CN106496171A - There is multi-ring many isopentene group phloroglucinol derivatives compounds, its preparation method and the application of anti-tumor activity - Google Patents

There is multi-ring many isopentene group phloroglucinol derivatives compounds, its preparation method and the application of anti-tumor activity Download PDF

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CN106496171A
CN106496171A CN201610914347.6A CN201610914347A CN106496171A CN 106496171 A CN106496171 A CN 106496171A CN 201610914347 A CN201610914347 A CN 201610914347A CN 106496171 A CN106496171 A CN 106496171A
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methanol
ethyl acetate
volume ratio
tumor activity
performance liquid
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CN106496171B (en
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苑春茂
郝小江
田东松
顾玮
黄烈军
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Key Laboratory of Natural Product Chemistry of Guizhou Academy of Sciences
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/79—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/835—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups having unsaturation outside an aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/18—Bridged systems

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Abstract

The invention discloses a kind of multi-ring many isopentene group phloroglucinol derivatives compounds with anti-tumor activity, its preparation method and application, its general structure is as follows：Belong to pharmaceutical technology field, dry from Fructus Garciniae oblongifoliae extract in branch and leaf isolated.The had anti tumor activity in vitro of the present invention, extraction separation method are simple, and raw material holds acquisition.

Description

There is multi-ring many isopentene group phloroglucinol derivatives compounds, its system of anti-tumor activity Preparation Method and application
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of multi-ring many isopentene group isophthalic with anti-tumor activity Three phenolic compounds, while be related to the preparation side of multi-ring many isopentene group phloroglucinol derivatives compounds with anti-tumor activity Method, and preparing human leukemia HL-60 cell's strain, SMMC-7721 cell line, human lung cancer A-549 cell strain, people's mammary gland Application in cancer MCF-7 cell strain and human colon carcinoma SW480 cell strain inhibitor.
Background technology
Natural multi-ring many isopentene group phloroglucinol derivatives compounds（polycyclic polyprenylated Acylphloroglucinols, abbreviation PPAPs）It is that a class is natural with multiple isopentene group phase heterozygosis by acyl phloroglucinol Product, this kind of compound have a complicated core texture such as rare bridged ring in natural product, volution or even diamantane (obsolete), and often Carry multiple isopentene group substituent groups.The constituents are also the exclusive characteristic constituents of Garcinia maingayii.Report at present Natural PPAPs classes compound about 300 or so, there is rare bridged ring in Secondary metabolites, volution and gold more The complexity such as firm alkane, the core skeleton of rigidity.As its structure is novel, biological activity is unique, extensively concerned in the world in recent years, For example, Xanthochymol (xanthochymol) and guttiferone (guttiferone E) have cell toxicant and suppress tubulin Activity, nemorosone has an activity of AntiHIV1 RT activity, and there is hyperforine (hyperforin) antidepressant and antitumor to live Property, garsubellin A have activity of anti-senile dementia etc..It is worth noting that the gamlogic acid extracted in Resina garciniae is opened National class anti-cancer agent (gamlogic acid injection) is sent out into, currently the second stage of clinical research, this is also caused from Guttiferae Finding PPAPs series antineoplastic medicaments becomes a study hotspot.Main source of the Garcinia maingayii as the constituents（Account for The 70% of PPAPs classes source）, that taken as own duty becomes the emphasis plant for finding such compound.
Fructus Garciniae oblongifoliae is Guttiferae（Guttiferae）Garcinia（Garcinia）Plant.About 450 kinds of the platymiscium, heat production band Asia, Africa south and Polynesia are western.China has 21 kinds, product South Taiwan, Fujian, Guangdong, Hainan, south Guangxi, South of Yunnan, the west and south to western part, Southeastern Tibet, South of Guizhou and the Hunan west and south [Chinese Plants will].Fructus Garciniae oblongifoliae is in the people Between for anti-inflammatory analgetic, control burn, scald, eczema, stomatitis, dyspepsia etc..
Content of the invention
It is an object of the invention to the one kind for overcoming disadvantages mentioned above and providing has anti tumor activity in vitro, separation side is extracted Method is simple, and raw material holds the multi-ring many isopentene group phloroglucinol derivatives compounds with anti-tumor activity for obtaining.
Another object of the present invention is to providing multi-ring many isopentene group phloroglucinol derivatives with anti-tumor activity The preparation method of compound.
It is still another object of the present invention to provide multi-ring many isopentene group phloroglucinol derivatives of anti-tumor activity should be had Compound is preparing human leukemia HL-60 cell's strain, SMMC-7721 cell line, human lung cancer A-549 cell strain, people's mammary gland Application in cancer MCF-7 cell strain and human colon carcinoma SW480 cell strain inhibitor.
The purpose of the present invention and solve its technical problem underlying and employ the following technical solutions to realize：
Multi-ring many isopentene group phloroglucinol derivatives compounds with anti-tumor activity of the present invention, its general structure are as follows：
Wherein:
R1, R2Can be identical or different, each independent group is hydrogen（–H）, hydroxyl（–OH）Or R1R2=oxygen bridge（–O–）
R3, R4Can be identical or different, each independent group is hydrogen（–H）, hydroxyl（–OH）Or R3R4=oxygen bridge（–O–）
R5For 2- hydroxy propanes（–CH OH (CH3)2）Or carbonyl（–CO–）Or acrylic（）R6, R7, R8It can be phase Same or different, each independent group is hydrogen（–H）, or R6R7=double bond（）Or R7R8=double bond（）.
