected from the straight chain of hydrogen, replacement or unsubstituted C1-8 and the alkyl of side chain separately, described R
4, R
5Also can Cheng Huan;
R
2Be hydrogen, alicyclic ring or nitrogen heterocyclic ring;
X is O or NH independently, or and R
1Constitute nitrogen heterocyclic ring together.
The straight chain of described C1-8 and the alkyl of side chain contain one or more substituting groups, and described substituting group is selected from hydrogen, C1-5 alkyl, C2-5 thiazolinyl, C2-5 alkynyl, C1-5 alkoxyl group, halogen, nitro, cyano group, hydroxyl, amino, carboxyl and oxo.
Preferably, R
1M be 2-4.
Preferably, R
2Be selected from pentamethylene base, cyclohexyl, morpholinyl, piperazinyl, N methyl piperazine base, piperidyl.
Described gambogic acid derivative is specially a kind of in the following formula:
The preparation method of gambogic acid derivative of the present invention comprises:
(1) morellic acid is dissolved in the acetic acid, strong protonic acid in adding then, under middle strong protonic acid catalysis, morellic acid is reset, and obtains compound S-31 and S-34;
(2) with S-31 and R
1XH or its salt react, thus the compound shown in the formula of formation (I); Or with S-34 and R
1XH or its salt react, thus the compound shown in the formula of formation (II);
(3) with the compound shown in the formula (I) with contain corresponding substituent reagent react and obtain the described compound of formula (III).
Middle strong protonic acid described in the step (1) is selected from sulfuric acid, methylsulfonic acid, tosic acid, hydrochloric acid etc.
The reaction conditions of step (1) is under the microwave condition under 60-80 ℃ or the normal pressure 60-100 ℃.
In the step (2) with S-31 or S-34 under base catalysis with R
1The hydroxy halogeno product reaction of OH obtains corresponding ester, and described alkali is NaOH, KOH, K
2CO
3, Na
2CO
3, NaHCO
3, Cs
2CO
3In a kind of.
In the step (2) with S-31 or S-34 by condensation catalytic reagent and alcohol or the corresponding ester of amine prepared in reaction or acid amides.
Described condensation reagent is N, N '-carbonyl dimidazoles (CDI), triphenylphosphine, azoformic acid diisopropyl ester (DIAD), 1-hydroxy benzo triazole (HOBT), N-hydroxyl-7-azepine benzotriazole (HOAT), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (EDCI), phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkane (pyBOP), 4-Dimethylamino pyridine (DMAP) or dicyclohexylcarbodiimide (DCC), O-benzotriazole-N, N, N ', a kind of in N '-tetramethyl-urea Tetrafluoroboric acid (TBTU), the Vinyl chloroformate.
The application of gambogic acid derivative of the present invention in preparation antitumour drug, antifungal drug or anti-angiogenic medicaments.
Described tumour is a kind of in mammary cancer, lung cancer, liver cancer, the colorectal carcinoma.
In the formula, R
1, R
2, X described as defined above, described R
1The salt of XH can be inorganic acid salt or organic acid salt; Work as COXR
1During for ester, S-31 also can with R
1The halo dewatered product reaction of OH obtains the formula I compound.S-34 method too makes the compound of formula (II).
Preferably, with S-31 under base catalysis with R
1The corresponding ester of hydroxy halogeno product prepared in reaction of OH, described alkali is selected from NaOH, KOH, K
2CO
3, Na
2CO
3, NaHCO
3, Cs
2CO
3Or among the NaH any.
Preferably, with S-31 by condensation catalytic reagent and alcohol or the corresponding ester of amine prepared in reaction or acid amides.The above condensation reagent can be independently selected from: N, N '-carbonyl dimidazoles (CDI), triphenylphosphine, azoformic acid diisopropyl ester (DIAD), 1-hydroxy benzo triazole (HOBT), N-hydroxyl-7-azepine benzotriazole (HOAT), 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (EDCI), phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkane (pyBOP), 4-Dimethylamino pyridine (DMAP) or dicyclohexylcarbodiimide (DCC), O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid (TBTU), propyl group phosphoric anhydride (T3P), Vinyl chloroformate.
