CN102796017A - Natural product deoxybostrycin derivatives and preparation method and application thereof - Google Patents

Natural product deoxybostrycin derivatives and preparation method and application thereof Download PDF

Info

Publication number
CN102796017A
CN102796017A CN2012103066995A CN201210306699A CN102796017A CN 102796017 A CN102796017 A CN 102796017A CN 2012103066995 A CN2012103066995 A CN 2012103066995A CN 201210306699 A CN201210306699 A CN 201210306699A CN 102796017 A CN102796017 A CN 102796017A
Authority
CN
China
Prior art keywords
deoxybostrycin
natural product
preparation
verivate
replacement
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN2012103066995A
Other languages
Chinese (zh)
Inventor
佘志刚
黎孟枫
龙玉华
陈洪
朱勋
钟莉莉
陈省平
林永成
吴珏珩
袁洁
杨斌
李嘉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sun Yat Sen University
National Sun Yat Sen University
Original Assignee
National Sun Yat Sen University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by National Sun Yat Sen University filed Critical National Sun Yat Sen University
Priority to CN2012103066995A priority Critical patent/CN102796017A/en
Publication of CN102796017A publication Critical patent/CN102796017A/en
Pending legal-status Critical Current

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses natural product deoxybostrycin derivatives and preparation method and application thereof. The deoxybostrycin derivative has a structure as shown in general formula (I). The invention also discloses the preparation method of the natural product deoxybostrycin derivatives and the anti-tumor application of the derivatives. The preliminary pharmacological research results of the derivatives show that: the derivatives have good anti-tumor activity and can be developed into novel anti-tumor medicines.

Description

Natural product deoxybostrycin verivate and preparation method thereof and application
Technical field
The present invention relates to one type new for the natural product deoxybostrycin verivate modified and preparation method thereof and the purposes in the preparation antitumor drug.
Background technology
Deoxybostrycin is a kind of tetrahydro-anthraquinone compound of redness, from the mangrove endophytic fungus Nigrospora sp No.1403 secondary metabolite of South China Sea ocean, separates obtaining (Planta.Med.2011,77; 1735 – 1738), has abundant pharmacologically active, for example: can produce plant poison (Appl.Environ.Microbiol.1982; 43,846 – 849), active (Chemical & Pharmaceutical Bulletin.2008,56 of malaria; 1687 – 1690), anti-microbial activity (Planta.Med.2011,77,1735 – 1738) and cytotoxic activity (Planta Medica.2005; 71,1063-1065).
Malignant tumour is serious threat human life's common disease and a frequently-occurring disease, and its mortality ratio and sickness rate are only second to cardiovascular disorder and are listed as second in residence.In numerous methods of treatment malignant tumour, chemotherapy is proved to be a kind of the most effectively cancer treatment method at present.But, since the dose limitation of anti-malignant tumor medicine, poor selectivity, toxic side effect is big, and resistance causes the malignant tumor patient immunologic hypofunction, and quality of life reduces, thereby has limited the general applicability of chemotherapeutics.Therefore, seek and find the new task of top priority that low toxicity highly selective, chemical sproof antitumor drug become whole world treating malignant tumor that has.
Ball surface-area 70% is taken up an area of in the ocean, and abundant mineral and the energy Biological resources that also are richly stored with are not only contained in the ocean.Cancer therapy drug research from the ocean accounts for leading role always in marine drug research, scientist's prediction, and the most promising cancer therapy drug is from the ocean.Make full use of oceanic resources, its effective constituent is carried out structural modification and composition optimizes, design, the compound that synthesis of biologically active is stronger are effective ways seeking new type antineoplastic medicine.The present invention is a lead compound with South China Sea ocean mangrove endophytic fungus #1403 secondary metabolite deoxybostrycin, and it is carried out structure of modification, and purpose is to seek the novel antitumor drug candidate of high-efficiency low-toxicity.
Summary of the invention
The contriver obtains compound d eoxybostrycin by extraction separation in the South China Sea thalassiomycetes #1403 secondary metabolite and has following 1 structure.
Figure BDA00002052139900021
The used fungi 1403 of the present invention has been preserved in Chinese typical culture collection center (CCTCC, Chinese Wuhan University are in the school), and preserving number is CCTCC NO:M201018, and preservation date is April 23 calendar year 2001.
