CN102532092A - Natural product Bostrycin derivative I as well as preparation method and application thereof - Google Patents

Natural product Bostrycin derivative I as well as preparation method and application thereof Download PDF

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CN102532092A
CN102532092A CN2012100125169A CN201210012516A CN102532092A CN 102532092 A CN102532092 A CN 102532092A CN 2012100125169 A CN2012100125169 A CN 2012100125169A CN 201210012516 A CN201210012516 A CN 201210012516A CN 102532092 A CN102532092 A CN 102532092A
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bostrycin
natural product
preparation
verivate
alkyl
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佘志刚
黎孟枫
陈洪
朱勋
林永成
吴珏珩
钟莉莉
袁洁
李嘉
何振健
蒋毅
文维韬
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Sun Yat Sen University
National Sun Yat Sen University
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Abstract

The invention discloses a natural product Bostrycin derivative I as well as a preparation method and application thereof. The natural product Bostrycin derivative I has a structure shown in the general formula (1) in the specification, wherein X is a structure shown in the specification, C=O, S=O or C=S; R<1> is H, hydroxymethyl or alkyl; R<2> is H, C1-10 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or aralkyl; R<3> is H, C1-10 alkyl, substituted or un substituted phenyl, substituted or unsubstituted benzyl, or aralkyl; R<4> is H, straight-chain or branch-chain alkyl, unsaturated alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or aralkyl; R<5> is H, straight-chain or branch-chain alkyl, unsaturated alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or aralkyl; and R<6> is H, alkyl or phenyl. Results of primary pharmacological research ( in vitro anti-tumor cell test) prove that the natural product Bostrycin derivative has excellent tumor cell resistance activity, can be further used for researching and developing novel antitumor drugs.