The invention provides the Gamboges acid derivative shown in a class general formula I, II, the III or its pharmacy acceptable salt, solvate, prodrug or polymorphic form.
The invention provides a kind of composition, the carrier that contains aforesaid arbitrary compound of safe and effective amount and pharmaceutically accept.Described " safe and effective amount " refers to: the amount of compound is enough to improve the state of an illness, and is unlikely to produce severe side effect.Safe and effective amount is determined according to waiting age, the state of an illness, the course for the treatment of of treatment target.
Gambogic acid derivative of the present invention can be prepared as the form of the salt of its pharmacy acceptance according to ordinary method.Comprise its inorganic acid salt and organic acid salt: mineral acid includes, but is not limited to hydrochloric acid, sulfuric acid, phosphoric acid, bisphosphate, Hydrogen bromide, nitric acid etc.; Organic acid includes, but is not limited to acetic acid, toxilic acid, fumaric acid, tartrate, succsinic acid, lactic acid, tosic acid, Whitfield's ointment, oxalic acid etc.
Compound of the present invention has good antineoplastic activity, they can be used for the treatment of tumour, comprise the cancer that positions such as esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, mammary gland, uterus, uterine endometrium, ovary, prostate gland, testis, bladder, kidney, liver, pancreas, bone, reticular tissue, skin, eye, brain and central nervous system take place, and thyroid carcinoma, leukemia, Huo Jiejinshi disease, lymphoma and myelomatosis etc.
In addition, The compounds of this invention also can the particularly anticancer compound coupling of a kind of with other (or multiple) anticancer active constituent, alkylating reagent for example is as alkyl sulfonic ester (busulfan), dacarbazine, procarbazine, nitrogen mustards compound (chlormethine, melphalan, Chlorambucil), endoxan or ifosfamide; Nitrosoureas is as carmustine, lomustine, semustine or streptozotocin; Anti-tumor biological alkali is as vincristine(VCR) or vinealeucoblastine(VLB); Taxanes, as taxol or docetaxel (taxotere), the antitumor antibiotics class is as actinomycin; Insert reagent, antitumor metabolite, antifol or methotrexate; The purine synthetic inhibitor; Purine analogue is as 6-mercapto guanine; Pyrimidine synthesis inhibitors, arimedex, card its shore of training or pyrimidine analogue are as Fluracil, gemcitabine, cytosine arabinoside and cytarabin; Brequinar (brequinar), topoisomerase enzyme inhibitor is as camptothecine or etoposide; Anticancer hormone agonist and antagonist comprise Tamoxifen; Kinase inhibitor, imatinib mesylate (imatinib), growth factor receptor inhibitors, anticancer metal composite, anthracycline antibiotics etc.
The present invention is by resetting morellic acid in various acid, a synthetic class has the morellic acid analogue of novel skeleton, and each relevant position is derived, and has improved compound water soluble, has strengthened antitumor activity of compound.
Beneficial effect:
The invention provides a class is the Chinese medicine natural product derivative of the novel structure of parent nucleus based on the morellic acid rearrangement product, this derivative has the anti-tumor activity of wide spectrum, multiple solid tumor there is the effect of significant inhibition growth, can salify and then significantly improve water-soluble, steady chemical structure, being expected to exploitation becomes the innovation antitumor drug.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
The derivative that compound of the present invention can adopt morellic acid or have a parent nucleus of gambogic acid compounds is the old luxuriant growth benevolence of raw material. the separation of morellic acid and the evaluation of structure (Jiangxi Medical College's journal, 1980,7. with Timothy J.R.Weakley, Sui X.Cai, Han-Zhong Zhang, and John F.W.Keana.Crystal structure of the pyridine salt of gambogic acid.J.Chem Crystallogr, December2001,31:11-12), obtain through number step prepared in reaction, method is simple, and yield is higher, is easy to realize industrialization.