The purpose of this invention is to provide a kind of novel natural product deoxybostrycin verivate.
Another object of the present invention provides the preparation method of above-mentioned novel natural product deoxybostrycin verivate.
Further purpose of the present invention provides the purposes of novel natural product deoxybostrycin verivate in the preparation antitumor drug.
The novel natural product deoxybostrycin verivate of the present invention has the structure of formula (I):
Figure BDA00002052139900022
Work as R 2During=H, R 1=NHR 3Or
Figure BDA00002052139900023
Wherein: R 3=direct-connected or branched-chain alkyl, undersaturated alkyl, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl, the alkyl that contains hydroxyl and oxygen containing alkyl;
R 4=H, direct-connected or branched-chain alkyl, undersaturated alkyl, replacement or unsubstituted phenyl, replacement or substituted benzyl not;
Y=C、O、N;
During as
Figure BDA00002052139900024
,
R 6The straight chained alkyl of=H, C1-C5, replacement or unsubstituted phenyl;
R 7The straight chained alkyl of=H, C1-C5, replacement or unsubstituted phenyl;
Natural product deoxybostrycin verivate of the present invention prepares through following method: employing deoxybostrycin is a raw material, in acid or do not have under the acid catalysis with the aminated compounds reaction and obtain compound 2 – 15; Under the catalysis of alkali, obtain compound 16 – 20 with the sulfur alcohol compound reaction.
Above-claimed cpd of the present invention is through preliminary pharmaceutical research, and through anticancer experiment in vitro, wherein majority of compounds shows good antineoplastic activity, can develop to be novel antitumor drug.
Preferred compound of the present invention has the structure of following compound 2 – 20:
The preparation process of The compounds of this invention 2-15 is following:
Figure BDA00002052139900041
The preparation technology of compound 2 – 15 comprises:
Deoxybostrycin and various amine reagent reacts obtain amino substituted deoxybostrycin verivate 2 – 15 (wherein, the preparation of compound 9 needs tosic acid to be heated to 50 ℃ as catalyzer and reaction solution) of corresponding 6-.
The preparation process of The compounds of this invention 16 – 20 is following:
Figure BDA00002052139900042
The preparation technology of compound 16-20 comprises:
It is corresponding 6 that Deoxybostrycin and the reaction of various thiol reagent obtain, the substituted deoxybostrycin verivate of 7-mercaptan 16-20.
Natural product deoxybostrycin 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.
Fusing point test is with Beijing X4 type micro melting point apparatus (TM is not proofreaied and correct).
1HNMR is with U.S. Varian Mercury-Plus 300 and Switzerland Bruker AVANCE AV-400NB.
TMS does interior mark.
Mass spectrum (ESI-MS) is with Thremo LCQ DECA XP LC-MS appearance.
Embodiment 1: the preparation of compound 2 – 15
Figure BDA00002052139900051
In the 25mL round-bottomed flask, add 50mg (0.156mmol; 1equiv) deoxybostrycin; Amine reagent (5equiv), 10mL methyl alcohol, at room temperature reaction; TLC shows raw material reaction complete (wherein, the preparation of compound 9 needs tosic acid to be heated to 50 ℃ as catalyzer and reaction solution).Stopped reaction, decompression steams unnecessary solvent.Crude product is through purification by silica gel column chromatography, and methylene dichloride and methyl alcohol are as eluent; Reverse phase silica gel (C18) column chromatography purification, first alcohol and water get corresponding compounds 2 – 15 as eluent.6-(Methylamino)1-Deoxy-6-demethoxybostrycin2：
Yield:40%;red?solid(MeOH);mp:221–223℃; 1H?NMR(400MHz,DMSO-d 6):δ14.23(s,1H),12.36(s,1H),7.95(q,1H,J=5.0Hz),5.55(s,1H),4.75(d,1H,J=5.1Hz),4.41(s,1H),3.63(dt,1H,J=7.3,5.1Hz),2.83(d,3H,J=5.0Hz),2.85(dd,1H,J=18.8,5.1Hz),2.77(d,1H,J=17.9Hz),2.68(dd,1H,J=18.8,7.3Hz),2.57(d,1H,J=17.9Hz),1.20(s,3H);ESI-MS?m/z:318.1[M-1] -.
