CN103601641B - Glaucocalyxin A derivative and in the application of preparing in antineoplastic - Google Patents

Glaucocalyxin A derivative and in the application of preparing in antineoplastic Download PDF

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CN103601641B
CN103601641B CN201310535621.5A CN201310535621A CN103601641B CN 103601641 B CN103601641 B CN 103601641B CN 201310535621 A CN201310535621 A CN 201310535621A CN 103601641 B CN103601641 B CN 103601641B
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glaucocalyxin
cinnamyl
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derivative
butyl
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CN103601641A (en
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金永生
刘洪川
陈海生
赵卫权
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Second Military Medical University SMMU
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Abstract

The present invention relates to medical technical field. The invention provides a class and have the glaucocalyxin A derivative shown in general formula I, compound of the present invention is tested through anticancer experiment in vitro, and result shows that glaucocalyxin A derivative of the present invention all has obvious antitumor action, can be used for preparing antineoplastic.

Description

Glaucocalyxin A derivative and in the application of preparing in antineoplastic
Technical field
The present invention relates to medical technical field, be specifically related to glaucocalyxin A derivative and in the application of preparing in antineoplastic.
Background technology
Rabdosia plant is China's widely used herbal medicine among the people, they mostly have clearing heat and detoxicating, activate blood circulation and disperse blood clots, anti-inflammation, the effect such as antitumor. Glaucocalyxin A is an isolated kaurene Diterpenes natural organic-compound from Labiatae Rabdosia plant.
Existing result of study show glaucocalyxin A to lung cancer, intestinal cancer, leukaemia etc. have antitumor action (referring to document Gaoet.al., Toxicol.inVitro, 2011,25:51-36; Chinese patent CN200910044882.0, denomination of invention is " in rabdosia japonica, diterpene-kind compound is in the application of preparing in cancer therapy drug ", application publication number: CN101455652).
Separately there is Chinese patent CN200910048554.8(denomination of invention for " glaucocalyxin A derivative, preparation method and its usage ", application publication number: CN101851273A) disclose taking glaucocalyxin A as parent, on its hydroxyl, introduce polypeptide chain structure, to lung cancer A549 cell, Mice Bearing Lewis Lung Cancer has activity.
Also have disclosure of the invention one class glaucocalyxin A aliphatic ester derivatives gastric carcinoma cells AGS, human esophagus cancer cell strain Eca-109, human liver cancer cell SMMC-7721, lung cell A549, KB tumour cell, cervical cancer cell Hela, human colon cancer cell SW480 are had to activity (referring to Chinese patent CN200910056458.8, denomination of invention is " derivative of fatty acid of glaucocalyxin A and its preparation method and application ", application publication number: CN101993359A; Chinese patent CN200910056457.3, denomination of invention is " glaucocalyxin A acid ester derivant and its preparation method and application ", application publication number: CN101993370A).
Separately there is invention to introduce benzene sulfonyl group at hydroxyl inhibited (referring to Chinese patent CN200910056459.2 to lung cell A549, human liver cancer cell SMMC-7721, breast cancer cell MCF-7, human esophagus cancer cell strain Eca-109, human oral cavity epithelial tumour KB cell, cervical cancer cell Hela, colon cancer cell SW480, denomination of invention is " chlorinated glaucocalyxin A derivative and its preparation method and application ", application publication number: CN101993373A); Separately there is structure that invention introduced forulic acid to have and suppress active etc. (referring to Chinese patent CN200910056456.9 gastric carcinoma cells AGS, human liver cancer cell SMMC-7721, lung cell A549, people kidney-A498 cell, human colon cancer cell SW480, denomination of invention is " ferulic acid derivative of glaucocalyxin A and its preparation method and application ", application publication number: CN102260173A). More than disclose the thing of chemical combination, all do not report about antileukemie effect.
Separately there is Chinese patent application CN201210015481.4 to disclose a class and obtain acetal or ketal with the hydroxyl reaction of 7 and 14 of aldehydes or ketones and glaucocalyxin A, and disclose these compounds to human chorionic cancer cell JEG-3, people's liver cancer HepG2 tumour cell, people's lung cancer A549 cell, human oral cavity epithelial tumour KB cell, human leukaemia K562 and HL-60 cell. (referring to, denomination of invention is " a kind of glaucocalyxin A derivative and its preparation method and application ", application publication number: CN102584780A).
Visible glaucocalyxin A and glaucocalyxin A derivative are the focuses of new drug development.
Summary of the invention
The object of the present invention is to provide the glaucocalyxin A derivative that a class is new, another object of the present invention is to provide the application of this compounds in the medicine of preparation prevention or treatment cancer.