Embodiment 1:S-31, S-34's is synthetic
In the 250ml reaction flask, add the 1g morellic acid, the 100ml Glacial acetic acid, the 4g tosic acid reacts 3h under 80 ℃ of conditions, reaction solution is placed be cooled to normal temperature, pours into then in the 200ml frozen water, uses CH
2Cl
25 times acid is removed with saturated NaCl washing, with the extraction liquid evaporate to dryness, used silica gel column chromatography then, the elutriant condition is ethyl acetate: sherwood oil: formic acid=1:20:0.05 obtains 0.40g S-31(yield 40%) and 0.2gS-34(yield 20%).
S-31：
1H?NMR(500MHz,CDCl
3):δ12.77(s,1H),7.52(d,J=6.6Hz,1H),5.99(t,J=7.4Hz,1H,),4.15(s,1H),3.48(t,J=4.1Hz,1H),3.03(t,J=7.2Hz,2H),2.56(m,2H),2.48(d,J=9.4Hz,1H),2.43(dd,J=14.0,3.5Hz,1H),2.31(dd,J=13.3,3.8Hz,1H),1.97(s,3H),1.96(m,1H),1.85(s,3H),1.83(m,2H),1.76(s,3H),1.71(s,3H),1.70(m，2H)，1.69(m,1H),1.62(s,3H),1.53(m,1H),1.50(s,3H),1.48(s,3H),1.37(m,1H),1.30(s,3H),1.29(s,3H).
ESI-MS：711[M+Na]
+。
Compound S-34:
1H NMR (500MHz, CDCl
3): δ 12.60 (s, 1H), 7.52 (d, J=7.0Hz, 1H), 5.91 (t, J=7.5Hz, 1H), 5.04 (t, J=7.0Hz, 1H), 3.48 (t, J=4.5Hz, 1H), 3.32 (dd, J=8.0,6.0Hz, 1H), 3.16-3.18 (m, 1H), 3.14 (m, 1H), 2.98 (d, J=9.5Hz, 1H), 2.97 (m, 1H), 2.52 (d, J=9.0Hz, 1H), 2.46 (m, 1H), 2.34 (m, 1H), 2.31 (m, 1H), 1.75-1.78 (m, 1H), 1.73 (s, 3H), 1.71 (s, 3H), 1.70 (s, 3H), 1.63 (s, 3H), 1.59 (m, 1H), 1.51-1.56 (m, 2H), 1.38 (1H, m), 1.33 (s, 3H), 1.31 (s, 3H), 1.29 (s, 3H), 0.73 (s, 3H).
13C?NMR(100MHz,CDCl
3):δ203.61(C12),178.93(C8),171.15(C30),161.59(C18),161.22(C6),155.11(C16),137.80(27),134.65(C10),133.93(C9),130.84(C33),128.19(C28),122.50(C32),108.93(C17),105.32(C5),100.45(C7),90.43(C14),85.22(C2),84.17(C13),83.85(C23),49.03(C22),46.08(C11),46.33(C37),38.87(C38),38.70(C20),37.03(C3),35.10(C4),33.49(C39),29.95(C24),29.33(C26),28.92(C25),27.38(C19),25.72(C35),25.64(C36),25.37(C21),21.88(C31),20.76(C29),18.18(C34),17.72(C40).
IR(KBr):3445,2925,2852,1681,1638,1433,1384,1322,1266,1197,1140cm
-1；ESI-MS:629[M+H]
+
Embodiment 2:S-31, S-34's is synthetic
In the 50ml reaction flask, add the 1g morellic acid, the 10ml Glacial acetic acid, the 0.4g tosic acid reacts 5min under 80 ℃ of conditions in microwave reactor, reaction solution is placed be cooled to normal temperature, pours into then in the 20ml frozen water, uses CH
2Cl
25 times acid is removed with saturated NaCl washing, with the extraction liquid evaporate to dryness, used silica gel column chromatography then, the elutriant condition is ethyl acetate: sherwood oil: formic acid=1:25:0.05 obtains 0.25g S-34(yield 25%) and 0.41g S-31(yield 41%).
The compound data are with embodiment 1.
