CN106496171B - Polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound, preparation method and application with anti-tumor activity - Google Patents

Polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound, preparation method and application with anti-tumor activity Download PDF

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CN106496171B
CN106496171B CN201610914347.6A CN201610914347A CN106496171B CN 106496171 B CN106496171 B CN 106496171B CN 201610914347 A CN201610914347 A CN 201610914347A CN 106496171 B CN106496171 B CN 106496171B
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methanol
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pentenyl
ethyl acetate
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CN106496171A (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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    • 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
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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
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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 one kind polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound with anti-tumor activity, preparation method and application, general structure are as follows: belonging to pharmaceutical technology field, extracts from the dry branches and leaves of garcinia multiflora isolated.The had anti tumor activity in vitro of the present invention, extraction separation method is simple, and raw material, which holds, to be obtained.

Description

Polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound with anti-tumor activity, its system Preparation Method and application
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of polycyclic polyisocyanate pentenyl isophthalic with anti-tumor activity Three phenolic compounds, while being related to the preparation side of the polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound with anti-tumor activity Method, and in preparation human leukemia HL-60 cell's strain, SMMC-7721 cell line, human lung cancer A-549 cell strain, human milk gland Application in cancer MCF-7 cell strain and human colon carcinoma SW480 cell strain inhibitor.
Background technique
Natural polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound (polycyclic polyprenylated Acylphloroglucinols, abbreviation PPAPs) it is a kind of by the natural of acyl phloroglucinol and multiple iso-amylene base phase heterozygosis Product, the nuclear structure that this kind of compound has bridged ring, loop coil or even adamantane rare in natural products etc. complicated, and often With multiple isopentene group substituent groups.The constituents are also the exclusive characteristic constituents of Garcinia maingayii.It has reported at present Natural PPAPs class compound about 300 or so, mostly with bridged ring, loop coil and gold rare in Secondary metabolites The core skeleton of the complexity such as rigid alkane, rigidity.Due to its structure novel, bioactivity is unique, is widely noticed in the world in recent years, For example, Xanthochymol (xanthochymol) and guttiferone (guttiferone E) have cell toxicant and inhibit tubulin Activity, nemorosone have AntiHIV1 RT activity activity, hyperforine (hyperforin) have antidepression and antitumor work Property, garsubellin A has the activity etc. of anti-senile dementia.It is worth noting that the gambogicacid extracted in gamboge is opened National a kind of anti-cancer agent (gambogicacid injection) is sent out into, currently the second stage of clinical research, this is but also from Guttiferae Finding PPAPs series antineoplastic medicament becomes a research hotspot.Garcinia maingayii (is accounted for as the main source of the constituents The 70% of PPAPs class source), that takes as own duty becomes the emphasis plant for finding such compound.
Garcinia multiflora be 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, produces 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].Garcinia multiflora is in the people Between be used for anti-inflammatory analgetic, control burn, scald, eczema, stomatitis, indigestion etc..
Summary of the invention
The one kind provided it is an object of the invention to overcome disadvantages mentioned above has anti tumor activity in vitro, extracts separation side Method is simple, and raw material holds the polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound with anti-tumor activity obtained.
Another object of the present invention is to provide the polycyclic polyisocyanate pentenyl phloroglucinol derivatives with anti-tumor activity Close the preparation method of object.
A further object of the present invention is to provide the polycyclic polyisocyanate pentenyl phloroglucinol derivatives with anti-tumor activity Object is closed in preparation human leukemia HL-60 cell's strain, SMMC-7721 cell line, human lung cancer A-549 cell strain, human milk gland Application in cancer MCF-7 cell strain and human colon carcinoma SW480 cell strain inhibitor.
It the purpose of the present invention and solves its technical problem underlying and adopts the following technical solutions to realize:
Polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound with anti-tumor activity of the invention, general structure is such as Under:
Wherein:
R1, R2Can be to be identical or different, group independent is hydrogen (- H), hydroxyl (- OH) or R1R2=oxygen bridge (- O -)
R3, R4Can be to be identical or different, group independent is hydrogen (- H), hydroxyl (- OH) or R3R4=oxygen bridge (- O -)
R5For 2- hydroxy propane (- CH OH (CH3)2) either carbonyl (- CO -) or acrylic () R6, R7, R8 Can be to be identical or different, group independent is hydrogen (- H) or R6R7 =double bond () or R7R8 =double bond ().