The invention provides a class glaucocalyxin A derivative, its chemical constitution is as shown in general formula I:
Wherein, R1、R2Be respectively one and represent that mono-of H is selected from following group, or R1、R2All be selected from following group:
(A) to fluoro benzoyl, to chlorobenzene formacyl, to benzoyl bromide, to iodobenzene formoxyl, between fluoro benzoyl, a chlorobenzene formacyl, a benzoyl bromide, an iodobenzene formoxyl, to methoxybenzoyl base, to ethoxybenzene formoxyl, to propoxyl group benzoyl, to butyl phenyl ether formoxyl;
(B) cinnamyl, 4 '-fluorine cinnamyl, 4 '-chlorine cinnamyl, 4 '-bromine cinnamyl, 4 '-iodine cinnamyl, 3 ', 4 '-difluoro cinnamyl, 3 ', 4 '-dichloro cinnamyl, 3 ', 4 '-dibromo cinnamyl, 3 ', 4 '-dichloro cinnamyl, 3 ', 4 '-diiodo-cinnamyl;
(C) p-nitrophenyl acetyl group;
（D）–COCH2CH2-R3, wherein R3Representative replaces acetyl group, propiono, bytyry, valeryl; To methoxybenzoyl base, to ethoxybenzene formoxyl, to propoxyl group benzoyl, to butyl phenyl ether formoxyl, meta-methoxy benzoyl, m-oxethyl benzoyl, between propoxyl group benzoyl, a butyl phenyl ether formoxyl, 3 ', 4 '-dimethoxy benzoyl, 3 ', 4 '-diethoxy benzoyl, 3 ', 4 '-dipropoxy benzoyl, 3 ', 4 '-dibutoxy benzoyl;
（E）
（F）Its R4Represent methylidene, ethyl, propyl group, isopropyl, butyl, sec-butyl, the tert-butyl group, isobutyl group, phenyl, benzyl;
(G) acetyl group, propiono, bytyry.
Above-mentioned glaucocalyxin A derivative, preferred, being combined as of R1 and R2 is as follows:
Work as R1During for H, R2Be selected from:
(A) to fluoro benzoyl, to chlorobenzene formacyl, to fluoro benzoyl, to chlorobenzene formacyl, to benzoyl bromide, to iodobenzene formoxyl;
（B）
（C）Its R4Represent methylidene, ethyl, propyl group, isopropyl, butyl, sec-butyl, the tert-butyl group, isobutyl group, phenyl, benzyl;
（D）–COCH2CH2-R3, wherein R3Representative replaces acetyl group, propiono, bytyry, valeryl; To methoxybenzoyl base, to ethoxybenzene formoxyl, to propoxyl group benzoyl, to butyl phenyl ether formoxyl, meta-methoxy benzoyl, m-oxethyl benzoyl, between propoxyl group benzoyl, a butyl phenyl ether formoxyl, 3 ', 4 '-dimethoxy benzoyl, 3 ', 4 '-diethoxy benzoyl, 3 ', 4 '-dipropoxy benzoyl, 3 ', 4 '-dibutoxy benzoyl;
(E) p-nitrophenyl acetyl group;
Work as R2During for H, R1Be selected from:
(A) to fluoro benzoyl, to chlorobenzene formacyl, to fluoro benzoyl, to chlorobenzene formacyl, to benzoyl bromide, to iodobenzene formoxyl;
(B) cinnamyl, 3 ', 4 '-difluoro cinnamyl, 3 ', 4 '-dichloro cinnamyl, 3 ', 4 '-dibromo cinnamyl, 3 ', 4 '-dichloro cinnamyl, 3 ', 4 '-diiodo-cinnamyl;
（C）Its R4Represent methylidene, ethyl, propyl group, isopropyl, butyl, sec-butyl, the tert-butyl group, isobutyl group;
（D）
（E）–COCH2CH2-R3, wherein R3Representative replaces acetyl group, propiono, bytyry, valeryl;
(F) p-nitrophenyl acetyl group;
Have in the compound shown in above-mentioned general formula I, preferred compound is:
RA01:7-is to fluorobenzoyl glaucocalyxin A;
RA02:14-is to fluorobenzoyl glaucocalyxin A
RA03:7-is to chlorobenzoyl glaucocalyxin A;
RA04:14-is to chlorobenzoyl glaucocalyxin A;
Iodobenzene formyl glaucocalyxin A between RA05:14-;
Iodobenzene formyl glaucocalyxin A between RA06:7-;
RA07:14-(3 ', 4 '-dichloro cinnamyl) glaucocalyxin A;
RA08:14-cinnamyl glaucocalyxin A;
RA09:7,14-bis-(2-((5-phenyl-1,3,4-oxadiazole-2-yl) sulphur) acetyl) glaucocalyxin A;
RA10:7-(-Boc-phenylalanyl) glaucocalyxin A;
RA11:7-(Boc-valyl base) glaucocalyxin A;
RA12:14-(Boc-valyl base) glaucocalyxin A;
RA13:7-(4-(3,4-Dimethoxyphenyl)-4-oxygen-bytyry) glaucocalyxin A;
RA14:14-(4-oxygen valeryl) glaucocalyxin A;
RA15:7-(4-oxygen valeryl) glaucocalyxin A;
RA16:7-(p-nitrophenyl acetyl group) glaucocalyxin A;
RA17:14-(p-nitrophenyl acetyl group) glaucocalyxin A;
RA18:7,14-diacetyl glaucocalyxin A.
The present invention also provides the synthetic route of compound of Formula I as follows:
Glaucocalyxin A and various acid are joined in dry carrene, and stirring and dissolving under room temperature, then adds a certain amount of p-N, N-lutidines, and N, N'-dicyclohexylcarbodiimide (DCC) and triethylamine or pyridine, continue to stir 6～12h. Then remove by filter insoluble matter, filtrate is revolved and is steamed except desolventizing, and remaining solid silica gel column chromatography separates (chloroform: methyl alcohol=100:1～20:1) or thin layer preparation, obtains the compound of general formula I of the present invention.
After RA18 adopts glaucocalyxin A to react under 60 degree with chloroacetic chloride, silica gel column chromatography separates and obtains.