6-(n-Propylamino)1-Deoxy-6-demethoxybostrycin?3：
Yield:44%;red?solid(MeOH);mp:215–216℃; 1H?NMR(400MHz,DMSO-d 6):δ14.23(s,1H),12.37(s,1H),7.86(t,1H,J=5.7Hz),5.63(s,1H),4.74(d,1H,J=5.1Hz),4.40(s,1H),3.63(dt,1H,J=7.3,5.1Hz),3.18(dt,2H,J=5.7,7.2Hz),2.85(1H,dd,J=18.7,5.1Hz),2.79(d,1H,J=17.9Hz),2.68(dd,1H,J=18.7,7.3Hz),2.57(d,1H,J=17.9Hz),1.61(sextet,2H,J=7.2Hz),1.20(s,3H),0.91(t,3H,J=7.4Hz);ESI-MS?m/z:346.2[M-1] -.
6-(n-Butylamino)1-Deoxy-6-demethoxybostrycin4：
Yield:40%;red?solid(MeOH);mp:215–217℃; 1H?NMR(400MHz,DMSO-d 6):δ14.22(s,1H),12.36(s,1H),7.85(t,1H,J=6.0Hz),5.61(s,1H),4.74(d,1H,J=5.1Hz),4.40(s,1H),3.63(dt,1H,J=7.4,5.2Hz),3.21(dt,2H,J=6.0,7.1Hz),2.85(dd,1H,J=18.7,5.2Hz),2.79(d,1H,J=17.9Hz),2.68(dd,1H,J=18.7,7.4Hz),2.57(d,1H,J=17.9Hz),1.57(pentet,2H,J=7.1Hz),1.35(sextet,2H,J=7.3Hz),1.20(s,3H),0.91(t,3H,J=7.3Hz);ESI-MS?m/z:360.2[M-1] -.6-(n-Hexylamino)1-Deoxy-6-demethoxybostrycin?5：
Yield:52%;red?solid(MeOH);mp:214-215℃; 1H?NMR(400MHz,DMSO-d 6):δ14.25(s,1H),12.38(s,1H),7.88(t,1H,J=6.1Hz),5.63(s,1H),4.75(d,1H,J=5.1Hz),4.41(s,1H),3.64(dt,1H,J=7.2,5.2Hz),3.21(dt,2H,J=6.1,7.0Hz),2.86(dd,1H,J=18.7,5.2Hz),2.80(d,1H,J=18.0Hz),2.69(dd,1H,J=18.7,7.2Hz),2.58(d,1H,J=18.0Hz),1.57(m,2H),1.37-1.25(m,6H),1.19(s,3H),0.87(t,3H,J=6.8Hz);ESI-MS?m/z:388.1[M-1] -.
6-(2′-Hydroxyethylamino)1-Deoxy-6-demethoxybostrycin?6：
Yield:30%;red?solid(MeOH);mp:232-234℃; 1H?NMR(400MHz,DMSO-d 6):?δ14.21(s,1H),12.36(s,1H),7.63(t,1H,J=5.9Hz),5.70(s,1H),4.89(br?t,1H),4.75(d,1H,J=4.2Hz),4.41(s,1H),3.66–3.59(m,3H),3.28(q,2H,J=5.9Hz),2.86(dd,1H,J=18.7,5.0Hz),2.80(d,1H,J=18.0Hz),2.69(dd,1H,J=18.7,7.4Hz),2.58(d,1H,J=18.0Hz),1.20(s,3H);ESI-MS?m/z:348.1[M-1] -.
6-(prop-2′-yn-1′-ylamino)1-Deoxy-6-demethoxybostrycin?7：
Yield:56%;red?solid(MeOH);mp:214–216℃; 1H?NMR(400MHz,DMSO-d 6):δ14.03(s,1H),12.36(s,1H),8.08(t,1H,J=5.8Hz),5.74(s,1H),4.76(d,1H,J=5.1Hz),4.42(s,1H),4.08(dd,2H,J=5.8,2.3Hz),3.64(dt,1H,J=7.3,5.2Hz),3.27(t,1H,J=2.3Hz),2.86(dd,1H,J=18.8,5.1Hz),2.80(d,1H,J=18.0Hz),2.69(dd,1H,J=18.8,7.3Hz),2.59(d,1H,J=18.0Hz),1.20(s,3H);ESI-MS?m/z:348.1[M-1] -.