The above-mentioned multi-ring many isopentene group phloroglucinol derivatives compounds with anti-tumor activity, preferably particular compound are such as Under：
A kind of preparation method of the multi-ring many isopentene group phloroglucinol derivatives compounds with anti-tumor activity of the present invention, including Following steps：
（1）Take Fructus Garciniae oblongifoliae and dry branch and leaf, after adopting 95% industrial methanol in the case where temperature is for 70 DEG C -80 DEG C to its reflux, extract, 3-5 time Reclaim methanol and be concentrated to give extractum, extractum is miscible into muddy thing with water, through ethyl acetate equal-volume extraction, is concentrated to give ethyl acetate Layer extractum；
（2）Ethyl acetate layer extractum adopts chloroform with ethyl acetate volume ratio for 60 through 300-400 mesh silica gel column chromatographies:1～ 0:The eluent gradient eluting of 1 ratio, point lamellae merge into 4 parts：Fr 1 、Fr 2、 Fr 3、 Fr 4；
（3）Silica gel column chromatography is carried out again to Fr in step 22, adopts chloroform with ethyl acetate volume ratio for 40:1～1:1 ratio The eluent gradient eluting of example, is again divided into 4 sub-parts：Fr 2a 、Fr 2b 、Fr 2c、Fr 2d；Fr 2b are through excessively stream Dynamic Sephadex LH-20 gel filtration chromatographies mutually for methanol, and compound 1 is obtained through more than half preparative high-performance liquid chromatographic purification, 2 and 3, the wherein mobile phase of half preparative high-performance liquid chromatographic is methanol:Water volume ratio is 88:12.
（4）Silica gel column chromatography is carried out to Fr in step 23, adopts chloroform with ethyl acetate volume ratio for 40:1～1:1 ratio The eluent gradient eluting of example, is again divided into, 5 sub-parts：Fr 3a, Fr 3b, Fr 3c, Fr 3d, Fr 3e, Fr 3d is through the Sephadex LH-20 gel filtration chromatographies that mobile phase is methanol, and obtains through more than half preparative high-performance liquid chromatographic purification Compound 4 and 5, the wherein mobile phase of half preparative high-performance liquid chromatographic are methanol:Water volume ratio is 78:22.
（5）Silica gel column chromatography is carried out to Fr in step 24, adopts chloroform with ethyl acetate volume ratio for 20:1～1:1 ratio The eluent gradient eluting of example, is again divided into 3 sub-parts：Fr 4a, Fr 4b, Fr 4c, Fr 4c through mobile phase are The Sephadex LH-20 gel filtration chromatographies of methanol, and compound 6 is obtained through more than half preparative high-performance liquid chromatographic purification, wherein half The mobile phase of preparative high-performance liquid chromatographic is methanol:Water volume ratio is 73:27.
Multi-ring many isopentene group phloroglucinol derivatives compounds with anti-tumor activity of the present invention are preparing human leukemia HL-60 cell strains, SMMC-7721 cell line, human lung cancer A-549 cell strain, MCF-7 Human Breast Cancer Cells strain and people's knot Application in intestinal cancer SW480 cell strain inhibitor.The present invention compared with prior art, with obvious beneficial effect, more than Technical scheme understands：The preparation method of the present invention includes that methanol extraction, extractum are concentrated, silica gel column chromatography, gradient elution, gel column Chromatography, half preparative high-performance liquid chromatographic purification, extraction separation method are simple, and its raw material for adopting easily is obtained in a large number.Using MTT It is thin to human leukemia HL-60 that method tests isolated multi-ring many isopentene group phloroglucinol derivatives compounds from Fructus Garciniae oblongifoliae's branch and leaf The extracorporeal anti-tumor function of born of the same parents' strain, it is significantly thin that result of the test shows that compound has to human leukemia HL-60 cell's strain in vitro Cytotoxicity, its IC50Value is respectively 14.44 μM, 2.47 μM, 18.08 μM, 2.93 μM, 11.53 μM, 13.90 μM；Survey Extracorporeal anti-tumor function of the isolated compound from Fructus Garciniae oblongifoliae's branch and leaf of examination to SMMC-7721 cell line, test As a result show that compound has notable cytotoxicity in vitro to SMMC-7721 cell line, its IC50Value is respectively 22.83 μM, 16.45 μM, 20.71 μM, 15.36 μM, 11.86 μM, 14.82 μM；Test is separated from Fructus Garciniae oblongifoliae's branch and leaf Extracorporeal anti-tumor function of the compound for obtaining to human lung cancer A-549 cell strain, result of the test show compound in vitro to people Lung cancer cell A-549 strain has notable cytotoxicity, its IC50Value is respectively 17.30 μM, 24.82 μM, 24.02 μM, 15.44 μM, 10.04 μM, 10.24 μM；The isolated compound from Fructus Garciniae oblongifoliae's branch and leaf of test is to human breast carcinoma MCF-7 The extracorporeal anti-tumor function of cell strain, result of the test show that compound has significantly to MCF-7 Human Breast Cancer Cells strain in vitro Cytotoxicity, its IC50Value is respectively 36.00 μM, 17.10 μM, 17.05 μM, 11.92 μM, 12.13 μM, 14.57 μ M；Extracorporeal anti-tumor function of the isolated compound from Fructus Garciniae oblongifoliae's branch and leaf of test to human colon carcinoma SW480 cell strains, examination Test result and show that compound has notable cytotoxicity to human colon carcinoma SW480 cell strains in vitro, its IC50Value is respectively 27.73 μM, 7.78 μM, 13.60 μM, 7.62 μM, 5.80 μM, 8.84 μM.Therefore the present invention divides from Fructus Garciniae oblongifoliae's branch and leaf There is anti tumor activity in vitro from the multi-ring many isopentene group phloroglucinol derivatives compounds for obtaining, thus have and prepare clinical tumor The prospect of prevention and treatment medicine, obtained compound are to develop the little new type antineoplastic medicine wound of good effect and toxic and side effects Condition is made.