Derivative disclosed in this invention adopts mtt assay to measure the human lung adenocarcinoma cell to A549(); HCT116(people's colon-cancer cell); CCRF-CEM(human leukemia cell); HL-60(human leukemia cell) antitumor activity. Result shows that test-compound all has good antitumor activity.
The present invention above-mentioned glaucocalyxin A derivative is also provided and in pharmacology acceptable salt or hydrate in the application of preparing aspect antineoplastic or health products.
The present invention above-mentioned glaucocalyxin A derivative is also provided and in pharmacology acceptable salt or hydrate in the application of preparation treatment leukemia medicament.
Acceptable salt or hydrate in compound of the present invention and pharmacology thereof, also have significant effect at aspects such as reducing blood lipid, norcholesterol, treatment and prevention of arterial sclerosis, can be applicable to treat medicine or the health products of cancer or above-mentioned disease.
Detailed description of the invention
Now in conjunction with the embodiments, the present invention is described in detail, but enforcement of the present invention is not limited only to this.
Agents useful for same of the present invention and raw material all commercially available obtaining maybe can be prepared by literature method. The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition, or the condition of advising according to manufacturer.
The preparation of embodiment 1:7-to fluorobenzoyl glaucocalyxin A (RA01)
Glaucocalyxin A 70mg and parafluorobenzoic acid 103mg are joined in dry carrene, add a small amount of p-N under stirring at room temperature, N-lutidines, then adds DCC152.2mg and triethylamine 0.5ml or pyridine 0.5ml, stirs 6～12h. Then remove by filter insoluble matter, filtrate is revolved and is steamed except desolventizing, and remaining solid silica gel column chromatography separates (chloroform: methyl alcohol=100:1～20:1) or thin layer preparation, obtains the compound of RA01.
Yield 42%.1H-NMR(δ,ppm)：5.45(1H,s,H-17α)，6.16(1H,s,H-17β)，5.61(1H,dd,J=12.0,3.5Hz,H-7)，4.93(1H,s,H-14)，3.71(1H,s,H-13)7.06(2H,m,H-23,H-27),7.84(2H,m,H-24,H-26)。13C-NMR(δ,ppm)：39.0(C-1),34.4(C-2),217.3(C-3),47.6(C-4),52.2(C-5),27.5(C-6),75.3(C-7),62.4(C-8),54.4(C-9),39.9(C-10),19.0(C-11),32.0(C-12),46.7(C-13),77.6(C-14),205.5(C-15),147.3(C-16),119.8(C-17),29.0(C-18),21.7(C-19),19.6(C-20),167.92(C-21),126.8(C-22),133.0(C-23),117.0(C-24),165.0(C-25),116.8(C-26),132.9(C-27)。MS：M+Na+=477.4，M+Cl-=489.4。
The preparation of embodiment 2:14-to fluorobenzoyl glaucocalyxin A (RA02)
Preparation method is with embodiment 1.
Yield 51%.1H-NMR(δ,ppm)：5.45(1H,s,H-17α)，6.17(1H,s,H-17β)，4.22(1H,dd,J=12.0,3.0Hz,H-7)，6.24(1H,s,H-14)，3.23(1H,s,H-13),7.06(2H,m,H-23,H-27),7.90(2H,m,H-24,H-26)。13C-NMR(δ,ppm)：39.1(C-1),34.6(C-2),217.6(C-3),47.8(C-4),53.0(C-5),29.7(C-6),73.8(C-7),63.0(C-8),55.3(C-9),40.0(C-10),19.0(C-11),33.0(C-12),45.4(C-13),77.5(C-14),207.0(C-15),147.0(C-16),119.1(C-17),28.7(C-18),22.0(C-19),19.5(C-20),167.8(C-21),127.4(C-22),133.2(C-23),116.5(C-24),166.1(C-25),116.7(C-26),133.2(C-27)。MS：M+Na+=477.3，M+Cl-=489.2。
The preparation of embodiment 3:7-to chlorobenzoyl glaucocalyxin A (RA03)
Preparation method is with embodiment 1, and wherein acid adopts parachlorobenzoic-acid.
Yield 42%.1H-NMR(δ,ppm)：5.46(1H,s,H-17α)，6.18(1H,s,H-17β)，5.64(1H,dd,J=12.0,3.5Hz,H-7)，4.94(1H,s,H-14)，3.22(1H,s,H-13),7.38(2H,m,H-23,H-27),7.78(2H,m,H-24,H-26)。13C-NMR(δ,ppm)：39.0(C-1),34.4(C-2),217.2(C-3),47.6(C-4),52.2(C-5),27.5(C-6),75.3(C-7),62.4(C-8),54.4(C-9),39.9(C-10),19.0(C-11),32.0(C-12),46.7(C-13),77.8(C-14),205.4(C-15),147.3(C-16),119.8(C-17),29.0(C-18),21.7(C-19),19.6(C-20),165.1(C-21),129.0(C-22),130.0(C-23),131.8(C-24),140.9(C-25),131.8(C-26),130.0(C-27)。MS：M+Na+=493.3，M+Cl-=505.2。
The preparation of embodiment 4:14-to chlorobenzoyl glaucocalyxin A (RA04)
Preparation method is with embodiment 3.