6-[(2′-(dimethylamino)ethyl)amino]1-Deoxy-6-demethoxybostrycin?8：
Yield:60%;red?solid(MeOH);mp:215–217℃; 1H?NMR(400MHz,DMSO-d 6):δ14.19(s,1H),12.29(s,1H),7.47(t,1H,J=5.4Hz),5.67(s,1H),4.75(d,1H,J=4.6Hz),4.41(s,1H),3.63(dt,1H,J=7.4,5.3Hz),3.37–3.26(m,4H),2.86(dd,1H,J=18.7,5.2Hz),2.79(d,1H,J=18.1Hz),2.68(dd,1H,J=18.7,7.4Hz),2.59(d,1H,J=18.1Hz),2.25(s,6H),1.20(s,3H);ESI-MS?m/z:375.1[M-1] -.
6-(Phenylamino)1-Deoxy-6-demethoxybostrycin9：
Yield:38%;red?solid(MeOH);mp:220–222℃; 1H?NMR(400MHz,DMSO-d 6):δ13.92(s,1H),12.49(s,1H),9.46(s,1H),7.487.24(m,5H),6.00(s,1H),4.76(br?s,1H),4.43(s,1H),3.64(br?t,1H),2.86(dd,1H,J=18.6,5.0Hz),2.82(d,1H,J=18.2Hz),2.69(dd,1H,J=18.8,7.4Hz),2.60(d,1H,J=18.2Hz),1.20(s,3H);ESI-MS?m/z:380.1[M-1] -.
6-(Benzylamino)1-Deoxy-6-demethoxybostrycin10：
Yield:29%;red?solid(MeOH);mp:220-222℃; 1H?NMR(300MHz,DMSO-d 6):δ12.37(s,1H),8.49(t,1H,J=6.4Hz),7.38-7.18(m,5H),5.53(s,1H),4.75(d,1H,J=5.3Hz),4.46(d,2H,J=6.4Hz),4.42(s,1H),3.61(dt,1H,J=7.5,5.3Hz),2.82(dd,1H,J=18.9,5.3Hz),2.77(d,1H,J=17.4Hz),2.66(dd,1H,J=18.9,7.5Hz),2.57(d,1H,J=17.4Hz,),1.17(s,3H);ESI-MS?m/z:394.1[M-1] -.
6-(p-Methoxybenzylamino)1-Deoxy-6-demethoxybostrycin11：
Yield:44%;red?solid(MeOH);mp:223–225℃; 1H?NMR(400MHz,DMSO-d 6):δ14.11(s,1H),12.39(s,1H),8.40(t,1H,J=6.5Hz),7.33–6.87(m,4H),5.57(s,1H),4.74(d,1H,J=5.1Hz),4.40(br?s,2H),4.39(s,1H),3.73(s,3H),3.63(dt,1H,J=7.2,5.2Hz),2.84(dd,1H,J=18.8,5.2Hz),2.80(d,1H,J=18.1Hz),2.68(dd,1H,J=18.8,7.2Hz),2.58(d,1H,J=18.1Hz),1.19(s,3H);ESI-MS?m/z:424.1[M-1] -.
6-(p-Fluorobenzylamino)1-Deoxy-6-demethoxybostrycin12：
Yield:47%;red?solid(MeOH);mp:234–236℃; 1H?NMR(400MHz,DMSO-d 6):δ14.07(s,1H),12.40(s,1H),8.46(t,1H,J=6.5Hz),7.44–7.14(m,4H),5.57(s,1H),4.74(d,1H,J=5.1Hz),4.46(d,2H,J=6.5Hz),4.41(s,1H),3.63(dt,1H,J=7.3,5.2Hz),2.85(dd,1H,J=18.8,5.2Hz),2.80(d,1H,J=18.1Hz),2.68(dd,1H,J=18.8,7.2Hz),2.58(d,1H,J=18.1Hz),1.19(s,3H);ESI-MS?m/z:412.1[M-1] -.
