CN107118126A - PPAP imine compounds and preparation method thereof, pharmaceutical composition and purposes - Google Patents
PPAP imine compounds and preparation method thereof, pharmaceutical composition and purposes Download PDFInfo
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- CN107118126A CN107118126A CN201710455007.6A CN201710455007A CN107118126A CN 107118126 A CN107118126 A CN 107118126A CN 201710455007 A CN201710455007 A CN 201710455007A CN 107118126 A CN107118126 A CN 107118126A
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- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
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Abstract
The invention discloses a kind of PPAP imine compounds and preparation method thereof, pharmaceutical composition and purposes, the PPAP imine compounds are compound or the compound with structure shown in formula I pharmaceutically acceptable salt, dynamic isomer, stereoisomer, precursor compound or hydrate：
Description
Technical field
The present invention relates to a kind of PPAP imine compounds and preparation method thereof, pharmaceutical composition and purposes, belong to medicine
Field.
Background technology
Malignant tumour is one of fatal disease main in the world, seriously threatens human health and life.Middle traditional Chinese medical science
Tumour hospital of subject institute, National Cancer Center He Jie academician, national tumour Register director professor Chen Wanqing are waited in CA:A
The Cancer in China statistics in 2015 delivered on Cancer Journal for Clinicians magazines show, in 2015
State there are about 429.2 million new tumor cases and 281.4 ten thousand deaths.With the aggravation of the Aging Problem of population, China
The incidence of disease of cancer is in rising trend, and great burden is caused to China's health resources and national economy, and cancer control has turned into existing
The emphasis of modern China's health strategy.National science and technology key special subjects " great new drug initiative " project, which is classified as clinic, to be needed medicine badly and grinds
One of 10 classes (kind) major disease of hair.
Guttiferae (Guttiferae) Garcinia (Garcinia Linn) plant Yunnan gamboge (Garcinia
Yunnanensis Hu) be China endemic species, be distributed in Gauge Railway in Southwest Yunnan Province, fruit is sour-sweet edible, and timber can make furniture,
Its rich in polycyclic many isopentene group phloroglucinol derivatives (Polycyclic polyprenylated acylphloroglucinols,
Abbreviation PPAPs) and mouth mountain ketone (Xanthones) compound, this two classes compound is with novel changeable structure and widely
Bioactivity, research shows that PPAPs and Xanthones have antineoplastic action, such as Chinese patent
CN201210507960.8, CN201410366679.6, CN201510056911.0, CN201610914347.6 etc. are reported
PPAPs classes compound is in the effect of anti-tumor aspect, the report such as Chinese patent CN201410280756.6, CN201510907922.5
Road effect of the Xanthones classes compound in anti-tumor aspect.
Although PPAPs has become the study hotspot of native compound, presently relevant report is also more, does not have also at present
The relevant report of PPAP imine compounds is related to, the more correlation without PPAP imine compounds in anti-tumor aspect is reported
Road.
The content of the invention
In view of the above-mentioned problems existing in the prior art, it is an object of the invention to provide a kind of PPAP imine compounds and its
Preparation method, pharmaceutical composition and purposes, to promote such compound in the extensive use of field of medicaments.
PPAP imine compounds of the present invention be compound or the compound with structure shown in formula I pharmaceutically
Acceptable salt, dynamic isomer, stereoisomer, precursor compound or hydrate：
Wherein：R1、R2、R3、R4、R5It is each independently selected from hydrogen, ORa, substituted or unsubstituted C1~C12 alkyl, substitution
Or unsubstituted C2~C12 alkenyls, substituted or unsubstituted C2~C12 alkynyls, substituted or unsubstituted C6~C30 aryl, take
Generation or unsubstituted C1~C30 heteroaryls in any one, Ra be selected from hydrogen, substituted or unsubstituted C1~C12 alkyl, take
Generation or unsubstituted C2~C12 alkenyls, substituted or unsubstituted C2~C12 alkynyls, substituted or unsubstituted C6~C30 aryl,
Any of substituted or unsubstituted C1~C30 heteroaryls.