Specific embodiment
Below in conjunction with preferred embodiment, according between the multi-ring many isopentene groups with anti-tumor activity proposed by the present invention Benzenetriol class compound, its preparation method and application specific embodiment, describe in detail as after.
Embodiment 1
A kind of preparation method of the multi-ring many isopentene group phloroglucinol derivatives compounds with anti-tumor activity, including following step Suddenly：
（1）Take Libo, Guizhou product Fructus Garciniae oblongifoliae and dry branch and leaf, adopt 95% industrial methanol to flow back which in the case where temperature is for 70 DEG C -80 DEG C After extracting 3-5 time, recovery methanol is concentrated to give extractum, and extractum is miscible into muddy thing with water, through ethyl acetate equal-volume extraction, dense Contract to obtain ethyl acetate layer extractum；
（2）Ethyl acetate layer extractum adopts chloroform with ethyl acetate volume ratio for 60 through 300-400 mesh silica gel column chromatographies:1～ 0:The eluent gradient eluting of 1 ratio, point lamellae merge into 4 parts：Fr 1 、Fr 2、 Fr 3、 Fr 4；
（3）Silica gel column chromatography is carried out again to Fr in step 22, adopts chloroform with ethyl acetate volume ratio for 40:1～1:1 ratio The eluent gradient eluting of example, is again divided into 4 sub-parts：Fr 2a 、Fr 2b 、Fr 2c、Fr 2d；Fr 2b are through excessively stream Dynamic Sephadex LH-20 gel filtration chromatographies mutually for methanol, and compound 1 is obtained through more than half preparative high-performance liquid chromatographic purification, 2 and 3, the wherein mobile phase of half preparative high-performance liquid chromatographic is methanol:Water volume ratio is 88:12.
（4）Silica gel column chromatography is carried out to Fr in step 23, adopts chloroform with ethyl acetate volume ratio for 40:1～1:1 ratio The eluent gradient eluting of example, is again divided into, 5 sub-parts：Fr 3a, Fr 3b, Fr 3c, Fr 3d, Fr 3e, Fr 3d is through the Sephadex LH-20 gel filtration chromatographies that mobile phase is methanol, and obtains through more than half preparative high-performance liquid chromatographic purification Compound 4 and 5, the wherein mobile phase of half preparative high-performance liquid chromatographic are methanol:Water volume ratio is 78:22.
（5）Silica gel column chromatography is carried out to Fr in step 24, adopts chloroform with ethyl acetate volume ratio for 20:1～1:1 ratio The eluent gradient eluting of example, is again divided into 3 sub-parts：Fr 4a, Fr 4b, Fr 4c, Fr 4c through mobile phase are The Sephadex LH-20 gel filtration chromatographies of methanol, and compound 6 is obtained through more than half preparative high-performance liquid chromatographic purification, wherein half The mobile phase of preparative high-performance liquid chromatographic is methanol:Water volume ratio is 73:27.
The Structural Identification of the 1-6 compounds adopts various spectroscopic techniques：Main utilization includes that high resolution mass spectrum, nuclear-magnetism are common Shake spectrum（1H NMR,13C NMR, 2D-NMR）, its structural formula is such as（1）~（6）Shown：
Compound 1：Using nucleus n-ness spectrum analysis of compounds, its data analysis is as follows：Colorless crystals, m.p. 306–309 °C; [α]19 D–6.3 (c= 0.15, CH3OH + CHCl3= 1:1); UV (CH3OH)λ max(logε) 203 (4.52), 300 (3.69) nm; IR (KBr)v max3490, 3429, 2980, 2927, 2872, 1731, 1702, 1669, 1612, 1518, 1452, 1382, 1328, 1287, 1214, 1201, 1165, 1119, 1103, 1074 cm-1; positive ESI-MS [M + Na]+ m/z655; HR-ESI-MS [M + Na]+ m/z 655.3236 (pred for C38H48O8Na, 655.3241);1H-NMR(400MHz,Pyridine-d 5)δ:8.30(1H, d,J= 2.0 Hz, H-9), 7.23 (1H, d,J= 8.3 Hz, H-12), 7.96(1H, dd,J= 8.3 Hz, 2.0 Hz, H-13), 2.72 (2H, m, H-14), 5.53 (1H, t,J= 7.5 Hz, H-15), 1.70 (3H, s, H-17),1.70 (3H, s, H-18),2.35 (1H, m, H-19α), 1.96 (1H, m, H-19β), 1.63 (1H, m, H-20), 1.81(3H, s, H-22), 1.91 (1H, m, H-23α), 2.02(1H, m, H-23β), 2.38 (1H, m, H-24α), 2.28(1H, m, H-24β), 5.02 (1H, t,J= 7.5 Hz, H-25), 1.73 (3H, s, H-27), 1.68(3H, s, H-28), 2.10(1H, m, H-29α), 2.21 (1H, m, H-29β), 2.18(1H, m, H-30), 0.90 (3H, s, H-32), 3.51 (1H, d,J= 15.7 Hz, H-33α), 2.04 (1H, m, H-33β), 2.69(1H, m, H-34α), 2.00(1H, m, H-34β), 1.50(3H, s, H-37), 1.67(3H, s, H-38).13C-NMR(100MHz, Pyridine-d 5)δ:70.4 (C-1), 203.7 (C-2), 63.8 (C-3), 213.5 (C-4), 65.0 (C-5), 91.9 (C-6), 200.5 (C-7), 134.3 (C-8), 118.5 (C-9), 146.0 (C-10), 149.4 (C-11), 115.1 (C-12), 122.8 (C-13), 26.7 (C-14), 120.5 (C-15), 134.1 (C-16), 26.1 (C-17), 18.5 (C-18), 47.5 (C-19), 51.9 (C- 20), 49.6 (C-21),22.7 (C-22),48.4 (C-23), 34.1 (C-24), 124.4 (C-25), 132.0 (C-26), 26.0 (C-27), 18.2 (C-28), 37.2 (C-29), 44.7 (C-30), 85.8 (C-31), 29.1 (C-32), 43.2 (C-33), 37.9 (C-34), 114.1 (C-35), 72.6 (C-36), 26.3 (C-37), 26.7 (C-38).
