CN103601641A - Glaucocalyxin derivatives and application thereof in preparation of antitumor drugs - Google Patents

Glaucocalyxin derivatives and application thereof in preparation of antitumor drugs Download PDF

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CN103601641A
CN103601641A CN201310535621.5A CN201310535621A CN103601641A CN 103601641 A CN103601641 A CN 103601641A CN 201310535621 A CN201310535621 A CN 201310535621A CN 103601641 A CN103601641 A CN 103601641A
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glaucocalyxin
benzoyl
cinnamyl
butyl
formyl radical
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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 invention relates to the technical field of medicines. The invention provides a class of glaucocalyxin derivatives shown as a general formula I, in-vitro antitumor experiments show that the glaucocalyxin derivatives have obvious antitumor effects, and can be used for the preparation of antitumor drugs.

Description

Glaucocalyxin A derivative and the application in preparing antitumor drug thereof
Technical field
The present invention relates to medical technical field, be specifically related to glaucocalyxin A derivative and the application in preparing antitumor drug thereof.
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, antisepsis and 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, leukemia etc. have antitumor action (referring to document Gao et.al., Toxicol.in Vitro, 2011,25:51-36; Chinese patent CN200910044882.0, denomination of invention is " application of diterpene-kind compound in preparing cancer therapy drug in rabdosia japonica ", 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 and take glaucocalyxin A as parent, on its hydroxyl, introduced 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 cells 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 structure is as shown in general formula I:
Wherein, R 1, R 2be respectively one and represent that mono-of H is selected from following group, or R 1, R 2all be selected from following group:
(A) to fluoro benzoyl, to chlorobenzene formacyl, to benzoyl bromide, to iodobenzene formyl radical, between fluoro benzoyl, a chlorobenzene formacyl, a benzoyl bromide, an iodobenzene formyl radical, to anisoyl, to phenetole formyl radical, to propoxy-benzoyl, to butyl phenyl ether formyl radical;
(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 ethanoyl;
() – COCH D 2cH 2-R 3, R wherein 3representative replaces ethanoyl, propionyl, butyryl radicals, pentanoyl; To anisoyl, to phenetole formyl radical, to propoxy-benzoyl, to butyl phenyl ether formyl radical, meta-methoxy benzoyl, m-oxethyl benzoyl, between propoxy-benzoyl, a butyl phenyl ether formyl radical, 3 ', 4 '-dimethoxy benzoyl, 3 ', 4 '-diethoxy benzoyl, 3 ', 4 '-dipropoxy benzoyl, 3 ', 4 '-dibutoxy benzoyl;
（E）
(F)
Figure BDA0000406745130000032
its R 4represent methylidene, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, isobutyl-, phenyl, phenmethyl;
(G) ethanoyl, propionyl, butyryl radicals.
Above-mentioned glaucocalyxin A derivative, preferred, being combined as of R1 and R2 is as follows:
Work as R 1during for H, R 2be selected from:
(A) to fluoro benzoyl, to chlorobenzene formacyl, to fluoro benzoyl, to chlorobenzene formacyl, to benzoyl bromide, to iodobenzene formyl radical;
（B）
Figure BDA0000406745130000033
(C)
Figure BDA0000406745130000034
its R 4represent methylidene, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, isobutyl-, phenyl, phenmethyl;
() – COCH D 2cH 2-R 3, R wherein 3representative replaces ethanoyl, propionyl, butyryl radicals, pentanoyl; To anisoyl, to phenetole formyl radical, to propoxy-benzoyl, to butyl phenyl ether formyl radical, meta-methoxy benzoyl, m-oxethyl benzoyl, between propoxy-benzoyl, a butyl phenyl ether formyl radical, 3 ', 4 '-dimethoxy benzoyl, 3 ', 4 '-diethoxy benzoyl, 3 ', 4 '-dipropoxy benzoyl, 3 ', 4 '-dibutoxy benzoyl;
(E) p-nitrophenyl ethanoyl;
Work as R 2during for H, R 1be selected from:
(A) to fluoro benzoyl, to chlorobenzene formacyl, to fluoro benzoyl, to chlorobenzene formacyl, to benzoyl bromide, to iodobenzene formyl radical;