Preferably, R1、R2、R3、R4It is each independently selected from H, CH3、OCH3, any one in OH, X, R5Choosing
From H, CH3、OCH3, any one in OH, X, Y；
X has Formula X -1, structure shown in X-2, X-3, X-4, X-5, X-6 or X-7：
Wherein：Rx1、Rx2、Rx3、Rx4、Rx5、Rx6、Rx7、
Rx8、Rx9、Rx10、Rx12、Rx13Any one in hydrogen, methyl, methoxyl group, hydroxyl, isopentene group is each independently selected from,
Rx11For isopentene group, Rx14Any one in hydrogen, methyl, methoxyl group, isopentene group, Rx15、Rx16Select independently of one another
From any one in hydrogen, methyl, methoxyl group, hydroxyl, isopentene group, and work as Rx15、Rx16In any one be hydroxyl when, remain
Remaining one can not be hydrogen, methoxyl group or hydroxyl；
Y has structure shown in formula Y-1 or Y-2：
Wherein：Ry1、Ry2、Ry3、Ry4、Ry5And Ry6It is each independently selected from
Hydrogen, methyl, methoxyl group, hydroxyl or isopentene group.
As further preferred scheme, the PPAP imine compounds are selected from the medicine of following compound or the compound
Acceptable salt, dynamic isomer, stereoisomer, precursor compound or hydrate on：
We are named as garciyunnanimine A；
We are named as garciyunnanimine B；
We are named as garciyunnanimine C；
We are named as garciyunnanimine D；
We are named as garciyunnanimine E.
Those skilled in the art should be understood that after the structure of PPAP imine compounds of the present invention is known, can be by a variety of
Method well known in the art, using known raw material, to obtain the PPAP imine compounds of the present invention, such as from plant (example
Such as Yunnan gamboge) middle extraction or chemical synthesis (such as PPAPS imidizations).
PPAP imine compounds Chinese style II of the present invention, formula III, the isolation and purification method of the compound of formula IV, including
Following steps：
A) extracted 3~5 times with 95wt% alcohol heat reflux after Yunnan gamboge is crushed, extract solution is evaporated under reduced pressure, must extract
Thing；
B) extract obtained by step a) is suspended in water, is extracted successively with petroleum ether, ethyl acetate, respectively obtain cloud
The petroleum ether extraction position of southern Resina garciniae extract, Ethyl acetate fraction；
C) by the petroleum ether extraction position of Yunnan Resina garciniae extract obtained by step b) by silica gel post separation, with petroleum ether and
Acetone is according to 100：0~50：The mixed solution gradient elution successively of 50 volume ratio formation, every part of eluent is passed through after being evaporated under reduced pressure
TLC tlc analysis, the main point identical eluate shown on TLC lamellaes is merged, 16 are obtained by eluting order
Component；
D) by the obtained in step c) the 5th component ODS post separation, with first alcohol and water according to 30：70~100：0
The mixed solution gradient elution successively of volume ratio formation, every part of eluent be evaporated under reduced pressure after through TLC tlc analysis, by TLC thin layers
The main point identical eluate shown on plate merges, and 26 components are obtained by eluting order；
E) by the 17th component Sphadex LH20 gel post separations in step d), eluted with methanol, obtain ten
Individual component, wherein the 3rd component is purified with preparative liquid chromatography, obtains the compound of formula III (garciyunnanimine B)；
F) the 18th component in step d) is purified with preparative liquid chromatography, obtains the compound of formula II
(garciyunnanimine A)；
G) the 23rd component in step d) is purified with preparative liquid chromatography, obtains the compound of formula IV
(garciyunnanimine C)。
The preparation method of PPAP imine compounds of the present invention, is to make the compound of formula VII in the presence of an organic
Obtain type I compound with ammonia reaction, or in the presence of acetic acid catalyst and organic solvent with the chemical combination of ammonia reaction acquisition formula I
Thing, specific reaction equation is as follows：
Wherein R1、R2、R3、R4、R5Such as the definition in formula I.
Preferably, the organic solvent is Non-alchoholic solvents, for example：Dioxane；Reaction temperature is 70~90 DEG C.
A kind of pharmaceutical composition of anti-curing oncoma, the composition includes the chemical combination with structure shown in formula I of therapeutically effective amount
At least one of thing or its pharmaceutically acceptable salt, dynamic isomer, stereoisomer, precursor compound, hydrate.
Preferably, the tumour is selected from least one of liver cancer, lung cancer, leukemia.
PPAP imine compounds of the present invention can be used to prepare prevention as active component and/or treat tumour
Medicine or health products.