Compound 2：Using nucleus n-ness spectrum analysis of compounds, its data analysis is as follows：yellow oil, [α]25 D– 53.0 (c= 0.37, CH3OH); UV (CH3OH)λ max(logε) 203 (4.05), 256 (3.57), 348 (3.24) nm; IR (KBr)v max3438, 2968, 2926, 2872, 2855, 1732, 1704, 1679, 1648, 1629, 1453, 1383, 1290, 1213, 1195, 1158, 1116, 1082, 1050 cm-1; positive ESI- MS [M + Na]+ m/z655; HR-ESI-MS [M + Na]+ m/z655.3245 (calcd for C38H48O8Na, 655.3241).1H-NMR(600MHz, Pyridine-d 5)δ:8.31(1H, overlap, H-9), 7.23 (1H, d,J = 8.1 Hz, H-12), 7.97(1H, overlap, H-13), 2.71 (2H, m, H-14), 5.53 (1H, t,J = 6.6 Hz, H-15), 1.70 (3H, s, H-17), 1.69 (3H, s, H-18), 2.40 (1H, dd,J= 9.0 Hz, 3.8 Hz, H-19α), 1.96 (1H, m, H-19β), 1.52 (1H, m, H-20), 1.78(3H, s, H-22), 1.89 (1H, m, H-23α), 2.01(1H, m, H-23β), 1.88 (1H, m, H-24α), 1.63(1H, m, H-24β), 2.03 (1H, m, H-25α),1.77 (1H, m, H-25β),4.82(1H, s, H-27),4.83(1H, s, H-27),1.74(3H, s, H-28), 2.16(1H, m, H-29α), 2.24 (1H, m, H-29β), 2.18(1H, m, H-30), 0.91 (3H, s, H-32), 3.52 (1H, d,J= 15.7 Hz, H-33α), 2.07 (1H, m, H-33β), 2.68(1H, m, H-34α), 1.98(1H, m, H-34β), 1.65(3H, s, H-37), 1.45(3H, s, H-38).13C-NMR(150MHz, Pyridine-d 5)δ:70.8 (C-1), 204.2 (C-2), 64.2 (C-3), 213.9 (C-4), 65.4 (C-5), 92.2 (C-6), 200.9 (C-7), 134.8 (C-8), 118.9 (C-9), 146.5 (C-10), 149.8 (C-11), 115.5 (C-12), 123.2 (C-13), 27.2 (C-14), 120.9 (C-15), 134.5 (C-16), 26.5 (C-17), 18.5 (C-18), 48.0 (C-19), 51.8 (C-20), 50.1 (C-21),23.2 (C-22),48.8 (C-23), 34.0 (C-24), 36.9 (C-25), 146.6 (C-26), 110.8 (C-27), 23.1 (C-28), 37.7(C-29), 45.1 (C-30), 86.3 (C-31), 29.6 (C-32), 43.6 (C-33), 38.2 (C-34), 114.5 (C-35), 73.0 (C-36), 27.0 (C-37), 26.6 (C- 38).