(B) cinnamyl, 3 ', 4 '-difluoro cinnamyl, 3 ', 4 '-dichloro cinnamyl, 3 ', 4 '-dibromo cinnamyl, 3 ', 4 '-dichloro cinnamyl, 3 ', 4 '-diiodo-cinnamyl;
(C)
Figure BDA0000406745130000041
its R 4represent methylidene, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, isobutyl-;
（D）
Figure BDA0000406745130000042
() – COCH E 2cH 2-R 3, R wherein 3representative replaces ethanoyl, propionyl, butyryl radicals, pentanoyl;
(F) p-nitrophenyl ethanoyl;
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-is valyl) glaucocalyxin A;
RA12:14-(Boc-is valyl) glaucocalyxin A;
RA13:7-(4-(3,4-Dimethoxyphenyl)-4-oxygen-butyryl radicals) glaucocalyxin A;
RA14:14-(4-oxygen pentanoyl) glaucocalyxin A;
RA15:7-(4-oxygen pentanoyl) glaucocalyxin A;
RA16:7-(p-nitrophenyl ethanoyl) glaucocalyxin A;
RA17:14-(p-nitrophenyl ethanoyl) glaucocalyxin A;
RA18:7,14-diacetyl glaucocalyxin A.
The present invention also provides the synthetic route of compound of Formula I as follows:
Figure BDA0000406745130000051
Glaucocalyxin A and various acid are joined in dry methylene dichloride, and stirring and dissolving under room temperature, then adds a certain amount of p-N, N-lutidine, and N, N'-dicyclohexylcarbodiimide (DCC) and triethylamine or pyridine, continue to stir 6～12h.Methyl alcohol=100:1～20:1) or thin layer preparation then remove by filter insolubles, filtrate is revolved and is steamed except desolventizing, the separated (chloroform:, obtain the compound of general formula I of the present invention of remaining solid silica gel column chromatography.
After RA18 adopts glaucocalyxin A to react under 60 degree with Acetyl Chloride 98Min., silica gel column chromatography separation 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) anti-tumor activity.Result shows that test-compound all has good anti-tumor 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 antitumor drug or healthcare 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-fat, decreasing cholesterol, treatment and prevention of arterial sclerosis, can be applicable to treat medicine or the healthcare products of cancer or above-mentioned disease.
Embodiment
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)
Figure BDA0000406745130000052
Glaucocalyxin A 70mg and parafluorobenzoic acid 103mg are joined in dry methylene dichloride, add a small amount of p-N under stirring at room, N-lutidine, then adds DCC152.2mg and triethylamine 0.5ml or pyridine 0.5ml, stirs 6～12h.Methyl alcohol=100:1～20:1) or thin layer preparation then remove by filter insolubles, filtrate is revolved and is steamed except desolventizing, the separated (chloroform:, obtain the compound of RA01 of remaining solid silica gel column chromatography.
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)
Figure BDA0000406745130000062
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)
Figure BDA0000406745130000071
Preparation method is with embodiment 1, and wherein acid adopts Chlorodracylic 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)
Figure BDA0000406745130000072
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-
Figure BDA0000406745130000081
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-
Figure BDA0000406745130000082
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)
Figure BDA0000406745130000091
Preparation method is with embodiment 1, and wherein acid adopts 3 ', 4 '-dichloro TRANSCINNAMIC 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)
Figure BDA0000406745130000101
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)
Figure BDA0000406745130000102
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-is valyl) preparation of glaucocalyxin A (RA11)
Preparation method is with embodiment 1, and wherein acid changes Boc-α-amino-isovaleric acid 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-are valyl) preparation of glaucocalyxin A (RA12)
Figure BDA0000406745130000112
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-butyryl radicals) preparation of glaucocalyxin A (RA13)
Figure BDA0000406745130000121