Preferably, the tumour is selected from least one of liver cancer, lung cancer, leukemia.
Composition of the present invention, the formulation of antineoplastic can be diversified, as long as can make activity into
Point effectively reaching internal formulation is all possible.Such as it may be selected from：It is tablet, capsule, powder, granule, syrup, molten
The common dosage forms such as liquid, suspension, injection, tincture, oral liquid, aerosol, mouth containing agent, electuary, pill, powder or nanometer formulation
Etc. slow release formulation.
Effective application dosage of active component of the present invention can be with composition used, the pattern and to be treated of administration
The order of severity of disease and change.
Heretofore described term is defined as follows：
Term " C1-C12 alkyl " refers to straight or branched alkyl or cycloalkyl with 1-12 carbon atom, for example：First
Base, methylene, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopropyl, cyclobutyl, cyclopenta, ring
Hexyl, suberyl, or similar group.
Term " C2-C12 alkenyls " refers to straight or brancheds with 2-6 carbon atom, with one or more double bonds
Alkenyl or cycloalkenyl group, for example：Vinyl, pi-allyl, 1- acrylic, isopropenyl, 1- cyclobutenyls, 2- cyclobutenyls, iso-amylene
Base, cyclohexenyl group, cycloheptenyl, 1,3- cyclohexadienyls, 1,4- cyclohexadienyls or similar group.
Term " C2-C12 alkynyls " refers to straight or brancheds with 2-12 carbon atom, with one or more three keys
Alkynyl, for example：Acetenyl, propinyl or similar group.
Term " C6~C30 aryl " refers to the aryl with 6~30 carbon atoms, including monocyclic or aryl bicyclic, for example：
Phenyl, naphthyl or similar group.
Term " C1~C30 heteroaryls " refers to the heteroaryl with 1~30 carbon atom, for example：Pyrrole radicals, pyridine radicals,
Furyl or similar group.
Term " substitution " refers to that one or more hydrogen atoms on group are selected from the substituent substitution of the following group：C1~C10
Alkyl, C3~C10 cycloalkyl, C1~C10 alkoxies, halogen, hydroxyl, amino, phenyl, isopentene group；Described phenyl includes
Unsubstituted phenyl or the substituted-phenyl with 1-3 substituent, described substituent be selected from halogen, C1-C10 alkyl, cyano group,
Hydroxyl, nitro, C3~C10 cycloalkyl, C1~C10 alkoxies, amino or isopentene group.
Term " pharmaceutically acceptable salt " refers to the compound and pharmaceutically acceptable inorganic acid or organic acid institute
The salt of formation, described inorganic acid includes：Hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid；Described organic acid includes：Formic acid, second
Acid, propionic acid, succinic acid, naphthalenedisulfonic acid (1,5), asiatic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, two
Ethyl acetic acid, malonic acid, butanedioic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, benzenpropanoic acid, Portugal
Saccharic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, citric acid, and amino acid.
Term " dynamic isomer " refers to because of a certain atom is produced in two rapid movements in position in molecule functional group
Isomers, for example：Enol and corresponding ketone.
Term " stereoisomer " refers to as the isomers produced by the spatially arrangement mode difference of atom in molecule, example
Such as：Cis-trans-isomer, enantiomter, rotamer, diastereoisomer etc..
Term " precursor compound " refer to it is inactive in vitro, but can be metabolized or be chemically reacted in vivo turn
The active component of the present invention is turned to, so as to play the compound of its pharmacological action.
Term " composition " refers in the composition, in addition to containing main active, can also containing a small amount of and
The submember and/or pharmaceutically acceptable carrier of active ingredient are not influenceed.For example, mouth can be improved containing sweetener
Taste, antioxidant are to prevent auxiliary material necessary to oxidation, and various preparations.
Term " pharmaceutically acceptable " refers to suitable for people without excessively bad side reaction (such as toxicity, stimulation and metamorphosis
Reaction), that is, have rational benefit/risk than material.
Compared with prior art, the present invention has following conspicuousness beneficial effect：
The result of study of the present invention is shown：The PPAP imine compounds with logical structure shown in formula I of the present invention can be bright
It is aobvious to suppress human liver cancer cell HepG2, Non-small cell lung carcinoma cell A549 and Multiple myeloma cell lines RPMI-822672
The activity of propagation, this explanation PPAP imine compounds with logical structure shown in formula I of the present invention have suppression tumour cell
The effect of propagation, can be used for the medicine or health products for preparing prevention and/or treatment tumour, with wide application prospect.