Yield 46%.1H-NMR(δ,ppm)：5.48(1H,s,H-17α)，6.20(1H,s,H-17β)，4.22(1H,dd,J=12.5,3.5Hz,H-7)，6.26(1H,s,H-14)，3.25(1H,s,H-13),7.38(2H,m,H-23,H-27),7.84(2H,m,H-24,H-26)。13C-NMR(δ,ppm)：39.1(C-1),34.6(C-2),217.6(C-3),47.8(C-4),53.0(C-5),29.7(C-6),73.8(C-7),63.0(C-8),55.3(C-9),40.0(C-10),19.0(C-11),33.0(C-12),45.4(C-13),77.6(C-14),207.0(C-15),147.0(C-16),119.1(C-17),28.9(C-18),22.0(C-19),19.5(C-20),166.2(C-21),129.6(C-22),132.0(C-23),129.8(C-24),140.6(C-25),129.8(C-26),132.2(C-27)。MS：M+Na+=493.4，M+Cl-=505.3。
The preparation of iodobenzene formyl glaucocalyxin A (RA05) between embodiment 5:14-
Preparation method is with embodiment 1, and wherein acid adopts 4-Iodobenzoic acid.
Yield 32%.1H-NMR(δ,ppm)：5.48(1H,s,H-17α)，6.18(1H,s,H-17β)，4.21(1H,dd,J=10.5,3.5Hz,H-7)，6.26(1H,s,H-14)，3.23(1H,s,H-13),8.22(1H,m,H-23),7.83(2H,m,H-25,H-27),7.10(1H,m,H-26)。13C-NMR(δ,ppm)：39.1(C-1),34.6(C-2),217.6(C-3),47.8(C-4),53.0(C-5),29.5(C-6),73.7(C-7),63.1(C-8),55.3(C-9),40.0(C-10),18.9(C-11),33.0(C-12),45.4(C-13),77.6(C-14),207.0(C-15),146.9(C-16),119.2(C-17),28.6(C-18),22.0(C-19),19.5(C-20),165.7(C-21),133.1(C-22),139.4(C-23),94.8(C-24),142.9(C-25),129.7(C-26),131.1(C-27)。MS：M+Na+=585.3。
The preparation of iodobenzene formyl glaucocalyxin A (RA06) between embodiment 6:7-
Preparation method is with embodiment 5.
Yield 30%.1H-NMR(δ,ppm)：5.44(1H,s,H-17α)，6.16(1H,s,H-17β)，5.64(1H,dd,J=12.0,3.6Hz,H-7)，4.92(1H,s,H-14)，3.20(1H,s,H-13),8.21(1H,m,H-23),7.72(2H,m,H-25)，7.12(1H，m，H-26)，7.85(1H，m，H-27)。13C-NMR(δ,ppm)：37.5(C-1),32.9(C-2),215.7(C-3),46.1(C-4),50.7(C-5),26.0(C-6),73.8(C-7),60.9(C-8),52.9(C-9),38.4(C-10),17.5(C-11),30.4(C-12),45.2(C-13),76.2(C-14),203.8(C-15),145.8(C-16),118.3(C-17),27.4(C-18),20.2(C-19),18.0(C-20),163.0(C-21),131.0(C-22),138.0(C-23),93.5(C-24),141.7(C-25),128.7(C-26),129.7(C-27)。MS：M+Na+=585.3，M+Cl-=597.2。
Embodiment 7:14-(3 ', 4 '-dichloro cinnamyl) preparation of glaucocalyxin A (RA07)
Preparation method is with embodiment 1, and wherein acid adopts 3 ', 4 '-dichloro cinnamic acid.
Yield 35%.1H-NMR(δ,ppm)：5.44(1H,s,H-17α)，6.21(1H,s,H-17β)，4.19(1H,dd,J=12.0,3.5Hz,H-7)，6.06(1H,s,H-14)，3.18(1H,s,H-13),6.32(1H,d,J=16.0Hz,H-22),7.50(1H,d,J=16.0Hz,H-23),7.55(1H,d,J=2.0Hz,H-25),7.41(1H,d,J=8.0Hz,H-28),7.28(1H,dd,J=13.5,3.5Hz,H-29)。13C-NMR(δ,ppm)：39.1(C-1),34.6(C-2),217.7(C-3),47.8(C-4),52.9(C-5),29.7(C-6),73.8(C-7),62.9(C-8),55.3(C-9),40.0(C-10),18.9(C-11),33.0(C-12),45.3(C-13),77.4(C-14),206.9(C-15),146.9(C-16),119.1(C-17),28.6(C-18),21.9(C-19),19.5(C-20),166.7(C-21),120.7(C-22),143.7(C-23),135.4(C-24),128.1(C-25),134.2(C-26),135.2(C-27),131.9(C-28),130.7(C-29)。MS：M+Na+=553.3，M+Cl-=565.2。
The preparation of embodiment 8:14-cinnamyl glaucocalyxin A (RA08)
Preparation method is with embodiment 7.
Yield 31%.1H-NMR(δ,ppm)：5.45(1H,s,H-17α)，6.23(1H,s,H-17β)，4.21(1H,m,H-7)，6.07(1H,s,H-14)，3.22(1H,s,H-13),6.35(1H,d,J=16.0Hz,H-22),7.63(1H,d,J=16.0Hz,H-23),7.48(2H,m,H-25,H-29),7.36(3H,m,H-26,H-27,H-28)。13C-NMR(δ,ppm)：39.1(C-1),34.6(C-2),217.6(C-3),47.8(C-4),53.0(C-5),30.0(C-6),73.9(C-7),62.7(C-8),55.4(C-9),40.0(C-10),19.0(C-11),33.0(C-12),45.4(C-13),77.6(C-14),206.9(C-15),147.0(C-16),119.1(C-17),28.7(C-18),21.9(C-19),19.5(C-20),167.2(C-21),118.5(C-22),146.8(C-23),135.1(C-24),129.2(C-25),129.9(C-26),131.6(C-27),129.9(C-28),129.2(C-29)。MS：M+Na+=485.4，M+Cl-=497.4
Embodiment 9:7, the preparation of 14-bis-(2-((5-phenyl-1,3,4-oxadiazole-2-yl) sulphur) acetyl) glaucocalyxin A (RA09)
Preparation method is with embodiment 1, and wherein acid changes 2-((5-phenyl-1,3,4-oxadiazole-2-yl) sulphur) acetic acid into.