Description

Natural product Bostrycin derivatives I, Preparation Method And The Use
Technical field
The present invention relates to the discovery field of pharmaceutical chemistry, lead compound, be specifically related to one type of new natural product bostrycin verivate, its preparation method and purposes in the preparation antitumor drug through modifying.
Background technology
Bostrycin is a kind of pigment of redness, at first from Bostryconema alpespre cesati (Tetrahedron Lett. 58:6087,1968; Tetrahedron Lett. 58:6091,1968; Tetrahedron. separate obtaining 26:1339,1968), can suppress gram positive bacterium.Report (Sankyo Kenkyusho Nenpo. 21:165 subsequently again from Nigrospora oryzae; 1969), Fungus Arthrinium phaeospermum (Experientia. 31:783; 1975), Alternaria eichhorniae (Appl Environ Microbiol. 43:846; 1982) separate obtaining in, and find that it has weeding activity.2000; Jiang Guangce, Lin Yongcheng, Zhou Shining (Zhongshan University's journal (natural science edition); 39:68; 2000) separation obtains Bos trycin from South China Sea mangrove endogenetic fungus #1403 secondary metabolite, and cell in vitro poison test-results shows: Bostrycin all can effectively suppress growth of various tumor cell strains (CN1347865A; CN1850765A; CN1762961A; CN101544556A).
For a long time, human health and life in malignant tumour serious threat always.The sickness rate and the lethality rate of tumor disease rise year by year; Yet the specifics of treatment tumor disease especially at present the selectivity of antitumor clinical used cytotoxic drug not high cause to Normocellular pernicious killing and wounding, thereby limited the general applicability of such medicine.Therefore, seek and find that the new antitumor drug with high-efficiency low-toxicity is worldwide research focus.
Yet ball surface-area 70% is taken up an area of in the ocean, and abundant Biological resources are also being contained in the ocean when containing the abundant mineral and the energy.Marine microorganism in quantity or the variety aspect is all quite abundant.Because the living environment of marine microorganism is special, the compound of energy metabolism novel structure, and have good pharmacologically active has been found the compound of antitumor in a large number, treatment cardiovascular disorder, antibiotic, antiviral isoreactivity at present.According to the report of John professor at 2010 " Natural Product Reports ", found that the marine natural product new compound surpassed 1000 kinds first in 2008, marine microorganism is one of main source (accounting for 23%).In addition, marine microorganism is easy to gather and cultivate, and the meta-bolites that the artificial fermentation produces is purified easily, and cost is low, meets the resources development and utilization principle of Sustainable development, so the active compound that therefrom screens is more conducive to suitability for industrialized production.
Make full use of oceanic resources; With its effective constituent is that lead compound carries out structure of modification and composition optimizes; Design is synthetic to have the more compound of strong biological activity, is an effective way seeking new type antineoplastic medicine, and the present invention is a lead compound with South China Sea ocean mangrove endophytic fungus #1403 secondary metabolite Bos trycin; It is carried out structure of modification, and purpose is to seek the natural antitumor drug candidate of high-efficiency low-toxicity.
Summary of the invention
The contriver obtains the structure that compound Bostrycin has following IV by extraction separation in the South China Sea thalassiomycetes #1403 secondary metabolite.
Figure 806835DEST_PATH_IMAGE001
（Ⅳ）
The used fungi 1403 of the present invention be preserved in Chinese typical culture collection center (CCTCC, in
State Wuhan University is in the school), preserving number is CCTCC NO:M201018, preservation day is April 23 calendar year 2001.
The purpose of this invention is to provide a kind of novel natural product Bostrycin derivatives I.
Another object of the present invention provides the preparation method of above-mentioned novel natural product Bostrycin verivate.
A purpose more of the present invention provides the purposes of novel natural product Bostrycin verivate in the preparation antitumor drug.
The novel natural product Bostrycin verivate of the present invention has the structure of formula (I):
Figure 2012100125169100002DEST_PATH_IMAGE002
Figure 723976DEST_PATH_IMAGE003
Wherein: X=
Figure 2012100125169100002DEST_PATH_IMAGE004
or
Figure 305044DEST_PATH_IMAGE005
or C=O; S=O; C=S;
R 1=H, methylol, alkyl;
R 2The alkyl of=H, C1-C10, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl;
R 3The alkyl of=H, C1-C10, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl;
R 4=H, direct-connected or branched-chain alkyl, undersaturated alkyl, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl;
R 5=H, direct-connected or branched-chain alkyl, undersaturated alkyl, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl;