Brief description of the drawings
Fig. 1 is the compound of formula II1H NMR and13C NMR data；
Fig. 2 is the compound of formula III1H NMR and13C NMR data；
Fig. 3 is the compound of formula IV1H NMR and13C NMR data；
Fig. 4 is the compound of formula V1H NMR and13C NMR data；
Fig. 5 is the compound of formula VI1H NMR and13C NMR data.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip
Part or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and number are calculated by weight.
In following implementation, Yunnan gamboge selects fruit, branch and the leaf of Dai-Jingpo Autonomous Prefecture of Dehong of Yunnan Province Yunnan gamboge；
MCI posts select CHP20P MCI gel (75-150 μm, Mitsubishi Chemical；Coparation,
Japan)；Silica gel column chromatography selects Qingdao Marine Chemical Co., Ltd.'s column chromatography silica gel (200-300 mesh)；
TLC tlc analysis selects Yantai Jiang You silica gel development corporation, Ltd. HSGF254 tlc silica gel plates；
Suppressed in ODS standby chromatographic column from reversed-phase C18 silica gel (50 μm, YMC, Kyoto,
Japan)；Gel column is filler from Sephadex LH-20 (GE Healthcare Bio-Sciences AB, Sweden)；
Mass spectrum be Waters ACQUITY UPLC/Synapt G2-Si MS ultra performance liquid chromatographies/electron spray level Four bar-
Flight time mass spectrum is combined, and chromatographic column used is Waters ACQUITY BEH C18 (2.1mm*100mm, 1.7 μm)；
Preparation HPLC be Waters 2535, preparations chromatographic column for Xbridge Prep C18 OBD column (19 ×
250mm, 5 μm), analysis is Xbridge C18 column (4.6 × 250mm, 5 μm) with HPLC chromatogram post；
Optical rotatory testing instrument device is Autopol VI polarimeter；
Ultraviolet specrophotometer is UV-2401 PC spectrophotometer；
Infrared spectrum is tested using the spectrometer of Perkin-Elmer 577；
Nuclear-magnetism is tested using Bruker AV-400 spectrometer；
Liquid phase is chromatographic grade with acetonitrile, and water is distilled water, and formic acid is analysis level；
Mass spectrum is mass spectrum level with acetonitrile, and water is the distilled water handled through Mill-Q, and formic acid is mass spectrum level；
Pressure and gel with methanol are analysis level in ODS, and water is distilled water；
Other reagents are synthesis level.
Embodiment 1
Formula II (garciyunnanimine A), (garciyunnanimine of formula III are isolated and purified from the gamboge of Yunnan
B), formula IV (garciyunnanimine C) compound：
A) the Yunnan gamboge (including fruit 12kg, branch 34kg and leaf 6kg) that 52kg is dried is extracted after crushing by extractor,
Every time with 95wt% ethanol (520L) circumfluence distillation 1 hour of 10 times of amounts, repeat to extract 3 times, reduction vaporization extract solution must be carried
Take thing；
B) extract obtained by step a) is suspended in water, is extracted successively with petroleum ether, ethyl acetate, respectively obtain cloud
The petroleum ether extraction position (2.5kg) of southern Resina garciniae extract, Ethyl acetate fraction (3.3kg)；
C) the petroleum ether extraction position of Yunnan Resina garciniae extract obtained by step b) is passed through into silica gel post separation (300-400 mesh
Silica gel is used as separation, 6kg；100-200 mesh silica gel mixed samples, 1.8kg), with petroleum ether and acetone according to 100：0~50：50 body
Product than formation mixed solution gradient elution successively, every part of eluent be evaporated under reduced pressure after through TLC tlc analysis, by TLC lamellaes
The main point identical eluate of upper display merges, and 16 components are obtained by eluting order；
D) by the obtained in step c) the 5th component ODS post separation, with first alcohol and water according to 30：70~100：0
The mixed solution gradient elution successively of volume ratio formation, eluent collects 2000mL every time, and every part of eluent is passed through after being evaporated under reduced pressure
TLC tlc analysis, the main point identical eluate shown on TLC lamellaes is merged, 26 are obtained by eluting order
Individual component；
E) by the 17th component Sphadex LH20 gel post separations in step d), eluted with methanol, obtain ten
Individual component, wherein the 3rd component purifies (acetonitrile with HPLC is prepared：0.1% formic acid water=65：35, v/v) chemical combination of formula III, is obtained
Thing garciyunnanimine B (light yellow gum solid, 6mg)；
F) the 18th component in step d) is purified into (acetonitrile with HPLC is prepared：0.1% formic acid water=72：28, v/
V), the compound garciyunnanimine A (light yellow gum solid, 10mg) of formula II are obtained；
G) the 23rd component in step d) is purified into (acetonitrile with HPLC is prepared：0.1% formic acid water=77：23, v/
V), the compound garciyunnanimine C (light yellow gum solid, 9mg) of formula IV are obtained.