Yield 33%.1H-NMR(δ,ppm)：5.37(1H,s,H-17α)，6.05(1H,s,H-17β)，5.37(1H,dd,J=11.0,4.5Hz,H-7)，6.06(1H,s,H-14)，3.17(1H,s,H-13),4.24(4H,m,H-2’,H-2’’),7.95(4H,m,H-6’,10’,6’’,10’’),7.47(6H,m,H-7’,8’,9’,7’’,8’’,9’’)。13C-NMR(δ,ppm)：37.9(C-1),33.4(C-2),216.3(C-3),46.7(C-4),51.6(C-5),25.5(C-6),76.0(C-7),60.8(C-8),54.7(C-9),39.0(C-10),17.8(C-11),32.1(C-12),44.2(C-13),76.9(C-14),202.8(C-15),144.8(C-16),118.8(C-17),27.8(C-18),20.8(C-19),18.6(C-20),167.3(C-1’),34.6(C-2’),123.4(C-3’),166.9(C-4’),126.7(C-5’),126.7(C-6’),129.0(C-7’),131.8(C-8’),129.0(C-9’),126.7(C-10’)167.3(C-1’’),33.6(C-2’’),123.4(C-3’’),166.9(C-4’’),126.7(C-5’’),126.7(C-6’’),129.0(C-7’’),131.7(C-8’’),129.0(C-9’’),126.7(C-10’’)。MS：M+H+=769.0
Embodiment 10:7-(Boc-phenylalanyl) preparation of glaucocalyxin A (RA10)
Preparation method is with embodiment 1, and wherein acid changes Boc-phenylalanine into.
Yield 32%.1H-NMR(δ,ppm)：5.41(1H,s,H-17α)，6.14(1H,s,H-17β)，5.38(1H,dd,J=12.0,3.6Hz,H-7)，4.67(1H,s,H-14)，3.10(1H,s,H-13),4.28(1H,dd,J=13.8,7.2Hz,H-2’),4.97(2H,d,J=7.2Hz，H3’x2),7.15(3H,m,H-5’,7’,9’),7.30(2H,m,H-6’,8’,NH)。13C-NMR(δ,ppm)：37.4(C-1),32.8(C-2),215.6(C-3),46.0(C-4),50.5(C-5),25.6(C-6),72.1(C-7),60.5(C-8),52.7(C-9),38.2(C-10),17.4(C-11),30.3(C-12),45.1(C-13),75.8(C-14),203.7(C-15),146.0(C-16),118.1(C-17),27.3(C-18),20.2(C-19),17.9(C-20),169.3(C-1’),49.2(C-2’),37.5(C-3’),135.3(C-4’),128.9(C-5’),128.2(C-6’),126.7(C-7’),128.7(C-8’),128.7(C-9’),157.6(C-1’’)76.0(C-2’’),27.7(C-3’’),27.7(C-4’’),27.7(C-5’’)。MS：M+Na+=602.5,M+Cl-=614.3
Embodiment 11:7-(Boc-valyl base) preparation of glaucocalyxin A (RA11)
Preparation method is with embodiment 1, and wherein acid changes Boc-valine into.
Yield 31%.1H-NMR(δ,ppm)：5.42(1H,s,H-17α)，6.09(1H,s,H-17β)，5.36(1H,dd,J=12.0,3.6Hz,H-7)，4.80(1H,s,H-14)，3.10(1H,brs,H-13),3.42(1H,m,H-2’),3.30(1H,s,H-3’),7.56(1H,s,NH)。13C-NMR(δ,ppm)：37.3(C-1),32.9(C-2),217.5(C-3),46.0(C-4),50.5(C-5),29.9(C-6),73.2(C-7),60.8(C-8),53.0(C-9),38.3(C-10),17.3(C-11),30.4(C-12),45.4(C-13),75.0(C-14),204.9(C-15),146.3(C-16),117.6(C-17),29.9(C-18),19.8(C-19),17.9(C-20),169.7(C-1’),59.6(C-2’),26.8(C-3’),17.6(C-4’),17.2(C-5’),157.9(C-1’’)79.3(C-2’’),27.3(C-3’’),27.3(C-4’’),27.3(C-5’’)。MS：M+Na+=554.5,M+Cl-=566.3 embodiment 12:14-(Boc-valyl bases) preparation of glaucocalyxin A (RA12)
Preparation method is with embodiment 11.