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 pentanoyl) preparation of glaucocalyxin A (RA14)
Figure BDA0000406745130000122
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 pentanoyl) 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 ethanoyl) preparation of glaucocalyxin A (RA16)
Figure BDA0000406745130000132
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 ethanoyl) preparation of glaucocalyxin A (RA17)
Figure BDA0000406745130000141
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)
Figure BDA0000406745130000142
Glaucocalyxin A 80mg, DMAP10mg, pyridine 10ml, newly steams Acetyl Chloride 98Min. 0.5ml, under nitrogen protection, in 60 degree, reacts 8h.Then reaction solution is poured in 200ml water, and is acidified to neutrality with dilute hydrochloric acid, then use chloroform extraction.Extraction liquid Na 2sO 4after dry, remove by filter, then revolve steaming and obtain solid.Separated (the chloroform: methyl alcohol 40:1) obtain target compound of Preparative TLC.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)
Figure BDA0000406745130000151
By glaucocalyxin A 80mg, DMAP10mg, pyridine 10ml, newly steams butyryl chloride 0.5ml, under nitrogen protection, reacts 6h.Then reaction solution is poured in 200ml water, and is acidified to neutrality with dilute hydrochloric acid, then use chloroform extraction.Extraction liquid Na 2sO 4after dry, remove by filter, then revolve steaming and obtain solid.Separated (the chloroform: methyl alcohol 50:1) obtain target compound and adopt aforesaid method preparation, yield 25% of Preparative TLC.MS：M+Na +=425.2
Embodiment 20: glaucocalyxin A 7,14-condensing benzaldehyde (RA20)
Figure BDA0000406745130000152
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)
Figure BDA0000406745130000153
Adopt the disclosed method preparation of patent documentation CN102584780A.M+Na +=381.0
Embodiment 22: the preparation of glaucocalyxin A (GA)
Reference < < CHINA JOURNAL OF CHINESE MATERIA MEDICA > >, the disclosed method preparation of 25 (2000) 678-679.
Embodiment 23: anti-tumor 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 concentration 4the cell suspension 100 μ l of individual/ml, put 37 ℃, 5%CO 2in incubator.After 24h, add sample liquid, 10 μ l/ holes, establish two multiple holes, and 37 ℃, 5%CO 2effect 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, by the long multi-functional microplate reader of all-wave, surveys 570nm OD value.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 leukemia cell CCRF and HL-60 have shown good restraining effect.
The in-vitro multiplication restraining effect of table 1 glaucocalyxin A derivative human body tumour cell
Figure BDA0000406745130000161
Figure BDA0000406745130000171
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 (5)

  1. One class glaucocalyxin A derivative and in pharmacology acceptable salt or hydrate, its chemical structure is as shown in general formula I:
    Figure FDA0000406745120000011
    Wherein, R 1, R 2be respectively one and represent that mono-of H is selected from following group, or R 1, R 2all be selected from following group:
    (A) to fluoro benzoyl, to chlorobenzene formacyl, to benzoyl bromide, to iodobenzene formyl radical, between fluoro benzoyl, a chlorobenzene formacyl, a benzoyl bromide, an iodobenzene formyl radical, to anisoyl, to phenetole formyl radical, to propoxy-benzoyl, to butyl phenyl ether formyl radical;
    (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 ethanoyl;
    () – COCH D 2cH 2-R 3, R wherein 3representative replaces ethanoyl, propionyl, butyryl radicals, pentanoyl; To anisoyl, to phenetole formyl radical, to propoxy-benzoyl, to butyl phenyl ether formyl radical, meta-methoxy benzoyl, m-oxethyl benzoyl, between propoxy-benzoyl, a butyl phenyl ether formyl radical, 3 ', 4 '-dimethoxy benzoyl, 3 ', 4 '-diethoxy benzoyl, 3 ', 4 '-dipropoxy benzoyl, 3 ', 4 '-dibutoxy benzoyl;
    （E）
    Figure FDA0000406745120000012
    (F) its R 4represent methylidene, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, isobutyl-, phenyl, phenmethyl;
    (G) ethanoyl, propionyl, butyryl radicals.