The compound garciyunnanimine A of formula II Structural Identification data：
[α]20 D11.7(c 0.03,MeOH)；
UV(MeOH)λmax(logε)255(4.03),317(3.85),350(3.78)nm；
ECD(c 4.99×10-4M,MeOH)λmax nm(Δε)208(+13.22),257(–3.39),282(2.70),
305(–3.36)；
IR(KBr)νmax 3258,2969,2922,2857,1715,1639,1577,1442,1376,1281,1202,
1115,1048,1024,1003,822,762,735,688cm-1；
HRESIMS m/z 602.3850[M+H]+(calcd for C38H52NO5,602.3845)；
1H NMR(DMSO-d6, 400MHz) and13C NMR(DMSO-d6, 100MHz) data as shown in Figure 1.
The compound garciyunnanimine B of formula III Structural Identification data：
[α]20 D–69.0(c 0.035,MeOH)；
UV(MeOH)λmax(logε)257(4.45),322(3.94),352(3.90)nm；
ECD(c 3.99×10-4M,MeOH)λmax nm(Δε)230(+5.17),265(–0.94),287(+16.73),
320(–5.90)；
IR(KBr)νmax 3237,3068,2968,2919,1715,1637,1577,1524,1442,1391,1373,
1282,1114,1048,1024,1003,887,862,762cm-1；
HRESIMS m/z 602.3845[M+H]+(calcd for C38H52NO5,602.3845)；
1H NMR(DMSO-d6, 400MHz) and13C NMR(DMSO-d6, 100MHz) data as shown in Figure 2.
The compound garciyunnanimine C of formula IV Structural Identification data：
[α]20 D11.4(c 0.041,MeOH)；
UV(MeOH)λmax(logε)255(4.16),317(3.97),352(3.92)nm；
ECD(c 4.37×10-4M,MeOH)λmax nm(Δε)206(+10.48),259(–1.97),282(+1.83),
302(–2.73)；
IR(KBr)νmax 3214,2967,2915,2857,1716,1639,1577,1441,1376,1280,1114,
1048,1024,1003,823,763cm-1；
HRESIMS m/z 670.4471[M+H]+(calcd for C43H60NO5,670.4471)；
1H NMR(DMSO-d6, 400MHz) and13C NMR(DMSO-d6, 100MHz) data as shown in Figure 3.
Embodiment 2
The compound garciyunnanimine A of chemical synthesis formula II：
Guttiferone K (20mg, 0.033mmol), the dioxane solution of 0.5M ammonias are added into reactor
(13.3mL, 6.6mmol, 200equiv.), acetic acid (1.89mL, 0.033mmol, 1equiv.) is small in 80 DEG C of insulation reactions four
When, terminate reaction, reaction solution is cooled to after room temperature the removing reaction dissolvent that is concentrated under reduced pressure, after concentrate methanol dissolves, adopted
With HPLC liquid phases are prepared, the formic acid water of acetonitrile -0.1% (80 that flow velocity is 20mL/min is used：20, v/v) elute, obtain the change of formula II
Compound (light yellow gum solid, 13.2mg), yield 66%.
The Structural Identification data of the compound of gained formula II are consistent with the corresponding data in embodiment 1.