Above-mentioned polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound with anti-tumor activity, preferably particular compound are such as Under:
The preparation method of one kind polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound with anti-tumor activity of the invention, The following steps are included:
(1) the dry branches and leaves of garcinia multiflora are taken, use 95% industrial methanol in the case where temperature is 70 DEG C -80 DEG C to its refluxing extraction 3-5 Recycling methanol is concentrated to give medicinal extract after secondary, and medicinal extract water is miscible at muddy object, by ethyl acetate equal-volume extraction, is concentrated to give acetic acid Methacrylate layer medicinal extract；
(2) ethyl acetate layer medicinal extract passes through 300-400 mesh silica gel column chromatography, use chloroform and ethyl acetate volume ratio for The eluent gradient of 60:1~0:1 ratio elutes, and point lamellae merges into 4 parts: Fr 1, Fr 2, Fr 3, Fr 4；
(3) silica gel column chromatography is carried out to Fr 2 in step 2 again, uses chloroform and ethyl acetate volume ratio for 40:1~1: The eluent gradient of 1 ratio elutes, and is again divided into 4 sub-parts: Fr 2a, Fr 2b, Fr 2c, Fr 2d；Fr 2b passes through Mobile phase is the Sephadex LH-20 gel filtration chromatography of methanol, and purifies to obtain compound through more than half preparative high-performance liquid chromatographics 1,2 and 3, wherein the mobile phase of half preparative high-performance liquid chromatographic is methanol: water volume ratio 88:12.
(4) silica gel column chromatography is carried out to Fr 3 in step 2, uses chloroform and ethyl acetate volume ratio for 40:1~1:1 ratio The eluent gradient elution of example, is again divided into, 5 sub-parts: Fr 3a, Fr 3b, Fr 3c, Fr 3d, Fr 3e, Fr 3d is the Sephadex LH-20 gel filtration chromatography of methanol by mobile phase, and purifies to obtain through more than half preparative high-performance liquid chromatographics Compound 4 and 5, wherein the mobile phase of half preparative high-performance liquid chromatographic is methanol: water volume ratio 78:22.
(5) silica gel column chromatography is carried out to Fr 4 in step 2, uses chloroform and ethyl acetate volume ratio for 20:1~1:1 ratio The eluent gradient elution of example, be again divided into 3 sub-parts: Fr 4a, Fr 4b, Fr 4c, Fr 4c are by mobile phase The Sephadex LH-20 gel filtration chromatography of methanol, and purify to obtain compound 6 through more than half preparative high-performance liquid chromatographics, wherein half The mobile phase of preparative high-performance liquid chromatographic is methanol: water volume ratio 73:27.
Polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound with anti-tumor activity of the invention is preparing 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 people's knot Application in intestinal cancer SW480 cell strain inhibitor.Compared with prior art, the present invention there is apparent beneficial effect, from above Known to technical solution: preparation method of the invention includes that methanol extracts, medicinal extract concentration, silica gel column chromatography, gradient elution, gel column Chromatography, the purifying of half preparative high-performance liquid chromatographic, extraction separation method is simple, and the raw material used is easy a large amount of obtain.Using MTT It is thin to human leukemia HL-60 that method tests polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound isolated from garcinia multiflora branches and leaves The extracorporeal anti-tumor function of born of the same parents' strain, test result show that compound in vitro has significantly carefully human leukemia HL-60 cell's strain Cytotoxicity, IC50Value is respectively 14.44 μM, 2.47 μM, 18.08 μM, 2.93 μM, 11.53 μM, 13.90 μM；It surveys Compound isolated from garcinia multiflora branches and leaves is tried to the extracorporeal anti-tumor function of SMMC-7721 cell line, test The result shows that compound has significant cytotoxicity, IC to SMMC-7721 cell line in vitro50Value is respectively 22.83 μM, 16.45 μM, 20.71 μM, 15.36 μM, 11.86 μM, 14.82 μM；Test is separated from garcinia multiflora branches and leaves Obtained compound shows compound in vitro to people the extracorporeal anti-tumor function of human lung cancer A-549 cell strain, test result Lung cancer cell A-549 strain has significant cytotoxicity, IC50Respectively 17.30 μM of value, 24.82 μM, 24.02 μM, 15.44 μM, 10.04 μM, 10.24 μM；Compound isolated from garcinia multiflora branches and leaves is tested to human breast carcinoma MCF-7 The extracorporeal anti-tumor function of cell strain, test result show that compound in vitro has significantly MCF-7 Human Breast Cancer Cells strain Cytotoxicity, IC50Respectively 36.00 μM of value, 17.10 μM, 17.05 μM, 11.92 μM, 12.13 μM, 14.57 μ M；Compound isolated from garcinia multiflora branches and leaves is tested to the extracorporeal anti-tumor function of human colon carcinoma SW480 cell strain, examination It tests the result shows that compound has significant cytotoxicity, IC to human colon carcinoma SW480 cell strain in vitro50Value 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 garcinia multiflora branches and leaves There is anti tumor activity in vitro from obtained polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound, thus have and prepare clinical tumor The prospect of drug is prevented and treated, obtained compound is the new type antineoplastic medicine wound that development efficacy is good and toxic side effect is small Condition is made.