R 6=H, alkyl, phenyl;
Natural product Bostrycin verivate of the present invention prepares through following method: employing Bostrycin is a raw material, and with 2, the reaction of 2-Propanal dimethyl acetal obtains compound under the catalysis of acid 1Under the catalysis of acid, obtain compound with 3-methyl-2-butene aldehyde reaction 2Under the catalysis of acid, obtain compound with polyformaldehyde reaction 3Under the catalysis of alkali, obtain compound with the solid phosgene reaction 4Under the catalysis of alkali, obtain compound with the thionyl chloride reaction 5
Above-claimed cpd of the present invention is through preliminary pharmaceutical research, and through anticancer experiment in vitro, wherein majority of compounds has shown good activity, has good antineoplastic activity, can develop to be novel natural antitumor medicine.
Preferred compound of the present invention has following compound 1,2,3,4,5Structure:
Figure 2012100125169100002DEST_PATH_IMAGE006
The compounds of this invention 1The preparation process following:
Figure 762570DEST_PATH_IMAGE007
Compound 1Preparation technology comprise:
Bostrycin is under Catalyzed by p-Toluenesulfonic Acid, and with 2, the reaction of 2-Propanal dimethyl acetal obtains 5,10,11-trihydroxy-7
-methoxy-2,2,3a-trimethyl-3a, 4,11,11a-tetrahydroanthra [2,3-d] [1,3] dioxole-6,9-dione (compound 1).
The compounds of this invention 2The preparation process following:
Figure 2012100125169100002DEST_PATH_IMAGE008
Compound 2Preparation technology comprise:
Bostrycin obtains 5,10,11-trihydroxy-7-methoxy-with 3-methyl-2-butene aldehyde reaction under Catalyzed by p-Toluenesulfonic Acid
3a-methyl-2-(2-methylprop-1-enyl)-3a, 4,11,11a-tetrahydroanthra [2,3-d] [1,3] dioxole-6,9-dione (compound 2).
The compounds of this invention 3The preparation process following:
Figure 576942DEST_PATH_IMAGE009
Compound 3Preparation technology comprise:
Bostrycin obtains 5 with polyformaldehyde reaction under Catalyzed by p-Toluenesulfonic Acid, 10-dihydroxy-11-(hydroxymethoxy)
-7-methoxy-3a-methyl-3a, 4,11,11a-tetrahydroanthra [2,3-d] [1,3] dioxole-6,9-dione (compound 3).
The compounds of this invention 4The preparation process following:
Compound 4Preparation technology comprise:
Bostrycin obtains 5,10,11-trihydroxy-7-methoxy-3a-Methyl with the solid phosgene reaction under to pyridine catalysis
-3a, 4,11,11a-tetrahydroanthra [2,3-d] [1,3] dioxole-2,6,9-trione (compound 4).
The compounds of this invention 5The preparation process following:
Natural product Bostrycin verivate involved in the present invention, preliminary pharmaceutical research (extracorporeal anti-tumor cell tests), the result shows that this compounds has good antitumor cell activity, can further develop to be novel antitumor drug.
Embodiment:
Further specify the present invention through embodiment below.Embodiment has provided synthetic, the dependency structure appraising datum and the compound activity data of representative new compound.Mandatory declaration, following embodiment is used to explain the present invention rather than limitation of the present invention.The simple modifications that essence according to the present invention is carried out the present invention all belongs to the present invention and requires the scope protected.
Beijing X is used in fusing point test 4Type micro melting point apparatus (TM is not proofreaied and correct).
1HNMR, 13C NMR is with U.S. Varian Inova-500 NB and Switzerland Bruker AVANCE AV-400NB,
TMS does interior mark.
Mass spectrum is measured with Thremo LCQ DECA XP LC-MS appearance and Thremo DSQ mass spectrograph.
Embodiment 1: compound 1Preparation
Figure 2012100125169100002DEST_PATH_IMAGE012
In the 25mL round-bottomed flask, add 50mg (0.149mmol) Bostrycin, 310mg (3.0mmol) 2,2-Propanal dimethyl acetal; 25.6mg (0.149mmol) tosic acid; The 10mL THF at room temperature reacts 20h, and TLC shows that raw material reaction is complete.Stopped reaction adds 10mL water, with dichloromethane extraction (50mL * 3), merges organic phase, and organic phase is water and saturated common salt water washing respectively, and anhydrous magnesium sulfate drying filters, and concentrates.Crude product is through purification by silica gel column chromatography, and eluent: V (methylene dichloride): V (sherwood oil)=1:1 gets the 48.5mg red solid, yield: 90%.mp：228-229℃； 1H?NMR（δ H,?CDCI 3，400MHz）：13.18?(1H，s),?12.6?(1H，s),?6.18?(1H，s),?5.51(1H，d， J=4?Hz),?4.41(1H,?d,? J=4?Hz),?3.93?(3H，s),?3.41?(1H,?d,? J=16?Hz),?2.72?(1H,?d,? J=16Hz),?1.64?(3H，s),?1.40(3H，s),?1.03(3H，s)；EI（m/z）：376（M +），361，318，301，289（100%），273，257，243。
Embodiment 2: compound 2Preparation
The reaction of Bostrycin and 3-methyl-2-butene, building-up process is with embodiment 1.Yield: 80%.mp：200-201℃； 1H?NMR（δ H,?CDCI 3，400MHz）：13.09(1H，s),?12.53?(1H，s),?6.12?(1H，s),?5.50(1H，d， J=7.6Hz),?5.45(1H,?d,? J=2.5Hz),?4.79-4.62(1H,?m)，4.20(1H,?d,? J=2.5Hz)，3.92?(3H，s),?3.51(1H,?d,? J=16?Hz),?2.67?(1H,?d,? J=16Hz)，1.67(3H，d， J=1.2?Hz)，1.60(3H，d， J=1.2?Hz)，1.57(3H，s)；EI（m/z）：402（M +），387，318(100%)，301，289，271，257，243。
Embodiment 3: compound 3Preparation