Embodiment 3
The compound garciyunnanimine B of chemical synthesis formula III：
Garcinol (20mg, 0.033mmol), the dioxane solution of 0.5M ammonias are sequentially added into reactor
(13.3mL, 6.6mmol, 200equiv.), acetic acid (1.89mL, 0.033mmol, 1equiv.), the stirring reaction four at 80 DEG C
Hour, reaction solution is cooled to after room temperature the removing reaction dissolvent that is concentrated under reduced pressure, after concentrate methanol dissolves, using preparation
HPLC liquid phases, use the formic acid water of acetonitrile -0.1% (80 that flow velocity is 20mL/min：20, v/v) elute, obtain the compound of formula III
(light yellow gum solid, 13.8mg), yield 69%.
The Structural Identification data of the compound of gained formula III are consistent with the corresponding data in embodiment 1.
Embodiment 4
The compound garciyunnanimine C of chemical synthesis formula IV：
Oblongifolin C (20mg, 0.030mmol) are sequentially added into reactor, the dioxane of 0.5M ammonias is molten
Liquid (14.8mL, 7.3mmol, 200equiv.), acetic acid (2.10mL, 0.030mmol, 1equiv.), the stirring reaction at 80 DEG C
Four hours, reaction solution was cooled to after room temperature the removing reaction dissolvent that is concentrated under reduced pressure, after concentrate methanol dissolves, using preparation
HPLC liquid phases, use the formic acid water of acetonitrile -0.1% (80 that flow velocity is 20mL/min：20, v/v) elute, obtain the compound of formula IV
(light yellow gum solid, 14.2mg), yield 71%.
The Structural Identification data of the compound of gained formula IV are consistent with the corresponding data in embodiment 1.
Embodiment 5
The compound garciyunnanimine D of chemical synthesis formula V：
Oblongifolin A (20mg, 0.033mmol) are sequentially added into reactor, the dioxane of 0.5M ammonias is molten
Liquid (13.3mL, 6.6mmol, 200equiv.), acetic acid (1.89mL, 0.033mmol, 1equiv.), in stirring reaction at 80 DEG C
Four hours, reaction solution was cooled to after room temperature the removing reaction dissolvent that is concentrated under reduced pressure, after concentrate methanol dissolves, using preparation
HPLC liquid phases, use the formic acid water of acetonitrile -0.1% (68 that flow velocity is 20mL/min：32, v/v) elute, obtain the compound of formula V
(light yellow gum solid, 12.4mg), yield 62%.
The compound garciyunnanimine D of formula V Structural Identification data：
[α]20 D25.4(c 0.04,MeOH)；
UV(MeOH)λmax(logε)255(4.48),317(3.94),352(3.90)nm；
ECD(c 6.66×10-4M,MeOH)λmax nm(Δε)202(+14.90),251(–3.13),282(+3.10),
314(–2.71)；
IR(KBr)νmax 3207,2970,2913,1718,1640,1577,1525,1441,1375,1283,1114,
1048,1025,1004,877,823,762,682cm-1；
HRESIMS m/z 602.3844[M+H]+(calcd for C38H52NO5,602.3845)；
1H NMR(DMSO-d6, 400MHz) and13C NMR(DMSO-d6, 100MHz) data as shown in Figure 4.
Embodiment 6
The compound garciyunnanimine E of chemical synthesis formula VI：
Oblongifolin B (20mg, 0.033mmol) are sequentially added into reactor, the dioxane of 0.5M ammonias is molten
Liquid (13.3mL, 6.6mmol, 200equiv.), acetic acid (1.89mL, 0.033mmol, 1equiv.), the stirring reaction at 80 DEG C
Four hours, reaction solution was cooled to after room temperature the removing reaction dissolvent that is concentrated under reduced pressure, after concentrate methanol dissolves, using preparation
HPLC liquid phases, use the formic acid water of acetonitrile -0.1% (80 that flow velocity is 20mL/min：20, v/v) elute, obtain the compound of formula VI
(light yellow gum solid, 11.8mg), yield 59%.
The compound garciyunnanimine E of formula VI Structural Identification data：
[α]20 D15.6(c 0.047,MeOH)；
UV(MeOH)λmax(logε)255(4.11),317(3.92),352(3.85)nm；
ECD(c 7.82×10-4M,MeOH)λmaxnm(Δε)207(+5.83),263(+3.11),307(–92)；
IR(KBr)νmax 3255,2970,2916,2856,1716,1639,1578,1525,1441,1393,1282,
1115,1024,1003,822,762cm-1；
HRESIMS m/z 602.3852[M+H]+(calcd for C38H52NO5,602.3845).；
1H NMR(DMSO-d6, 400MHz) and13C NMR(DMSO-d6, 100MHz) data as shown in Figure 5.