Embodiment 3:S-45's is synthetic
In the 50ml reaction flask, add 500mg S-31(0.73mmol), 504mg K
2CO
3(3.63mmol), 130mg(0.8mmol) chloropropyl morpholine and 10ml DMF stir 7h under 40 ℃ of conditions, show with the TCL detection to react completely, and pour 30mlCH into
2Cl
2, with saturated NaCl solution washing 20mL * 5 times, with the extraction liquid evaporate to dryness, use silica gel column chromatography then, the elutriant condition is CH
2Cl
2: CH
3OH=97:3 obtains 506mg S-45(yield 82%).
S-45:
1H?NMR(400MHz,CDCl
3):δ12.85(s,1H),7.50(d,J=6.8Hz,1H),5.99(t,J=6.7Hz,1H),4.28(s,1H),3.99-3.86(m,2H),3.74-3.64(m,4H),3.49-3.42(m,1H),2.94(t,J=5.6Hz,2H,),2.71-2.53(m,2H),2.52-2.26(m,9H),1.99(s,3H),1.93(s,3H),1.77(s,3H),1.67(s,3H),1.65(s,3H),1.52(s,3H),1.50(s,3H),1.41(s,3H),1.29(s,3H).
ESI-MS：816[M+H]
+。
Embodiment 4:S-46's is synthetic
In the 50ml reaction flask, add 500mg S-31(0.73mmol), 153.9mg EDCI(0.8mmol), 108.5mgHOBT(0.8mmol), 115.4mg(0.8mmol) the anhydrous CH of aminopropyl morpholine and 10ml
2Cl
2, stir 4h under the normal temperature condition, show with the TCL detection to react completely, use CH
2Cl
2With saturated NaCl solution washing 20mL * 5 times, with the extraction liquid evaporate to dryness, use silica gel column chromatography then, the elutriant condition is CH
2Cl
2: CH
3OH=96:4 obtains 472.5mg S-46(yield 75%).
S-46:
1H?NMR(400?MHz,CDCl
3):δ12.90(s,1H),7.53(d,J=6.9Hz,1H),6.88(t,J=5.3Hz,1H),5.26(t,J=7.8Hz,1H),4.32(s,1H),3.75-3.66(m,4H),3.50-3.42(m,1H),3.38-3.20(m,2H),2.77-2.58(m,4H),2.54-2.37(m,8H),2.32(dd,J=13.5,4.5Hz,1H),1.99(s,3H),1.94(s,3H),1.78(s,3H),1.77(s,3H),1.67(s,3H),1.52(s,3H),1.51(s,3H),1.44(s,3H),1.29(s,3H)。
ESI-MS：815[M+H]
+.
Embodiment 5:S-48's is synthetic
In the 50ml reaction flask, add 500mg S-31(0.73mmol), 504mg K
2CO
3(3.63mmol), 120mg(0.8mmol) chloroethyl morpholine and 10ml DMF stir 7h under 40 ℃ of conditions, show with the TCL detection to react completely, and pour 30mlCH into
2Cl
2, with saturated NaCl solution washing 20mL * 5 times, with the extraction liquid evaporate to dryness, use silica gel column chromatography then, the elutriant condition is CH
2Cl
2: CH
3OH=97:3 obtains 468mg S-48(yield 80%).
S-48:
1H?NMR(400?MHz,CDCl
3)δ12.86(s,1H),7.50(d,J=6.9Hz,1H),6.01(t,J=6.7Hz,1H),4.28(s,1H),4.08–3.91(m,2H),3.71–3.61(m,4H),3.48–3.41(m,1H),2.94(d,J=7.1Hz,2H),2.71–2.54(m,2H),2.53–2.39(m,8H),2.30(dd,J=13.4,4.6Hz,2H),1.99(s,3H),1.93(s,3H),1.77(s,3H),1.68(s,3H),1.65(s,3H),1.52(s,3H),1.50(s,3H),1.41(s,3H),1.29(s,3H).
ESI-MS：802[M+H]
+.