Compound 3：Using nucleus n-ness spectrum analysis of compounds, its data analysis is as follows：yellow oil, [α]22 D–9.9 (c= 0.28, CH3OH); UV (CH3OH)λ max(logε) 203 (4.37), 261 (3.90), 318 (3.72), 372 (3.79) nm; IR (KBr)v max3429, 2971, 2929, 2882, 1738, 1707, 1641, 1597, 1520, 1449, 1380, 1341, 1292, 1193, 1178, 1119, 1058, 1026, 990, 580 cm-1; positive ESI-MS [M + Na]+ m/z657; HR-ESI-MS [M + Na]+ m/z657.3401 (calcd for C38H50O8Na, 657.3398).1H-NMR(600MHz, Pyridine-d 5)δ:8.25(1H, overlap, H-9), 7.05 (1H, d,J= 7.9 Hz, H-12), 8.02(1H, overlap, H-13), 2.83 (1H, m, H-14α),2.99 (1H, m, H-14β),5.64 (1H, t,J= 6.7 Hz, H-15), 1.68 (3H, s, H-17), 1.65 (3H, s, H-18), 2.18 (1H, m, H-19α), 1.85 (1H, m, H-19β), 1.72 (1H, m, H-20), 1.26 (3H, s, H-22), 1.69 (1H, m, H-23α), 2.73(1H, m, H-23β), 2.21 (2H, m, H-24), 5.02 (1H, t,J= 6.5 Hz, H-25), 1.67(3H, s, H-27), 1.49(3H, s, H-28), 2.68 (1H, m, H-29α), 1.92 (1H, m, H-29β), 1.81(1H, m, H-30), 1.38 (3H, s, H-32), 3.64 (1H, d,J= 15.7 Hz, H-33α), 2.72 (1H, m, H-33β), 2.20(1H, m, H-34α), 1.62(1H, m, H-34β), 3.73(1H, t,J= 6.7 Hz, H-35), 1.18(3H, s, H-37), 1.28(3H, s, H-38).13C-NMR(150MHz, Pyridine-d 5)δ:69.0 (C-1), 205.6 (C-2), 67.5 (C-3), 211.9 (C-4), 64.5 (C-5), 83.6 (C-6), 204.1 (C-7), 130.2 (C-8), 118.5 (C-9), 146.8 (C-10), 152.4 (C-11), 115.3 (C-12), 124.1 (C-13), 26.4 (C-14), 120.1 (C-15), 138.8 (C-16), 26.0 (C-17), 17.9 (C-18), 42.5 (C-19), 51.3 (C-20), 47.0 (C-21),19.0 (C-22),42.8 (C-23), 33.0 (C-24), 123.9 (C-25), 131.8 (C-26), 25.8 (C-27), 17.9 (C-28), 34.7(C-29), 41.9 (C-30), 84.9 (C-31), 27.9 (C-32), 42.9 (C-33), 36.3 (C-34), 81.7 (C-35), 70.1 (C-36), 26.6 (C-37), 26.9 (C-38).
Compound 4：Using nucleus n-ness spectrum analysis of compounds, its data analysis is as follows：yellow oil, [α]25 D–5.0 (c= 0.24, CH3OH); UV (CH3OH)λ max(logε) 204 (4.19), 241 (3.68), 262 (3.74), 316 (3.61), 373 (3.64), 487 (2.08), 563 (2.08) nm; IR (KBr)v max= 3428, 2969, 2927, 2856, 1739, 1705, 1643, 1597, 1520, 1440, 1378, 1344, 1291, 1197, 1125, 1115, 1084, 1060, 1045 cm-1; positive ESI-MS [M + Na]+ m/z641; HR-ESI-MS [M + Na]+ m/z641.3446 (calcd for C38H50O7Na, 641.3449).1H-NMR(400MHz, Pyridine-d 5)δ: 8.70(1H, overlap, H-9), 7.15 (1H, d,J= 7.8 Hz, H-12), 8.51(1H, overlap, H- 13), 2.90 (1H, m, H-14α),3.18(1H, m, H-14β), 5.77 (1H, t,J= 7.5 Hz, H-15), 1.71 (3H, s, H-17), 1.67 (3H, s, H-18), 2.19 (1H, m, H-19α), 1.88 (1H, m, H- 19β), 1.72 (1H, m, H-20), 1.32(3H, s, H-22), 1.65 (1H, m, H-23α), 2.89(1H, m, H-23β), 2.33 (2H, m, H-24), 5.07 (1H, t,J= 6.5 Hz, H-25), 1.69(3H, s, H- 27), 1.58(3H, s, H-28), 2.57(1H, m, H-29α), 2.18 (1H, m, H-29β), 1.34(1H, m, H-30), 1.33 (3H, s, H-32), 3.28 (1H, d,J= 15.7 Hz, H-33α), 3.17 (1H, m, H- 33β), 2.17(1H, m, H-34α), 2.06(1H, m, H-34β), 5.18(1H, t,J= 6.2 Hz, H-35), 1.67(3H, s, H-37), 1.47(3H, s, H-38).13C-NMR(100MHz, Pyridine-d 5)δ:72.4 (C- 1), 208.0 (C-2), 67.6 (C-3), 211.2 (C-4), 67.6 (C-5), 84.8 (C-6), 205.2 (C- 7), 130.0 (C-8), 118.5 (C-9), 146.8 (C-10), 152.6 (C-11), 115.7 (C-12), 124.9 (C-13), 27.0 (C-14), 120.6 (C-15), 133.3 (C-16), 26.1 (C-17), 17.9 (C-18), 44.0 (C-19), 51.9 (C-20), 47.3 (C-21),19.9 (C-22),42.3 (C-23), 33.8 (C-24), 124.4 (C-25), 131.8 (C-26), 25.9 (C-27), 18.2 (C-28), 31.7(C-29), 41.7 (C- 30), 74.2 (C-31), 30.9 (C-32), 46.8 (C-33), 30.5 (C-34), 124.0 (C-35), 132.2 (C-36), 25.9 (C-37), 17.9 (C-38).