Embodiment 7
Formula II, formula III, formula IV, formula V, the compound of formula VI suppress human tumor cells proliferation test：
7.1 experiment material
A549 (human lung adenocarcinoma cell), RPMI-8226 (multiple myeloma cells) is purchased from ATCC and the Chinese Academy of Sciences
Marine growth chemistry and Institute of Cell Biology cell bank；Cell is placed in 37 DEG C, 5%CO2Cultivated in incubator, when thin
Born of the same parents are used for external activity test when reaching for 8 to 15 generation；CCK-8 kits are purchased from Japanese colleague's chemistry institute (Dojindo).
7.2 cell proliferation experiment
Cell suspension is added in 96 orifice plates with every μ L of hole 180,37 DEG C, 5%CO2 overnight incubations make cell attachment；Next day
The crude extract prepared or compound solution are added in respective aperture；Cultivate after 72h, culture medium is abandoned in suction, add and contain 10%
CCK-8 culture medium, is placed in incubator and cultivates 2h；In enzyme-linked immunosorbent assay instrument (MDS, Sunnyvale, CA450nm) wavelength
It is lower to determine per hole absorbance value.
Cell inhibitory rate calculation formula is as follows：
Inhibiting rate (%)=(ODDMSO-ODTest group)/ODDMSO× 100%；
Experimental data is represented with mean+/-standard error.
7.3 experimental result
Garciyunnanimine A (compound of formula II), garciyunnanimine B (compound of formula III),
Garciyunnanimine C (compound of formula IV), garciyunnanimine D (compound of formula V),
Garciyunnanimine E (compound of formula VI) act on a variety of human tumour 72h IC50As shown in table 1.
The IC of the compound of table 150It is worth (μM)
| Compound | A549 | HepG2 | RPMI-8226 |
| garciyunnanimine A | 3.9±0.5 | 4.7±1.0 | 3.5±0.4 |
| garciyunnanimine B | 4.4±0.2 | 10.1±2.3 | 1.7±0.1 |
| garciyunnanimine C | 7.7±0.8 | 23.7±3.4 | 3.5±1.9 |
| garciyunnanimine D | 6.8±1.8 | 15.0±3.5 | 1.9±0.3 |
| garciyunnanimine E | 8.2±1.5 | 12.8±2.7 | 5.8±0.9 |
| etoposide | 9.2±1.4 | 11.7±1.5 | ＜ 0.25 |
From table 1, noval chemical compound garciyunnanimine A (compound of formula II), garciyunnanimine B
(compound of formula III), garciyunnanimine C (compound of formula IV), garciyunnanimine D (compound of formula V),
Garciyunnanimine E (compound of formula VI) are for human liver cancer cell HepG2, Non-small cell lung carcinoma cell A549 and people
Multiple myeloma cell line RPMI-8226 is respectively provided with the significant effect for suppressing tumor cell proliferation, is better than positive control drug
Etoposide (etoposide), with potential antitumor action, can be used as the medicine or guarantor for preventing and/or treating tumour
Strong product.
Finally need it is pointed out here that be：It the above is only the part preferred embodiment of the present invention, it is impossible to be interpreted as to this hair
The limitation of bright protection domain, those skilled in the art according to the present invention the above make some it is nonessential improvement and
Adjustment belongs to protection scope of the present invention.
Claims (9)
1. a kind of PPAP imine compounds, it is characterised in that be the pharmacy of compound with structure shown in formula I or the compound
Upper acceptable salt, dynamic isomer, stereoisomer, precursor compound or hydrate：
Wherein：R1、R2、R3、R4、R5Be each independently selected from hydrogen, ORa, substituted or unsubstituted C1~C12 alkyl, substitution or not
Substituted C2~C12 alkenyls, substituted or unsubstituted C2~C12 alkynyls, substituted or unsubstituted C6~C30 aryl, substitution or
Any one in unsubstituted C1~C30 heteroaryls, Ra be selected from hydrogen, substituted or unsubstituted C1~C12 alkyl, substitution or
Unsubstituted C2~C12 alkenyls, substituted or unsubstituted C2~C12 alkynyls, substituted or unsubstituted C6~C30 aryl, substitution
Any of or unsubstituted C1~C30 heteroaryls.