Figure 2012100125169100002DEST_PATH_IMAGE014
The reaction of Bostrycin and Paraformaldehyde 96, building-up process is with embodiment 1.Yield: 24%.mp：233-234℃； 1H?NMR（δ H,?CDCI 3，400MHz）；13.23(1H，s),?12.64?(1H，s),?6.17?(1H，s),?5.23(1H，d， J=7.2Hz),?5.19(1H，d， J=4.4Hz)，5.12(1H,?dd,? J=7.5,1.6?Hz),?5.07(1H,?d,? J=4.4?Hz)，5.04(1H,?d,? J=7.2?Hz)，3.92(3H,?s)，3.63(1H,?d,? J=7.5?Hz)，3.18(1H,?d,? J=19.2?Hz)，2.69(1H,?dd,? J=18.8,1.6?Hz)，1.50(3H,?s)；EI(m/z)：378（M +），348，330，300(100%)，272，257，247，219。
Embodiment 4: compound 4Preparation
Figure 740704DEST_PATH_IMAGE015
In the 25mL round-bottomed flask, add 100mg (0.298mmol) Bostrycin; 235mg (0.298mmol) pyridine, the 5mL methylene dichloride is under 0 ℃; The dichloromethane solution of 177mg (0.6mmol) solid phosgene is slowly dripped in the above-mentioned system reaction 30min.TLC shows that raw material reaction is complete.Stopped reaction slowly adds the 2mL saturated aqueous ammonium chloride, and 5mL water with dichloromethane extraction (50mL * 3), merges organic phase, and organic phase is used 2M hydrochloric acid, water and saturated common salt water washing respectively, and anhydrous magnesium sulfate drying filters, and concentrates.Crude product is through purification by silica gel column chromatography, and eluent: V (methylene dichloride): V (methyl alcohol)=100:0.5 gets the 30.2mg red solid, yield: 28%.mp：246-247℃； 1H?NMR（δ H,?DMSO-d 6，400MHz）：13.14(1H，s),?12.32?(1H，s),?6.45?(1H，s),?6.20(1H，d， J=4Hz),?5.33(1H，dd， J=4，3.2?Hz)，4.88(1H,?d,? J=2.8?Hz),?3.92(3H,?s)，3.54(1H,?d,? J=14.4?Hz)，2.81(1H,?d,? J=14.4?Hz)，1.76(3H，s)；EI(m/z)：362（M +），318，300(100%)，282，254，229，216，201。
Embodiment 5: compound 5Preparation
Figure DEST_PATH_IMAGE016
The reaction of Bostrycin and thionyl chloride, building-up process is with embodiment 4.Yield: 15%.mp：193-194℃； 1H?NMR（δ H,?DMSO-d 6，400MHz）：13.13(1H，s),?12.26?(1H，s),?6.45?(1H，s),?5.34(1H，d， J=2.6?Hz),?5.16(1H，d， J=2.6?Hz)，3.92(3H,?s)，3.56(1H,?d,? J=16.8?Hz)，3.38(3H,?s)，2.71(1H,?d,? J=16.8?Hz)，1.90(3H，s)；EI(m/z)：396(M +)，364，332，315，303，286，273(100%)，257。
Embodiment 6: the test of extracorporeal anti-tumor cytoactive
1. material:
1.1 tetrazolium bromide (MTT): (3-(4 with the phosphate buffered saline buffer (PBS) of 0.01mol/L dissolving MTT; 5-dimethythiazol-z-yl) 2,5-diphenyl-tetrazolium bromide, SIGMA) final concentration 5mg/mL; Filtration sterilization, 4 ℃ keep in Dark Place after the packing.
1.2 the preparation of target cell: recovery and the cultivation of MCF-7 MCF-7 and MDA-MB-435, human lung cancer cell line A549 human hepatoma cell line HepG2, CCL188 HT-116.
A. from liquid nitrogen container, take out the cold pipe of depositing of MCF-7 MCF-7 and MDA-MB-435, human lung cancer cell line A549 human hepatoma cell line HepG2, CCL188 HT-116; Insert rapidly in 37 ℃ of water baths; Do not stop to shake and make it to dissolve rapidly, aseptic technique moves in the centrifuge tube;
B. add DMEM complete culture solution to 10 mL, the centrifugal 5min of 1000rmp abandons supernatant;
C. repeat above operation once;
D. move in the culturing bottle 5%CO after making the cell mixing with the piping and druming of DMEM complete culture solution 2, 37 ℃ of cultivations;
E. the observation of cell growing state is in time changed nutrient solution, divides bottle.
1.3 cell counting:
A. choose the logarithmic phase cell, trysinization, the DMEM perfect medium stops, and moves in the centrifuge tube, adds the DMEM perfect medium to 10mL;
B. get 10 μ L cell suspensions and splash in the tally one side groove, the TCS of microscopically counting four big lattice, divided by 4 takes advantage of 10 4, be every milliliter of contained cell count of nutrient solution;
C. adjust cell count to 1 * 10 5/ mL.
1.4 natural product Bostrycin derivative solution configuration:
Get natural product Bostrycin verivate and join in the DMEM perfect medium, adjustment concentration is 500 μ g/mL, ultrasonic emulsification, filtration sterilization, 4 ℃ of preservations.
2. TP
A. each hole of 96 orifice plates adds MCF-7 MCF-7 and MDA-MB-435, human lung cancer cell line A549 human hepatoma cell line HepG2, CCL188 HT-116 100 μ L (1 * 10 5/ mL), cultivate 4h for 37 ℃.
B. the study subject 100 μ L that add different concns, contrast adds DMEM perfect medium 100 μ L, continues to cultivate 48h..
C. add each 10 μ L of MTT (5mg/mL), continue to cultivate 4h.
D. remove nutrient solution, every hole adds DMSO 100 μ L, and the 5-10min that vibrates gently makes the particle dissolving.
E. enzyme linked immunological appearance 570nm measures every hole OD value down.
F. calculate inhibiting rate:
Tumor cell destruction %=[the average OD value that (the average OD value of average OD value-dosing group mensuration that control group is measured)/control group is measured] * 100%.
G. with the logarithm mapping of inhibiting rate, try to achieve IC to drug level 50Value:
With lgc is X-coordinate, and inhibiting rate is an ordinate zou, tries to achieve IC 50Value.
Table 1Be the extracorporeal anti-tumor cytoactive result of The compounds of this invention.
                   