Embodiment 6:S-54's is synthetic
In the 50ml reaction flask, add 500mg S-31(0.73mmol), 154mg EDCI(0.8mmol), 108mg HOBT(0.8mmol) and, 94mg(0.8mmol) N, the anhydrous CH of N-diethylethanolamine and 10ml
2Cl
2, stir 4h under the normal temperature condition, show with the TCL detection to react completely, pour 30mlCH into
2Cl
2, with saturated NaCl solution washing 20mL * 5 times, with the extraction liquid evaporate to dryness, use silica gel column chromatography then, the elutriant condition is CH
2Cl
2: CH
3OH=96:4 obtains 488mg S-54(yield 85%).
S-54:
1H?NMR(CDCl
3)δ(ppm):12.85(s,1H),7.50(d,J=6.8Hz,1H),5.99(t,J=6.7Hz,1H),4.29(s,1H),4.02–3.88(m,2H),3.45(s,1H),2.95(d,J=6.9Hz,2H),2.42-2.72(m,10H),2.30(dd,J=13.4,3.8Hz,1H),1.99(s,3H),1.93(s,3H),1.77(s,3H),1.67(s,3H),1.65(s,3H),1.52(s,3H),1.50(s,3H),1.41(s,3H),1.29(s,3H),1.00(t,J=7.0Hz,6H).
ESI-MS：788[M+H]
+.
Embodiment 7:S-55's is synthetic
In the 50ml reaction flask, add 500mg S-31(0.73mmol), 154mg EDCI(0.8mmol), 108mg HOBT(0.8mmol) and, 100mg(0.8mmol) N-(3-aminopropyl) imidazoles and the anhydrous CH of 10ml
2Cl
2, stir 4h under the normal temperature condition, show with the TCL detection to react completely, pour 30mlCH2Cl2 into, with saturated NaCl solution washing 20mL * 5 times, with the extraction liquid evaporate to dryness, use silica gel column chromatography then, the elutriant condition is CH2Cl2:CH3OH=96:4, obtains 494mg S-55(yield 85%).
S-55:
1H?NMR(CDCl
3)δ(ppm):12.89(s,1H),7.56(s,1H),7.53(d,J=6.6Hz,1H),7.08-6.98(m,3H,),5.19(t,J=8.8Hz,1H),4.32(s,1H),4.12-3.98(m,2H),3.48(s,1H),3.43-3.16(m,2H,),2.72-2.36(m,6H),2.32(dd,1H),1.97(s,3H),1.94(s,3H),1.79(s,3H),1.75(s,3H),1.66(s,3H),1.51(s,3H),1.49(s,3H),1.43(s,3H),1.28(s,3H).
ESI-MS：796[M+H]
+。.
Embodiment 8:S-59's is synthetic
In the 50ml reaction flask, add 500mg S-31(0.73mmol), 154mg EDCI(0.8mmol), 108mg HOBT(0.8mmol) and, 104mg(0.8mmol) the anhydrous CH of N-hydroxyethyl piperazine and 10ml
2Cl
2, stir 4h under the normal temperature condition, show with the TCL detection to react completely, pour 30mlCH into
2Cl
2, with saturated NaCl solution washing 20mL * 5 times, with the extraction liquid evaporate to dryness, use silica gel column chromatography then, the elutriant condition is CH
2Cl
2: CH
3OH=95:5 obtains 467mg S-59(yield 80%).
S-59:
1H?NMR(CDCl
3)δ(ppm):12.89(s,1H),7.51(d,J=6.8Hz,1H),5.45(s,1H),4.31(s,1H,),3.68(m,1H),3.67-3.58(m,2H),3.41(d,J=4.4Hz,2H),3.35-3.19(m,2H),2.76-2.14(m,13H),1.99(s,3H),1.94(s,3H),1.75(s,6H),1.66(s,3H),1.52(s,3H),1.51(s,3H),1.42(s,3H),1.26(s,3H).
ESI-MS：801[M+H]
+。
Embodiment 9:S-61's is synthetic
In the 50ml reaction flask, add 500mg S-31(0.73mmol), 154mg EDCI(0.8mmol), 108mg HOBT(0.8mmol) and, 80mg(0.8mmol) the anhydrous CH of methylpiperazine and 10ml
2Cl
2, stir 4h under the normal temperature condition, show with the TCL detection to react completely, pour 30mlCH into
2Cl
2, with saturated NaCl solution washing 20mL * 5 times, with the extraction liquid evaporate to dryness, use silica gel column chromatography then, the elutriant condition is CH
2Cl
2: CH
3OH=96:4 obtains 477mg S-61(yield 85%).