Compound 5：Using nucleus n-ness spectrum analysis of compounds, its data analysis is as follows：yellow oil, [α]25 D– 79.2 (c= 0.29, CH3OH); UV (CH3OH)λ max(logε) 204 (4.24), 262 (3.80), 316 (3.68), 373 (3.67) nm; IR (KBr)v max= 3431, 3076, 2966, 2929, 2856, 1739, 1705, 1645, 1597, 1520, 1448, 1377, 1292, 1198, 1126, 1116, 1086, 1044, 889 cm-1; positive ESI-MS [M + Na]+ m/z641; HR-ESI-MS [M + Na]+ m/z641.3449 (calcd for C38H50O7Na, 641.3449).1H-NMR(400MHz, Pyridine-d 5)δ:8.72(1H, overlap, H-9), 7.15 (1H, d,J= 8.4 Hz, H-12), 8.47(1H, overlap, H-13), 2.88 (1H, m, H-14α), 3.20(1H, m, H-14β), 5.78 (1H, t,J= 7.5 Hz, H-15), 1.71 (3H, s, H-17), 1.66 (3H, s, H-18), 2.21 (1H, m, H-19α), 1.84 (1H, m, H-19β), 1.63 (1H, m, H-20), 1.29(3H, s, H-22), 1.64 (1H, m, H-23α), 2.89(1H, m, H-23β), 1.81 (1H, m, H-24 α), 1.65(1H, m, H-24β), 2.05 (1H, m, H-29α),1.79 (1H, m, H-25β), 4.79(1H, s, H-27),4.78(1H, s, H-27), 1.70(3H, s, H-28), 2.59(1H, m, H-29α), 2.22 (1H, m, H-29β), 1.35(1H, m, H-30), 1.34 (3H, s, H-32), 3.28 (1H, d,J= 15.7 Hz, H-33 α), 3.16 (1H, m, H-33β), 2.17(1H, m, H-34α), 2.09(1H, m, H-34β), 5.20(1H, t,J = 6.2 Hz, H-35),1.69(3H, s, H-37), 1.51(3H, s, H-38).13C-NMR(100MHz, Pyridine-d 5)δ:72.4 (C-1), 208.0 (C-2), 67.6 (C-3), 211.1 (C-4), 67.6 (C-5), 84.6 (C- 6), 205.3 (C-7), 130.1 (C-8), 118.5 (C-9), 146.7 (C-10), 152.5 (C-11), 115.7 (C-12), 124.8 (C-13), 27.0 (C-14), 120.6 (C-15), 133.3 (C-16), 26.1 (C-17), 17.9 (C-18), 44.1 (C-19), 51.5 (C-20), 47.4 (C-21),20.0 (C-22),42.3 (C-23), 33.3 (C-24), 36.5 (C-25), 146.3 (C-26), 110.2 (C-27), 22.7 (C-28), 31.7 (C- 29), 41.6 (C-30), 74.1 (C-31), 30.9 (C-32), 46.9 (C-33), 30.6 (C-34), 124.0 (C-35), 132.2 (C-36), 25.9 (C-37), 18.0 (C-38).
Compound 6：Using nucleus n-ness spectrum analysis of compounds, its data analysis is as follows：yellow oil, [α]22 D–3.5 (c= 0.35, CH3OH); UV (CH3OH)λmax (logε) 203 (4.44), 263 (4.07), 322 (3.89), 379 (4.03) nm; IR (KBr)v max3429, 2966, 2929, 2857, 1740, 1707, 1641, 1597, 1520, 1448, 1439, 1383, 1342, 1294, 1222, 1191, 1116, 1059, 1027, 931 cm-1; positive ESI-MS [M + Na]+ m/z613; HR-ESI-MS [M + Na]+ m/z613.2780 (calcd for C35H42O8Na, 613.2772).1H-NMR(400MHz, Pyridine-d 5)δ:8.39(1H, d,J= 1.4 Hz,, H- 9), 7.13 (1H, d,J= 7.0 Hz, H-12), 8.11(1H, dd,J= 1.4 Hz,7.0 Hz, H-13), 2.83 (1H, m, H-14α),3.01(1H, m, H-14β), 5.66 (1H, t,J= 7.0 Hz, H-15), 1.71 (3H, s, H-17), 1.69 (3H, s, H-18), 2.21 (1H, m, H-19α), 1.88 (1H, m, H-19β), 1.81 (1H, m, H-20), 1.34 (3H, s, H-22), 1.74 (1H, m, H-23α), 2.89(1H, m, H-23 β), 2.29 (2H, m, H-24), 5.06 (1H, t,J= 5.7 Hz, H-25), 1.68(3H, s, H-27), 1.52(3H, s, H-28), 2.46(1H, m, H-29α), 1.97 (1H, m, H-29β), 2.05(1H, m, H- 30), 1.53 (3H, s, H-32), 3.80 (1H, d,J= 15.2 Hz, H-33α), 2.85 (1H, m, H-33 β), 3.07(1H, m, H-34α), 2.17(1H, m, H-34β).13C-NMR(100MHz, Pyridine-d 5)δ:69.5 (C-1), 205.9 (C-2), 67.8 (C-3), 211.3 (C-4), 65.0 (C-5), 83.5 (C-6), 202.9 (C-7), 129.6 (C-8), 118.7 (C-9), 147.0 (C-10), 153.4 (C-11), 115.8 (C-12), 124.6 (C-13), 26.4 (C-14), 120.0 (C-15), 134.1 (C-16), 26.1 (C-17), 18.0 (C- 18), 42.4 (C-19), 51.5 (C-20), 47.1 (C-21),18.7 (C-22),42.6 (C-23), 33.1 (C- 24), 123.9 (C-25), 132.2 (C-26), 25.9 (C-27), 18.0 (C-28), 32.8(C-29), 40.1 (C-30), 89.0 (C-31), 29.6 (C-32), 41.7 (C-33), 39.0 (C-34), 175.1 (C-35).