Specific embodiment
In conjunction with the preferred embodiment, between polycyclic polyisocyanate pentenyl with anti-tumor activity proposed according to the present invention Benzenetriol class compound, preparation method and apply specific embodiment, detailed description is as follows.
Embodiment 1
A kind of preparation method of polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound with anti-tumor activity, including it is following Step:
(1) it takes Libo, Guizhou to produce the dry branches and leaves of garcinia multiflora, uses 95% industrial methanol in the case where temperature is 70 DEG C -80 DEG C to it Recycling methanol is concentrated to give medicinal extract after refluxing extraction 3-5 times, and medicinal extract water is miscible at muddy object, extracts in equal volume by ethyl acetate It takes, be concentrated to give ethyl acetate layer medicinal extract；
(2) ethyl acetate layer medicinal extract passes through 300-400 mesh silica gel column chromatography, use chloroform and ethyl acetate volume ratio for The eluent gradient of 60:1~0:1 ratio elutes, and point lamellae merges into 4 parts: Fr 1, Fr 2, Fr 3, Fr 4；
(3) silica gel column chromatography is carried out to Fr 2 in step 2 again, uses chloroform and ethyl acetate volume ratio for 40:1~1: The eluent gradient of 1 ratio elutes, and is again divided into 4 sub-parts: Fr 2a, Fr 2b, Fr 2c, Fr 2d；Fr 2b passes through Mobile phase is the Sephadex LH-20 gel filtration chromatography of methanol, and purifies to obtain compound through more than half preparative high-performance liquid chromatographics 1,2 and 3, wherein the mobile phase of half preparative high-performance liquid chromatographic is methanol: water volume ratio 88:12.
(4) silica gel column chromatography is carried out to Fr 3 in step 2, uses chloroform and ethyl acetate volume ratio for 40:1~1:1 ratio The eluent gradient elution of example, is again divided into, 5 sub-parts: Fr 3a, Fr 3b, Fr 3c, Fr 3d, Fr 3e, Fr 3d is the Sephadex LH-20 gel filtration chromatography of methanol by mobile phase, and purifies to obtain through more than half preparative high-performance liquid chromatographics Compound 4 and 5, wherein the mobile phase of half preparative high-performance liquid chromatographic is methanol: water volume ratio 78:22.
(5) silica gel column chromatography is carried out to Fr 4 in step 2, uses chloroform and ethyl acetate volume ratio for 20:1~1:1 ratio The eluent gradient elution of example, be again divided into 3 sub-parts: Fr 4a, Fr 4b, Fr 4c, Fr 4c are by mobile phase The Sephadex LH-20 gel filtration chromatography of methanol, and purify to obtain compound 6 through more than half preparative high-performance liquid chromatographics, wherein half The mobile phase of preparative high-performance liquid chromatographic is methanol: water volume ratio 73:27.