  2. According to the class glaucocalyxin A derivative shown in claim 1 and in pharmacology acceptable salt or hydrate, it is characterized in that, being combined as of R1 and R2 is as follows:
    Work as R 1during for H, R 2be selected from:
    (A) to fluoro benzoyl, to chlorobenzene formacyl, to fluoro benzoyl, to chlorobenzene formacyl, to benzoyl bromide, to iodobenzene formyl radical;
    （B）
    Figure FDA0000406745120000021
    (C)
    Figure FDA0000406745120000022
    its R 4represent methylidene, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, isobutyl-, phenyl, phenmethyl;
    () – COCH D 2cH 2-R 3, R wherein 3representative replaces ethanoyl, propionyl, butyryl radicals, pentanoyl; To anisoyl, to phenetole formyl radical, to propoxy-benzoyl, to butyl phenyl ether formyl radical, meta-methoxy benzoyl, m-oxethyl benzoyl, between propoxy-benzoyl, a butyl phenyl ether formyl radical, 3 ', 4 '-dimethoxy benzoyl, 3 ', 4 '-diethoxy benzoyl, 3 ', 4 '-dipropoxy benzoyl, 3 ', 4 '-dibutoxy benzoyl;
    (E) p-nitrophenyl ethanoyl;
    Work as R 2during for H, R 1be selected from:
    (A) to fluoro benzoyl, to chlorobenzene formacyl, to fluoro benzoyl, to chlorobenzene formacyl, to benzoyl bromide, to iodobenzene formyl radical;
    (B) cinnamyl, 3 ', 4 '-difluoro cinnamyl, 3 ', 4 '-dichloro cinnamyl, 3 ', 4 '-dibromo cinnamyl, 3 ', 4 '-dichloro cinnamyl, 3 ', 4 '-diiodo-cinnamyl;
    (C)
    Figure FDA0000406745120000023
    its R 4represent methylidene, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, isobutyl-;
    （D）
    Figure FDA0000406745120000024
    () – COCH E 2cH 2-R 3, R wherein 3representative replaces ethanoyl, propionyl, butyryl radicals, pentanoyl;
    (F) p-nitrophenyl ethanoyl.
  3. According to the class glaucocalyxin A derivative shown in claim 1 and in pharmacology acceptable salt or hydrate, 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-phenylalanyl) glaucocalyxin A;
    7-(Boc-is valyl) glaucocalyxin A;
    14-(Boc-is valyl) glaucocalyxin A;
    7-(4-(3,4-Dimethoxyphenyl)-4-oxygen-butyryl radicals) glaucocalyxin A;
    14-(4-oxygen pentanoyl) glaucocalyxin A;
    7-(4-oxygen pentanoyl) glaucocalyxin A;
    7-(p-nitrophenyl ethanoyl) glaucocalyxin A;
    14-(p-nitrophenyl ethanoyl) glaucocalyxin A, or
    7,14-diacetyl glaucocalyxin A.
  4. 4. the class glaucocalyxin A derivative as shown in claim 1 and acceptable salt or the application of hydrate in preparing antitumor drug or healthcare products in pharmacology thereof.
  5. 5. the class glaucocalyxin A derivative as shown in claim 1 and acceptable salt or the application of hydrate in preparation treatment leukemia medicament in pharmacology thereof.
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CN105153060A (en) * 2015-07-10 2015-12-16 南京大学 Shikonin carboxylate derivatives, and synthetic method and application thereof
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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
CN114028368A (en) * 2021-11-30 2022-02-11 南京基树医药科技有限公司 RhoC covalent binding inhibitor
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CN110063949A (en) * 2019-05-14 2019-07-30 大连理工大学 Common rabdosia leaf B prime is preparing the purposes in the drug for treating lung cancer
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
CN111187278A (en) * 2020-01-16 2020-05-22 新乡医学院 Glaucocalyxin A small molecular probe and preparation method and application thereof
CN114028368A (en) * 2021-11-30 2022-02-11 南京基树医药科技有限公司 RhoC covalent binding inhibitor
US11905263B1 (en) 2023-10-13 2024-02-20 King Faisal University 4-nitro-N′-(2-(5-phenyl-1,3,4-oxadiazol-2-ylthio)acetoxy)benzimidamide as an antimicrobial compound
US11932632B1 (en) 2023-10-13 2024-03-19 King Faisal University N'-(2-(5-phenyl-1,3,4-oxadiazol-2-ylthio)acetoxy)benzo[d][1,3]dioxole-5 carboximidamide as an antimicrobial compound

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