Test example：The extracorporeal anti-tumor of six multi-ring many isopentene group phloroglucinol derivatives compound 1-6 in Fructus Garciniae oblongifoliae's branch and leaf Activity
1. experiment material：
96 well culture plate of import, DEME culture fluid（HyClone companies of the U.S. produce）, hyclone（Hangzhou Ilex purpurea Hassk.[I.chinensis Sims company gives birth to Produce）, 0.25% pancreatin（Trypsin）For U.S.'s HyClone products, Methyl thiazoly tetrazolium assay (3- (4,5-Dimethyl- thiazol-2-yl-tetrazolium bromide；MTT) Sigma companies, dimethyl sulfoxide are purchased from（dimethyl sulfoxide；DMSO）For Beijing Suo Laibao Science and Technology Ltd product, Allegra X-15R desk centrifuges（U.S. Bake Man）, Axio Vert.A1 inverted biological microscopes（German Carl Zeiss Inc.）, TS100 binoculars inverted phase contrast is biological to be shown Micro mirror (Japanese Nikon company）, microplate reader（BIOTEK companies of the U.S..From tumor cell line be：Human leukemia HL-60 cell Strain, SMMC-7721 cell line, human lung cancer A-549 cell strain, MCF-7 Human Breast Cancer Cells strain and human colon carcinoma SW480 Cell strain.Medicine DMSO（Dimethyl sulfoxide）Storing liquid is made into after dissolving, and -20 DEG C save backup.
. process of the test
Tumor cell in cryopreservation tube is thawed in 37 DEG C of water baths rapidly, after cell is collected by centrifugation, with containing 10% tire Sanguis Bovis seu Bubali Clear and 1% penicillin, the DMEM culture fluid of 1% streptomycin, are trained into 37 DEG C, the incubator of 5% CO2 constant temperature saturated humidities Support, change liquid every other day.Passed on when cell 80% converges, choose exponential phase cell and tested.Take about 80% area The culture dish of cell being covered with, cell being transferred to after centrifuge tube, 800 r/min are centrifuged 5min, and new culture is added after abandoning supernatant Liquid adjustment cell concentration is inoculated in 96 well culture plates to 1 × 104/ml density, adds 100 μ l Cell saps per hole, adherent thin Born of the same parents shift to an earlier date 12 hours inoculated and cultured.Add testing compound（The compounds of this invention 1-6）Solution（40 μM of primary dcreening operations of fixed concentration, Compound of the concentration to growth of tumour cell suppression ratio near 50% sets 5 concentration and enters gradient secondary screening）, per hole final volume 200 μ l, every kind of process are all provided with 3 multiple holes.After continuing culture 96 hours in 37 DEG C, 50 μ l MTT solution are added to incubate in 37 DEG C per hole After changing 4 hours, supernatant is abandoned or adopted, 200 μ l DMSO are added per hole, after shaken at room temperature 10min, examined at 570nm using microplate reader OD values are surveyed, if A1（Contain 200 μ l DMSO）For blank control wells, with cisplatin（cisplatin）, paclitaxel（Taxol）Right for the positive According to.After obtaining each group OD value, Cytostatic to tumor cell rate is calculated by following equation（This part Experiment is repeated 3 times）：
Growth inhibition ratio（%）=（Blank group absorbance values-dosing group absorbance values）/ blank group absorbance values × 100%.Acquired results bring IC into50Software for calculation, obtains IC50Value.
Result of the test
Table 1 is cytotoxicity of the multi-ring many isopentene group phloroglucinol derivatives compound 1-6 to five kinds of human tumor cell lines.
1 result of table shows that compound 1-6 shows the cell toxicant of moderate strength in vitro to multiple human tumor cell lines Effect.Cytotoxic activity of the compound 2 to human colon carcinoma SW480 cell strains（IC507.78μM）With to human leukemia HL-60 cell The cytotoxic activity of strain（IC502.47μM）, cytotoxic activity with one of positive control cisplatin on human colon cancer SW480 cell strain （IC508.17μM）With the cytotoxic activity to human leukemia HL-60 cell's strain（IC502.06μM）Substantially suitable.
Cytotoxic activity of the compound 4 to MCF-7 Human Breast Cancer Cells strain（IC5011.92μM）With to human colon carcinoma SW480 The cytotoxic activity of cell strain（IC507.62μM）It is slightly stronger than the thin of one of positive control cisplatin on human breast cancer cell line MCF-7 Born of the same parents' cytotoxic activity（IC5013.93μM）With the cytotoxic activity to human colon carcinoma SW480 cell strains（IC508.17μM）.
Cytotoxic activity of the compound 5 to human colon carcinoma SW480 cell strains（IC505.80μM）, more suitable than one of positive control Cytotoxic activity of the platinum to human colon carcinoma SW480 cell strains（IC508.17μM）1.4 times of difference, activity are more notable.
Above-mentioned experiment results proved the compounds of this invention 1-6 has the biological activity of good extracorporeal anti-tumor, is wooden bamboo In terms of the comprehensive utilization of sub- plant, treating cancer drug development, there is provided novel drugs and new approach.