The Structural Identification of the 1-6 compound uses various spectroscopic techniques: main using total including high resolution mass spectrum, nuclear-magnetism Vibration spectrum (1H NMR, 13C NMR, 2D-NMR), structural formula is such as shown in (1) ~ (6):
Compound 1: using nucleus n-ness spectrum analysis of compounds, and data are analyzed 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 (log ε) 203 (4.52), 300 (3.69) nm; IR (KBr) v max 3490, 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/z 655; 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, and data are analyzed as follows: yellow oil, [α]25 D– 53.0 (c = 0.37, CH3OH); UV (CH3OH) λ max (log ε) 203 (4.05), 256 (3.57), 348 (3.24) nm; IR (KBr) v max 3438, 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/z 655; HR-ESI-MS [M + Na]+ m/z 655.3245 (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, and data are analyzed as follows: yellow oil, [α]22 D–9.9 (c = 0.28, CH3OH); UV (CH3OH) λ max (log ε) 203 (4.37), 261 (3.90), 318 (3.72), 372 (3.79) nm; IR (KBr) v max 3429, 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/z 657; HR-ESI-MS [M + Na]+ m/z 657.3401 (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, and data are analyzed as follows: yellow oil, [α]25 D–5.0 (c = 0.24, CH3OH); UV (CH3OH) λ max (log ε) 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/z 641; HR-ESI-MS [M + Na]+ m/z 641.3446 (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, and data are analyzed as follows: yellow oil, [α]25 D– 79.2 (c = 0.29, CH3OH); UV (CH3OH) λ max (log ε) 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/z 641; HR-ESI-MS [M + Na]+ m/z 641.3449 (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, and data are analyzed as follows: yellow oil, [α]22 D–3.5 (c = 0.35, CH3OH); UV (CH3OH) λmax (log ε) 203 (4.44), 263 (4.07), 322 (3.89), 379 (4.03) nm; IR (KBr) v max 3429, 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/z 613; HR-ESI-MS [M + Na]+ m/z 613.2780 (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 polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound 1-6 in garcinia multiflora branches and leaves Activity
1. experimental material:
96 well culture plate of import, DEME culture solution (production of HyClone company, the U.S.), (Hangzhou Chinese holly is public for fetal calf serum Department's production), 0.25% pancreatin (Trypsin) is U.S. HyClone product, Methyl thiazoly tetrazolium assay (3- (4,5- Dimethyl-thiazol-2-yl-tetrazolium bromide；MTT Sigma company, dimethyl sulfoxide) are purchased from (dimethyl sulfoxide；It DMSO) is Beijing Suo Laibao Science and Technology Ltd product, Allegra X-15R desk centrifuge (U.S. Bake Mann), Axio Vert.A1 inverted biologic microscope (German Carl Zeiss Inc.), TS100 binocular are inverted phase Poor biomicroscope (Japanese Nikon company), microplate reader (BIOTEK company, the U.S..The tumor cell line of selection are as follows: 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 people's knot Intestinal cancer SW480 cell strain.Drug DMSO(dimethyl sulfoxide) dissolution after be made into storing liquid, -20 DEG C save backup.
Process is tested
Tumour cell in cryopreservation tube is thawed rapidly in 37 DEG C of water baths, after cell is collected by centrifugation, with containing 10% tire The DMEM culture solution of cow's serum and 1% penicillin, 1% streptomysin, until 37 DEG C, in the incubator of 5% CO2 constant temperature saturated humidity into Row culture, changes liquid every other day.It is passed on when cell 80% converges, chooses logarithmic growth phase cell and tested.Take about 80% Area is covered with the culture dish of cell, and after cell is transferred to centrifuge tube, 800 r/min are centrifuged 5min, is added newly after abandoning supernatant Culture solution adjustment cell concentration to 1 × 104/ml density is inoculated in 96 well culture plates, and 100 μ l cell liquid, patch is added in every hole Parietal cell shifts to an earlier date 12 hours inoculated and cultureds.Untested compound (the compounds of this invention 1-6) solution is added (at the beginning of 40 μM of fixed concentration Sieve, sets 5 concentration to compound of the growth of tumour cell inhibiting rate near 50% in the concentration and enters gradient secondary screening), every hole is whole 200 μ l of volume, every kind of processing are all provided with 3 multiple holes.After 37 DEG C are continued culture 96 hours, 50 μ l MTT solution are added in 37 in every hole DEG C after hatching 4 hours, supernatant is abandoned or adopted, after 200 μ l DMSO, shaken at room temperature 10min are added in every hole, using microplate reader in 570nm Place's detection OD value, if A1(contains 200 μ l DMSO) it is blank control wells, with cis-platinum (cisplatin), taxol (Taxol) is sun Property control.After obtaining each group OD value, Cytostatic to tumor cell rate (this part Experiment is repeated 3 times) is calculated according to the following formula:
Growth inhibition ratio (%)=(blank group absorbance values-dosing group absorbance values)/blank group absorbance is flat Mean value × 100%.Acquired results bring IC into50Software for calculation finds out IC50Value.
Test result
Table 1 is cytotoxicity of the polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound 1-6 to five kinds of human tumor cell lines.