Yield 30%.1H-NMR(δ,ppm)：5.38(1H,s,H-17α)，6.12(1H,s,H-17β)，3.75(1H,d,J=6.0Hz,H-7)，6.00(1H,s,H-14)，3.04(1H,brs,H-13),3.31(1H,m,H-2’),3.30(1H,m,H-3’),7.41(1H,s,NH)。13C-NMR(δ,ppm)：37.4(C-1),33.0(C-2),217.8(C-3),46.2(C-4),51.5(C-5),28.2(C-6),71.8(C-7),61.1(C-8),53.9(C-9),38.3(C-10),17.3(C-11),32.9(C-12),44.1(C-13),75.9(C-14),205.4(C-15),145.6(C-16),117.1(C-17),29.4(C-18),20.0(C-19),17.5(C-20),172.1(C-1’),59.2(C-2’),27.1(C-3’),17.8(C-4’),18.1(C-5’),156.2(C-1’’)79.7(C-2’’),27.5(C-3’’),27.5(C-4’’),27.5(C-5’’)。MS：M+Na+=554.2,M+Cl-=566.0
Embodiment 13:7-(4-(3,4-Dimethoxyphenyl)-4-oxygen-bytyry) preparation of glaucocalyxin A (RA13)
Preparation method is with embodiment 1, and wherein 4-(3,4-Dimethoxyphenyl)-4-oxygen-butyric acid is changed in acid.
Yield 51%.1H-NMR(δ,ppm)：5.41(1H,s,H-17α)，6.14(1H,s,H-17β)，5.42(1H,dd,J=12.0,4.2Hz,H-7),4.82(1H,s,H-14)，3.14(1H,brs,H-13),7.49(1H,m,H-26),7.18(1H,m,H-29),7.58(1H,m,H-30)。13C-NMR(δ,ppm)：37.5(C-1),32.9(C-2),215.9(C-3),49.0(C-4),50.6(C-5),28.0(C-6),73.6(C-7),60.6(C-8),52.7(C-9),38.3(C-10),17.5(C-11),32.3(C-12),45.1(C-13),75.4(C-14),204.2(C-15),146.1(C-16),118.0(C-17),27.3(C-18),20.2(C-19),17.5(C-20),170.2(C-21),25.8(C-22)30.3(C-23),195.7(C-24),148.5(C-25),114.9(C-26),153.0(C-27),155.8(C-28),122.3(C-29),129.0(C-30),55.5(OCH3),55.6(OCH3’)。MS：M+Na+=574.7
Embodiment 14:14-(4-oxygen valeryl) preparation of glaucocalyxin A (RA14)
Preparation method is with embodiment 1, and wherein acid changes 4-oxy pentanoic acid into.
Yield 29%.1H-NMR(δ,ppm)：5.42(1H,s,H-17α)，6.18(1H,s,H-17β)，4.17(1H,dd,J=10.2,4.8Hz,H-7),5.96(1H,s,H-14)，3.11(1H,brs,H-13)。13C-NMR(δ,ppm)：37.6(C-1),33.1(C-2),216.1(C-3),46.3(C-4),51.5(C-5),28.1(C-6),72.2(C-7),61.3(C-8),53.8(C-9),38.4(C-10),17.4(C-11),31.5(C-12),43.7(C-13),75.5(C-14),206.4(C-15),145.5(C-16),117.4(C-17),27.1(C-18),20.4(C-19),17.4(C-20),171.7(C-21),27.5(C-22),37.4(C-23),205.4(C-24),29.2(C-25)。MS：M+Na+=453.4,M+Cl-=465.3
Embodiment 15:7-(4-oxygen valeryl) preparation of glaucocalyxin A (RA15)
Preparation method is with embodiment 14.
Yield 32%.1H-NMR(δ,ppm)：5.43(1H,s,H-17α)，6.16(1H,s,H-17β)，5.38(1H,dd,J=12.0,3.6Hz,H-7),4.82(1H,s,H-14)，3.15(1H,brs,H-13)。13C-NMR(δ,ppm)：37.5(C-1),32.9(C-2),215.8(C-3),46.1(C-4),50.6(C-5),27.9(C-6),73.6(C-7),60.6(C-8),52.7(C-9),38.3(C-10),17.5(C-11),31.5(C-12),45.1(C-13),75.4(C-14),205.7(C-15),146.1(C-16),118.0(C-17),27.5(C-18),20.2(C-19),17.9(C-20),169.9(C-21),25.8(C-22),37.3(C-23),204.1(C-24),28.7(C-25)。MS：M+Na+=453.4,M+Cl-=465.3
Embodiment 16:7-(p-nitrophenyl acetyl group) preparation of glaucocalyxin A (RA16)
Preparation method is with embodiment 1, wherein sour paranitrophenylacetic acid.
Yield 26%.1H-NMR(δ,ppm)：5.40(1H,s,H-17α)，6.11(1H,s,H-17β)，5.41(1H,dd,J=12.0,3.6Hz,H-7),4.74(1H,s,H-14)，3.08(1H,brs,H-13),3.70(2H,s,H-22),7.39(2H,m,H-24,H-28),8.16(2H,m,H-25,H-27)。13C-NMR(δ,ppm)：37.4(C-1),32.8(C-2),215.5(C-3),46.0(C-4),50.7(C-5),27.7(C-6),73.5(C-7),60.6(C-8),52.8(C-9),38.5(C-10),17.4(C-11),30.2(C-12),45.1(C-13),75.7(C-14),203.9(C-15),145.9(C-16),118.1(C-17),27.4(C-18),20.2(C-19),17.9(C-20),167.4(C-21),40.6(C-22)139.7(C-23),129.7(C-24),123.5(C-25),145.3(C-26),123.5(C-27),129.7(C-28)。MS：M+Na+=518.4,M+Cl-=530.1
Embodiment 17:14-(p-nitrophenyl acetyl group) preparation of glaucocalyxin A (RA17)
Preparation method is with embodiment 16.