S-61:
1H?NMR(CDCl
3)δ(ppm):12.89(s,1H),7.50(d,J=6.6Hz,1H),5.44(s,1H),4.31(s,1H,),3.7-3.6(m,1H),3.46-3.17(m,4H),2.75-2.25(m,11H),2.29(s,3H),1.98(s,3H),1.93(s,3H),1.84(s,3H),1.74(s,3H),1.65(s,3H),1.52(s,3H),1.51(s,3H),1.41(s,3H),1.25(s,3H).
ESI-MS：771[M+H]
+。
Embodiment 10:S-63's is synthetic
Compound S-61(0.389mmol), the anhydrous THF of 3ml morpholine and 10ml stirs 1h under the room temperature condition to add 300mg in the 50ml reaction flask, shows with the TCL detection to react completely, and pours 30mlCH into
2Cl
2, with saturated NaCl solution washing 20mL * 5 times, anhydrous Na
2SO
4Drying with the extraction liquid evaporate to dryness, obtains compound S-63 crude product, uses silica gel (200-300 order) column chromatography then, and the elutriant condition is CH
2Cl
2: CH
3OH=96:4 obtains compound S-63 307mg(yield 92%).
S-63:
1H?NMR(CDCl
3)δ(ppm):12.07(s,1H),5.92(t,J=6.2Hz,1H),4.33(s,1H),3.61(brs,4H,),3.37-3.55(m,4H),3.27(d,J=13.1Hz,2H),2.80-2.33(m,13H),2.29(s,3H),2.01(s,3H),1.95(s,3H),1.88(s,3H),1.69(s,3H),1.55(s,3H),1.53(s,3H),1.40(s,3H),1.38(s,3H),1.12(s,3H)。
ESI-MS：858[M+H]
+。
Embodiment 11: the anti tumor activity in vitro testing experiment
1. experimental cell strain:
This experiment adopts tumor cell line system to be respectively: the A549(human lung carcinoma cell), the HCT116(human colon cancer cell), the MDA-MB-231(human breast cancer cell) (by Shanghai Institute of Pharmaceutical Industry pharmacological evaluation chamber frozen and go down to posterity).
2. sample preparation:
Use DMSO(Merck) after the dissolving, add PBS (-) and be made into the solution of 1000 μ g/ml or suspension uniformly, then with PBS (-) dilution that contains DMSO.Positive control drug is morellic acid.
3. test method
Mtt assay: it is 4～5 * 10 that the every hole of 96 orifice plates adds concentration
4The cell suspension 100 μ l of individual/ml put 37 ℃, 5%CO
2In the incubator.Behind the 24h, add sample liquid, two multiple holes are established in 10 μ l/ holes, and 37 ℃, 5%CO
2Effect 72h.Every hole adds the MTT solution 20 μ l of 5mg/ml, adds lysate behind the effect 4h, and put in the incubator in 100 μ l/ holes, and 570nm OD value is measured with the full-automatic microplate reader of MK-2 in the dissolving back.(anti tumor activity in vitro sees Table 2)
Table 2. sample segment is to the in-vitro multiplication restraining effect of human body tumour cell
As known from Table 2, most morellic acid rearrangement products of the present invention and derivative are better than morellic acid to the restraining effect of 3 kinds of human body tumour cells, have shown its broad-spectrum anti-tumor activity.Document shows that morellic acid also has better antitumor activity to cancer of the stomach, liver cancer, cervical cancer and carcinoma of the pancreas, and therefore, gambogic acid derivative of the present invention also has active preferably to these tumours.Especially it is worthy of note that compound of the present invention can also be by salify and then improved significantly that it is water-soluble, this helps to improve the bioavailability of this compounds.Everything shows that all compound of the present invention has the excellent development prospect.