2. PPAP imine compounds according to claim 1, it is characterised in that：R1、R2、R3、R4It is each independently selected from
H、CH3、OCH3, any one in OH, X, R5Selected from H, CH3、OCH3, any one in OH, X, Y；
X has Formula X -1, structure shown in X-2, X-3, X-4, X-5, X-6 or X-7：
Wherein：Rx1、Rx2、Rx3、Rx4、Rx5、Rx6、Rx7、
Rx8、Rx9、Rx10、Rx12、Rx13Any one in hydrogen, methyl, methoxyl group, hydroxyl, isopentene group is each independently selected from,
Rx11For isopentene group, Rx14Any one in hydrogen, methyl, methoxyl group, isopentene group, Rx15、Rx16Select independently of one another
From any one in hydrogen, methyl, methoxyl group, hydroxyl, isopentene group, and work as Rx15、Rx16In any one be hydroxyl when, remain
Remaining one can not be hydrogen, methoxyl group or hydroxyl；
Y has structure shown in formula Y-1 or Y-2：
Wherein：Ry1、Ry2、Ry3、Ry4、Ry5And Ry6It is each independently selected from hydrogen, first
Base, methoxyl group, hydroxyl or isopentene group.
3. PPAP imine compounds according to claim 2, it is characterised in that the PPAP imine compounds are selected from
Following compound or the compound pharmaceutically acceptable salt, dynamic isomer, stereoisomer, precursor compound or water
Compound：
4. PPAP imine compounds according to claim 3, it is characterised in that formula II, formula III, point of the compound of formula IV
From purification process, comprise the following steps：
A) extracted 3~5 times with 95wt% alcohol heat reflux after Yunnan gamboge is crushed, extract solution is evaporated under reduced pressure, extract is obtained；
B) extract obtained by step a) is suspended in water, is extracted successively with petroleum ether, ethyl acetate, respectively obtain Yunnan rattan
The petroleum ether extraction position of yellow extract, Ethyl acetate fraction；
C) by the petroleum ether extraction position of Yunnan Resina garciniae extract obtained by step b) by silica gel post separation, with petroleum ether and acetone
According to 100：0~50：The mixed solution gradient elution successively of 50 volume ratio formation, every part of eluent be evaporated under reduced pressure after through TLC
Tlc analysis, the eluent that identical main point is shown on TLC lamellaes is merged, 16 components are obtained by eluting order；
D) by the obtained in step c) the 5th component ODS post separation, with first alcohol and water according to 30：70~100：0 volume
Than the mixed solution gradient elution successively of formation, every part of eluent be evaporated under reduced pressure after through TLC tlc analysis, by TLC lamellaes
Show that the eluent of identical main point merges, 26 components are obtained by eluting order；
E) by the 17th component Sphadex LH20 gel post separations in step d), eluted with methanol, obtain ten groups
Point, wherein the 3rd component is purified with preparative liquid chromatography, obtain the compound of formula III；
F) the 18th component in step d) is purified with preparative liquid chromatography, obtains the compound of formula II；
G) the 23rd component in step d) is purified with preparative liquid chromatography, obtains the compound of formula IV.
5. the preparation method of the PPAP imine compounds described in a kind of claim 1, it is characterised in that be to make the compound of formula VII
In the presence of an organic with ammonia reaction obtain type I compound, or in the presence of acetic acid catalyst and organic solvent with ammonia
Solid/liquid/gas reactions obtain type I compound, and specific reaction equation is as follows：
Wherein R1、R2、R3、R4、R5With the definition in formula I.
6. a kind of pharmaceutical composition of anti-curing oncoma, it is characterised in that：The composition will comprising therapeutically effective amount such as right
Ask compound with structure shown in formula I or its pharmaceutically acceptable salt described in 1, it is dynamic isomer, stereoisomer, precursor
At least one of compound, hydrate.
7. pharmaceutical composition according to claim 6, it is characterised in that：The tumour is in liver cancer, lung cancer, leukemia
It is at least one.
8. a kind of purposes of the PPAP imine compounds described in claim 1, it is characterised in that：With described PPAP imines
Medicine or health products that compound is used to prepare prevention and/or treatment tumour as active component.
9. purposes according to claim 8, it is characterised in that：The tumour in liver cancer, lung cancer, leukemia at least one
Kind.
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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 |
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