Yield 31%.1H-NMR(δ,ppm)：5.41(1H,s,H-17α)，6.18(1H,s,H-17β)，4.20(1H,dd,J=12.0,3.6Hz,H-7),6.00(1H,s,H-14)，3.20(1H,brs,H-13),3.70(2H,s,H-22),7.40(2H,m,H-24,H-28),8.16(2H,m,H-25,H-27)。13C-NMR(δ,ppm)：37.4(C-1),32.8(C-2),215.5(C-3),46.0(C-4),50.7(C-5),25.8(C-6),73.5(C-7),60.6(C-8),52.8(C-9),38.3(C-10),17.4(C-11),30.2(C-12),45.1(C-13),76.3(C-14),203.9(C-15),145.9(C-16),118.1(C-17),27.4(C-18),20.2(C-19),17.9(C-20),167.4(C-21),40.6(C-22)139.7(C-23),129.7(C-24),123.5(C-25),145.3(C-26),123.5(C-27),129.7(C-28)。MS：M+Na+=518.4
Embodiment 18:7, the preparation of 14-diacetyl glaucocalyxin A (RA18)
Glaucocalyxin A 80mg, DMAP10mg, pyridine 10ml, newly steams chloroacetic chloride 0.5ml, under nitrogen protection, reacts 8h in 60 degree. Then reactant liquor is poured in 200ml water, and is acidified to neutrality with watery hydrochloric acid, then use chloroform extraction. Extract Na2SO4After dry, remove by filter, then revolve steaming and obtain solid. Preparative TLC separates (chloroform: methyl alcohol 40:1) and obtains target compound. Yield 30%.
1H-NMR(δ,ppm)：5.48(1H,s,H-17α)，6.09(1H,s,H-17β)，5.20(1H,dd,J=12.0,3.5Hz,H-7),6.02(1H,s,H-14)，3.14(1H,brs,H-13)。13C-NMR(δ,ppm)：39.4(C-1),35.2(C-2),219.9(C-3),48.4(C-4),53.2(C-5),27.3(C-6),75.9(C-7),63.1(C-8),56.7(C-9),40.9(C-10),19.5(C-11),33.9(C-12),46.3(C-13),76.8(C-14),206.1(C-15),148.3(C-16),118.9(C-17),28.7(C-18),22.1(C-19),19.6(C-20),173.0(C-1’),22.0(C-2’),172.3(C-1’’),22.0(C-2’’)。MS：M+Na+=439.3，M+Cl-=451.1
The preparation of embodiment 19:14-butyryl glaucocalyxin A (RA19)
By glaucocalyxin A 80mg, DMAP10mg, pyridine 10ml, newly steams butyl chloride 0.5ml, under nitrogen protection, reacts 6h. Then reactant liquor is poured in 200ml water, and is acidified to neutrality with watery hydrochloric acid, then use chloroform extraction. Extract Na2SO4After dry, remove by filter, then revolve steaming and obtain solid. Preparative TLC separates (chloroform: methyl alcohol 50:1) and obtains the preparation of target compound employing said method, yield 25%. MS:M+Na+=425.2
Embodiment 20: glaucocalyxin A 7,14-condensing benzaldehyde (RA20)
Adopt the disclosed method preparation of patent documentation CN102584780A. MS:M+Na+=443.5
Embodiment 21: glaucocalyxin A 7,14-condensing benzaldehyde (RA20) acetal (RA21)
Adopt the disclosed method preparation of patent documentation CN102584780A. M+Na+=381.0
Embodiment 22: the preparation of glaucocalyxin A (GA)
Bibliography " CHINA JOURNAL OF CHINESE MATERIA MEDICA ", the disclosed method preparation of 25 (2000) 678-679.
Embodiment 23: antitumor activity test
Glaucocalyxin A derivative of the present invention (RA1-RA18), and reference examples RA19, RA20, RA21 and GA, adopt and carried out with the following method the human lung adenocarcinoma cell to A549(); HCT116(people's colon-cancer cell); CCRF-CEM(human leukemia cell); HL-60(human leukemia cell) anti-tumor experiment. It is 4-10 × 10 that the 96 every holes of orifice plate add concentration4The cell suspension 100 μ l of individual/ml, put 37 DEG C, 5%CO2In incubator. After 24h, add sample liquid, 10 μ l/ holes, establish two multiple holes, and 37 DEG C, 5%CO2Effect 72h. Every hole adds the MTT solution 20 μ l of 5mg/ml, after effect 4h, adds lysate, and 100 μ l/ holes, put in incubator, after dissolving, surveys 570nmOD value with the long multi-functional ELIASA of all-wave. Pharmacological evaluation concrete outcome all test-compounds as shown in table 1 have all shown good antitumor action, and compound R A01～RA09, RA12～18 couple leukaemia CCRF and HL-60 have shown good inhibitory action.
The in-vitro multiplication inhibitory action of table 1 glaucocalyxin A derivative human body tumour cell
Below the preferred embodiment of the invention is illustrated, but the invention is not limited to described embodiment, those of ordinary skill in the art also can make all modification being equal to or replacement under the prerequisite without prejudice to the invention spirit, and the modification that these are equal to or replacement are all included in the application's claim limited range.