Table 1 the result shows that, compound 1-6 all shows the cell toxicant of moderate strength to a variety of human tumor cell lines in vitro Effect.Cytotoxic activity (IC of the compound 2 to human colon carcinoma SW480 cell strain507.78 μM) and to human leukemia HL-60 cell Cytotoxic activity (the IC of strain502.47 μM), the cytotoxic activity with one of positive control cisplatin on human colon cancer SW480 cell strain (IC508.17 μM) and to human leukemia HL-60 cell strain cytotoxic activity (IC502.06 μM) substantially quite.
Cytotoxic activity (IC of the compound 4 to MCF-7 Human Breast Cancer Cells strain5011.92 μM) and to human colon carcinoma SW480 Cytotoxic activity (the IC of cell strain507.62 μM) 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 (IC5013.93 μM) and to the cytotoxic activity (IC of human colon carcinoma SW480 cell strain508.17 μM).
Cytotoxic activity (IC of the compound 5 to human colon carcinoma SW480 cell strain505.80 μM), it is more suitable than one of positive control Cytotoxic activity (IC of the platinum to human colon carcinoma SW480 cell strain508.17 μM) 1.4 times of difference is active more significant.
Above-mentioned experiment results proved the compounds of this invention 1-6 has the bioactivity of good extracorporeal anti-tumor, is wood bamboo The comprehensive utilization of sub- plant, treating cancer drug development aspect, provides novel drugs and new approach.
The above described is only a preferred embodiment of the present invention, being not intended to limit the present invention in any form, appoint What is to the above embodiments according to the technical essence of the invention any simply to repair without departing from technical solution of the present invention content Change, equivalent variations and modification, all of which are still within the scope of the technical scheme of the invention.

Claims (3)

1. a kind of polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound with anti-tumor activity, structural formula are as follows:
2. the preparation side of polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound with anti-tumor activity as described in claim 1 Method, comprising the following steps:
(1) the dry branches and leaves of garcinia multiflora are taken, use 95% industrial methanol in the case where temperature is 70 DEG C -80 DEG C to its refluxing extraction 3-5 times Recycling methanol is concentrated to give medicinal extract afterwards, and medicinal extract water is miscible at muddy object, by ethyl acetate equal-volume extraction, is concentrated to give acetic acid second Ester layer medicinal extract；
(2) ethyl acetate layer medicinal extract passes through 300-400 mesh silica gel column chromatography, use chloroform and ethyl acetate volume ratio for 60:1~ The eluent gradient of 0:1 ratio elutes, and point lamellae merges into 4 parts: Fr 1, Fr 2, Fr 3, Fr 4；
(3) silica gel column chromatography is carried out to Fr 2 in step 2 again, uses chloroform and ethyl acetate volume ratio for 40:1~1:1 ratio The eluent gradient elution of example, is again divided into 4 sub-parts: Fr 2a, Fr 2b, Fr 2c, Fr 2d, Fr 2b is by flowing Mutually it is the Sephadex LH-20 gel filtration chromatography of methanol, and purifies to obtain compound 1,2 through more than half preparative high-performance liquid chromatographics With 3, wherein the mobile phase of half preparative high-performance liquid chromatographic is methanol: water volume ratio 88:12；
(4) silica gel column chromatography is carried out to Fr 3 in step 2, uses chloroform and ethyl acetate volume ratio for 40:1~1:1 ratio Eluent gradient elution, be again divided into 5 sub-parts: Fr 3a, Fr 3b, Fr 3c, Fr 3d, Fr 3e, Fr 3d are through overcurrent It is dynamic to be mutually the Sephadex LH-20 gel filtration chromatography of methanol, and purify to obtain compound 4 through more than half preparative high-performance liquid chromatographics With 5, wherein the mobile phase of half preparative high-performance liquid chromatographic is methanol: water volume ratio 78:22；
(5) silica gel column chromatography is carried out to Fr 4 in step 2, uses chloroform and ethyl acetate volume ratio for 20:1~1:1 ratio Eluent gradient elution, be again divided into 3 sub-parts: Fr 4a, Fr 4b, Fr 4c, Fr 4c are methanol by mobile phase Sephadex LH-20 gel filtration chromatography, and purify to obtain compound 6 through more than half preparative high-performance liquid chromatographics, wherein half prepares height The mobile phase of effect liquid phase chromatogram is methanol: water volume ratio 73:27.
3. as claim 1 polycyclic polyisocyanate pentenyl phloroglucinol derivatives compound with anti-tumor activity is preparing 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 people's knot Application in intestinal cancer SW480 cell strain inhibitor.
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