The above, is only presently preferred embodiments of the present invention, not makees any pro forma restriction to the present invention, appoints What any is simply repaiied according to what the technical spirit of the present invention made to above example without departing from technical solution of the present invention content Change, equivalent variations and modification, still fall within the range of technical solution of the present invention.

Claims (4)

1. there are multi-ring many isopentene group phloroglucinol derivatives compounds of anti-tumor activity, its general structure is as follows：
Wherein:
R1, R2Can be identical or different, each independent group is hydrogen（–H）, hydroxyl（–OH）Or R1R2=oxygen bridge（–O–）
R3, R4Can be identical or different, each independent group is hydrogen（–H）, hydroxyl（–OH）Or R3R4=oxygen bridge（–O–）
R5For 2- hydroxy propanes（–CH OH (CH3)2）Or carbonyl（–CO–）Or acrylic（）R6, R7, R8It can be phase Same or different, each independent group is hydrogen（–H）, or R6R7=double bond（）Or R7R8=double bond（ ）.
2. multi-ring many isopentene group phloroglucinol derivatives compounds with anti-tumor activity as claimed in claim 1, preferably have Body compound is as follows：
.
3. there is the system of multi-ring many isopentene group phloroglucinol derivatives compounds of anti-tumor activity as claimed in claim 1 or 2 Preparation Method, comprises the following steps：
（1）Take Fructus Garciniae oblongifoliae and dry branch and leaf, after adopting 95% industrial methanol in the case where temperature is for 70 DEG C -80 DEG C to its reflux, extract, 3-5 time Reclaim methanol and be concentrated to give extractum, extractum is miscible into muddy thing with water, through ethyl acetate equal-volume extraction, is concentrated to give ethyl acetate Layer extractum；
（2）Ethyl acetate layer extractum adopts chloroform with ethyl acetate volume ratio for 60 through 300-400 mesh silica gel column chromatographies:1～ 0:The eluent gradient eluting of 1 ratio, point lamellae merge into 4 parts：Fr 1 、Fr 2、 Fr 3、 Fr 4；
（3）Silica gel column chromatography is carried out again to Fr in step 22, adopts chloroform with ethyl acetate volume ratio for 40:1～1:1 ratio The eluent gradient eluting of example, is again divided into 4 sub-parts：Fr 2a, Fr 2b, Fr 2c, Fr 2d, Fr 2b are through excessively stream Dynamic Sephadex LH-20 gel filtration chromatographies mutually for methanol, and compound 1 is obtained through more than half preparative high-performance liquid chromatographic purification, 2 and 3, the wherein mobile phase of half preparative high-performance liquid chromatographic is methanol:Water volume ratio is 88:12；
（4）Silica gel column chromatography is carried out to Fr in step 23, adopts chloroform with ethyl acetate volume ratio for 40:1～1:1 ratio Eluent gradient eluting, is again divided into, 5 sub-parts：Fr 3a, Fr 3b, Fr 3c, Fr 3d, Fr 3e, Fr 3d are passed through The Sephadex LH-20 gel filtration chromatographies that mobile phase is methanol are crossed, and chemical combination are obtained through more than half preparative high-performance liquid chromatographic purification Thing 4 and 5, the wherein mobile phase of half preparative high-performance liquid chromatographic are methanol:Water volume ratio is 78:22；
（5）Silica gel column chromatography is carried out to Fr in step 24, adopts chloroform with ethyl acetate volume ratio for 20:1～1:1 ratio Eluent gradient eluting, is again divided into 3 sub-parts：Fr 4a, Fr 4b, Fr 4c, Fr 4c are methanol through mobile phase Sephadex LH-20 gel filtration chromatographies, and obtain compound 6 through more than half preparative high-performance liquid chromatographic purification, wherein half prepares The mobile phase of high performance liquid chromatography is methanol:Water volume ratio is 73:27.
4. as the multi-ring many isopentene group phloroglucinol derivatives compounds with anti-tumor activity of claim 1 or 2 are preparing people Leukemia HL-60 cell strain, SMMC-7721 cell line, human lung cancer A-549 cell strain, MCF-7 Human Breast Cancer Cells strain With the application in human colon carcinoma SW480 cell strain inhibitor.
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CN109053762A (en) * 2018-09-26 2018-12-21 贵州省中国科学院天然产物化学重点实验室 PPAP hemiketal class compound, Its Preparation Method And Use
CN110511202A (en) * 2019-08-13 2019-11-29 厦门大学 Polycyclic polyisocyanate pentenyl acyl phloroglucinol class compound and the preparation method and application thereof
CN111056935A (en) * 2020-01-02 2020-04-24 中国科学院昆明植物研究所 Dearylated isopentenyl acyl phloroglucinol derivative and pharmaceutical composition and application thereof
CN111233886A (en) * 2020-03-26 2020-06-05 中国科学院昆明植物研究所 Dearylated isopentenyl acylated phloroglucinol heteroterpenoid compound and pharmaceutical composition and application thereof
CN111233886B (en) * 2020-03-26 2022-06-17 中国科学院昆明植物研究所 Dearylated isopentenyl acylated phloroglucinol heteroterpenoid compound and pharmaceutical composition and application thereof
CN115466173A (en) * 2022-08-16 2022-12-13 沈阳药科大学 Polyprenyl adamantane type benzophenone compound and preparation method and application thereof

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