To sum up, gambogic acid derivative of the present invention has broad-spectrum anti-tumor activity, and particularly part of compounds has stronger anti-tumor activity to lung cancer, colorectal carcinoma and mammary cancer, has good exploitation and is worth.Gambogic acid derivative of the present invention is representing a class mechanism of action uniqueness, the brand-new compound of structure, and this is for furtheing investigate and developing new antitumor drug and opened up new approach and direction.
Claims (10)
1. gambogic acid derivative, this derivative is suc as formula shown in I, II or the III:
Wherein, R
1For hydrogen or nitrogen heterocyclic ring or-(CH
2)
mR
3, wherein m is 1-8, R
3Be nitrogen heterocyclic ring or NR
4R
5Described R
4, R
5Independently be selected from the straight chain of hydrogen, C1-8 and the alkyl of side chain separately, perhaps described R
4, R
5Cheng Huan;
R
2Be hydrogen, alicyclic ring or nitrogen heterocyclic ring;
X is O or NH independently, or and R
1Constitute nitrogen heterocyclic ring together.
2. gambogic acid derivative according to claim 1, it is characterized in that: the straight chain of described C1-8 and the alkyl of side chain contain one or more substituting groups, and described substituting group is selected from hydrogen, C1-5 alkyl, C2-5 thiazolinyl, C2-5 alkynyl, C1-5 alkoxyl group, halogen, nitro, cyano group, hydroxyl, amino, carboxyl, oxo.
3. gambogic acid derivative according to claim 1 is characterized in that: R
1M be 2-4; R
2Be selected from pentamethylene base, cyclohexyl, morpholinyl, piperazinyl, N methyl piperazine base, piperidyl.
4. gambogic acid derivative according to claim 1 is characterized in that: described gambogic acid derivative is specially a kind of in the following formula:
5. as the preparation method of the described gambogic acid derivative of claim 1-4, comprising:
(1) morellic acid is dissolved in the acetic acid, strong protonic acid in adding then, morellic acid is reset under middle strong protonic acid catalysis, obtains compound S-31 and S-34;
(2) with S-31 and R
1XH or its salt react, and form the compound shown in the formula (I); Or with S-34 and R
1XH or its salt react, and form the compound shown in the formula (II);
(3) with the compound shown in the formula (I) with contain corresponding substituent reagent react and obtain the described compound of formula (III).
6. the preparation method of gambogic acid derivative according to claim 5, it is characterized in that: the middle strong protonic acid described in the step (1) is selected from sulfuric acid, methylsulfonic acid, tosic acid, hydrochloric acid; The reaction conditions of step (1) is under the microwave condition under 60-80 ℃ or the normal pressure 60-100 ℃.
7. the preparation method of gambogic acid derivative according to claim 5 is characterized in that: in the step (2) with S-31 or S-34 under base catalysis with R
1The hydroxy halogeno product reaction of OH obtains corresponding ester; Described alkali is NaOH, KOH, K
2CO
3, Na
2CO
3, NaHCO
3, Cs
2CO
3In a kind of.
8. the preparation method of gambogic acid derivative according to claim 5 is characterized in that: in the step (2) with S-31 or S-34 by condensation catalytic reagent and alcohol or the corresponding ester of amine prepared in reaction or acid amides; Described condensation reagent is N, N '-carbonyl dimidazoles, triphenylphosphine, azoformic acid diisopropyl ester, 1-hydroxy benzo triazole, N-hydroxyl-7-azepine benzotriazole, 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride, phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkane, 4-Dimethylamino pyridine or dicyclohexylcarbodiimide, O-benzotriazole-N, N, N ', a kind of in N '-tetramethyl-urea Tetrafluoroboric acid, the Vinyl chloroformate.
9. the preparation method of gambogic acid derivative according to claim 5, it is characterized in that: the corresponding substituent reagent that contains described in the step (3) is morpholine.
10. as the application of the described gambogic acid derivative of claim 1-4 in preparation antitumour drug, antifungal drug or anti-angiogenic medicaments.
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| CN107648217A (en) * | 2017-09-29 | 2018-02-02 | 中国农业科学院哈尔滨兽医研究所 | Neo-garcinolic acid or derivatives thereof is being prepared for preventing and/or treating by the purposes in the medicine of bacterial relevant disease |
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