Table 1
Figure 2012100125169100002DEST_PATH_IMAGE017
EPI (Pharmorubicin ) be U.S. Pharmacia Company products

Claims (10)

1. natural product Bostrycin verivate I, it is characterized in that having the structure of logical formula I,
Figure 2012100125169100001DEST_PATH_IMAGE001
Figure 2012100125169100001DEST_PATH_IMAGE002
Wherein: X=
Figure 2012100125169100001DEST_PATH_IMAGE003
; ; C=O; S=O or C=S;
R 1=H, methylol, alkyl;
R 2The alkyl of=H, C1-C10, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl;
R 3The alkyl of=H, C1-C10, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl;
R 4=H, direct-connected or branched-chain alkyl, undersaturated alkyl, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl; R 5=H, direct-connected or branched-chain alkyl, undersaturated alkyl, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl; R 6=H, alkyl, phenyl.
2. the preparation method of the said natural product Bostrycin of claim 1 verivate 1; The structural formula of natural product Bostrycin verivate 1 is as follows; Its preparation method is that employing Bostrycin is a raw material; With 2, the reaction of 2-Propanal dimethyl acetal obtains corresponding compounds under the catalysis of acid;
Figure 2012100125169100001DEST_PATH_IMAGE005
。
3. the preparation method of the said natural product Bostrycin of claim 1 verivate 2; The structural formula of natural product Bostrycin verivate 2 is as follows; Its preparation method is that employing Bostrycin is a raw material, under the catalysis of acid, obtains corresponding compounds with 3-methyl-2-butene aldehyde reaction;
Figure 2012100125169100001DEST_PATH_IMAGE006
。
4. the preparation method of the said natural product Bostrycin of claim 1 verivate 3; The structural formula of natural product Bostrycin verivate 3 is as follows; Its preparation method is that employing Bostrycin is a raw material, under the catalysis of acid, obtains corresponding compounds with polyformaldehyde reaction;
Figure 2012100125169100001DEST_PATH_IMAGE007
。
5. the preparation method of the said natural product Bostrycin of claim 1 verivate 4; The structural formula of natural product Bostrycin verivate 4 is as follows; Its preparation method is that employing Bostrycin is a raw material, under the catalysis of alkali, obtains corresponding compounds with the solid phosgene reaction;
?
Figure 2012100125169100001DEST_PATH_IMAGE008
。
6. the preparation method of the said natural product Bostrycin of claim 1 verivate 5; The structural formula of natural product Bostrycin verivate 5 is as follows; Its preparation method is that employing Bostrycin is a raw material, under the catalysis of alkali, obtains corresponding compounds with the thionyl chloride reaction;
Figure 2012100125169100001DEST_PATH_IMAGE009
。
7. like claim 2,3 or 4 described preparing methods, it is characterized in that said acid is tosic acid.
8. like claim 5 or 6 described preparing methods, it is characterized in that said alkali is pyridine or 4-(N, N-dimethyl-) EL-970.
9. the application of the said natural product Bostrycin of claim 1 verivate in the preparation antitumor drug.
10. application as claimed in claim 9 is characterized in that said antitumor be anti-breast cancer, lung cancer, liver cancer or colorectal carcinoma.
CN2012100125169A 2012-01-16 2012-01-16 Natural product Bostrycin derivative I as well as preparation method and application thereof Pending CN102532092A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1850765A (en) * 2006-05-26 2006-10-25 中山大学 Quinone compounds, and their preparing method and antitumour use
CN1962961A (en) * 2006-10-26 2007-05-16 大连海事大学 Method for preparing polythiophene composite film on stainless steel surface
CN101544556A (en) * 2008-06-06 2009-09-30 中山大学 Quinone compound Bostrycin, preparation method thereof and anti-tumor application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1850765A (en) * 2006-05-26 2006-10-25 中山大学 Quinone compounds, and their preparing method and antitumour use
CN1962961A (en) * 2006-10-26 2007-05-16 大连海事大学 Method for preparing polythiophene composite film on stainless steel surface
CN101544556A (en) * 2008-06-06 2009-09-30 中山大学 Quinone compound Bostrycin, preparation method thereof and anti-tumor application thereof

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Application publication date: 20120704