Claims (7)

  1. One class glaucocalyxin A derivative and in pharmacology acceptable salt, its chemical constitution is as shown in general formula I:
    Wherein, R1、R2Be respectively one and represent that mono-of H is selected from following group, or R1、R2All be selected from following group:
    (A) to fluoro benzoyl, to chlorobenzene formacyl, to benzoyl bromide, to iodobenzene formoxyl, between fluoro benzoyl, between chlorobenzene formacyl, a benzoyl bromide, an iodobenzene formoxyl, to methoxybenzoyl base, to ethoxybenzene formoxyl, to propoxyl group benzoyl, to butyl phenyl ether formoxyl;
    (B) cinnamyl, 4 '-fluorine cinnamyl, 4 '-chlorine cinnamyl, 4 '-bromine cinnamyl, 4 '-iodine cinnamyl, 3 ', 4 '-difluoro cinnamyl, 3 ', 4 '-dichloro cinnamyl, 3 ', 4 '-dibromo cinnamyl, 3 ', 4 '-diiodo-cinnamyl;
    (C) p-nitrophenyl acetyl group;
    Its R4Represent methylidene, ethyl, propyl group, isopropyl, butyl, sec-butyl, the tert-butyl group, isobutyl group, phenyl, benzyl.
  2. According to the class glaucocalyxin A derivative shown in claim 1 and in pharmacology acceptable salt, it is characterized in that, being combined as of R1 and R2 is as follows:
    Work as R1During for H, R2Be selected from:
    (A) to fluoro benzoyl, to chlorobenzene formacyl, to benzoyl bromide, to iodobenzene formoxyl;
    Its R4Represent methylidene, ethyl, propyl group, isopropyl, butyl, sec-butyl, the tert-butyl group, isobutyl group, phenyl, benzyl;
    (D) p-nitrophenyl acetyl group;
    Work as R2During for H, R1Be selected from:
    (A) to fluoro benzoyl, to chlorobenzene formacyl, to benzoyl bromide, to iodobenzene formoxyl;
    (B) cinnamyl, 3 ', 4 '-difluoro cinnamyl, 3 ', 4 '-dichloro cinnamyl, 3 ', 4 '-dibromo cinnamyl, 3 ', 4 '-diiodo-cinnamyl;
    Its R4Represent methylidene, ethyl, propyl group, isopropyl, butyl, sec-butyl, the tert-butyl group, isobutyl group;
    (E) p-nitrophenyl acetyl group.
  3. According to the class glaucocalyxin A derivative shown in claim 1 and in pharmacology acceptable salt, it is characterized in that, described glaucocalyxin A derivative is:
    7-is to fluorobenzoyl glaucocalyxin A;
    14-is to fluorobenzoyl glaucocalyxin A
    7-is to chlorobenzoyl glaucocalyxin A;
    14-is to chlorobenzoyl glaucocalyxin A;
    Iodobenzene formyl glaucocalyxin A between 14-;
    Iodobenzene formyl glaucocalyxin A between 7-;
    14-(3 ', 4 '-dichloro cinnamyl) glaucocalyxin A;
    14-cinnamyl glaucocalyxin A;
    7,14-bis-(2-((5-phenyl-1,3,4-oxadiazole-2-yl) sulphur) acetyl) glaucocalyxin A;
    7-(Boc-amphetamine acyl group) glaucocalyxin A;
    7-(Boc-valyl base) glaucocalyxin A;
    14-(Boc-valyl base) glaucocalyxin A;
    7-(p-nitrophenyl acetyl group) glaucocalyxin A, or
    14-(p-nitrophenyl acetyl group) glaucocalyxin A.
  4. One class glaucocalyxin A derivative and in pharmacology acceptable salt,, it is characterized in that, described glaucocalyxin A derivative is:
    14-(4-oxygen valeryl) glaucocalyxin A, or
    7-(4-oxygen valeryl) glaucocalyxin A.
  5. A class glaucocalyxin A derivative as shown in claim 1 to 4 is arbitrary and in pharmacology acceptable salt in the application of preparing in antineoplastic or health products.
  6. 6. the class glaucocalyxin A derivative as shown in claim 1 to 4 is arbitrary and the application of acceptable salt in preparation treatment leukemia medicament in pharmacology thereof.
  7. 7. a class glaucocalyxin A derivative and the application of acceptable salt in preparation treatment leukemia medicament in pharmacology thereof; described glaucocalyxin A derivative is 7-(4-(3; 4-Dimethoxyphenyl)-4-oxygen-bytyry) glaucocalyxin A or 7,14-diacetyl glaucocalyxin A.
CN201310535621.5A 2013-11-01 2013-11-01 Glaucocalyxin A derivative and in the application of preparing in antineoplastic Expired - Fee Related CN103601641B (en)

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JP6694894B2 (en) * 2015-03-26 2020-05-20 蘇州滬雲腫瘤研究中心股▲ふん▼有限公司Ｓｕｚｈｏｕ Ｐｈａｒｍａｖａｎ Ｃａｎｃｅｒ Ｒｅｓｅａｒｃｈ Ｃｅｎｔｅｒ Ｃｏ．， Ｌｔｄ． Glococalixin A derivative, its preparation method and application
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CN111187278A (en) * 2020-01-16 2020-05-22 新乡医学院 Glaucocalyxin A small molecular probe and preparation method and application thereof
CN111187279A (en) * 2020-01-16 2020-05-22 新乡医学院 Glaucocalyxin A-biotin small molecular probe and preparation method and application thereof
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