6-(Piperidin-1-yl)1-Deoxy-6-demethoxybostrycin13：
Yield:30%;red?solid(MeOH);mp:188–190℃; 1H?NMR(400MHz,DMSO-d 6):δ13.86(s,1H),12.66(s,1H),5.98(s,1H),4.74(d,1H,J=5.1Hz),4.39(s,1H),3.63(dt,1H,J=7.3,5.2Hz),3.55(br?s,4H),2.83(dd,1H,J=18.7,5.2Hz),2.79(d,1H,J=18.2Hz),2.67(dd,1H,J=18.7,7.3Hz),2.57(d,1H,J=18.2Hz),1.65(br?s,6H),1.19(s,3H);ESI-MS?m/z:372.1[M-1] -.
6-(4′-Methylpiperidin-1-yl)1-Deoxy-6-demethoxybostrycin14：
Yield:32%;red?solid(MeOH);mp:198-200℃; 1H?NMR(400MHz,DMSO-d 6):δ13.85(s,1H),12.66(s,1H),5.98(s,1H),4.74(d,1H,J=5.1Hz),4.39(s,1H),4.09(br?d,2H),3.63(dt,1H,J=7.3,5.2Hz),3.01(br?t,2H),2.81(dd,1H,J=18.7,5.2Hz),2.79(d,1H,J=18.2Hz),2.67(dd,1H,J=18.7,7.3Hz),2.56(d,1H,J=18.2Hz),1.75(m,2H),1.67(m,1H),1.31(m,2H),1.19(s,3H),0.94(d,3H,J=6.3Hz);ESI-MS?m/z:386.1[M-1] -.
6-(4′-Phenylpiperidin-1-yl)1-Deoxy-6-demethoxybostrycin15：
Yield:28%;red?solid(MeOH);mp:227-228℃; 1H?NMR(400MHz,DMSO-d 6):δ13.85(s,1H),12.70(s,1H),7.36-7.17(m,5H),6.07(s,1H),4.75(d,1H,J=5.1?Hz),4.41(s,1H),4.27(br?d,2H),3.64(dt,1H,J=7.3,5.2Hz),3.14(br?t,2H),2.87(m,2H),2.79(d,1H,J=18.2Hz,),2.69(dd,1H,J=18.7,7.2Hz),2.58(d,1H,J=18.2Hz),1.81(m,4H),1.20(s,3H);ESI-MS?m/z:448.2[M-1] -.
Embodiment 2: the preparation of compound 16 – 20
Figure BDA00002052139900091
In the 25mL round-bottomed flask, add 50mg (0.156mmol, 1equiv) deoxybostrycin, thiol reagent (4equiv), triethylamine (8equiv), 10mL methyl alcohol, in 5 ℃ of 0 – reaction down, TLC shows that raw material reaction is complete.Stopped reaction, decompression steams unnecessary solvent.Crude product is through purification by silica gel column chromatography, and methylene dichloride and methyl alcohol are as eluent; Reverse phase silica gel (C18) column chromatography purification, first alcohol and water get corresponding compounds 16 – 20 as eluent.
6,7-bis(Ethylthio)1-Deoxy-6-demethoxybostrycin16：
Yield:35%;red?solid(MeOH);mp:186–188℃; 1H?NMR(400MHz,DMSO-d 6):δ13.11(s,2H),4.79(br?s,1H),4.46(s,1H),3.63(brt,1H),3.26(q,4H,J=7.4Hz),2.83(dd,1H,J=18.1,5.4Hz),2.79(d,1H,J=18.7Hz),2.66(dd,1H,J=19.0,7.4Hz),2.58(d,1H,J=18.7Hz),1.21(m,9H);ESI-MS?m/z:409.0[M-1] -.
6,7-bis(n-Butylthio)1-Deoxy-6-demethoxybostrycin17：
Yield:39%;red?solid(MeOH);mp:178-180℃; 1H?NMR(400MHz,DMSO-d 6):δ13.12(s,2H),4.80(br?s,1H),4.46(s,1H),3.63(br?t,1H),3.25(t,4H,J=7.2Hz),2.83(dd,1H,J=19.0,5.6Hz),2.78(d,1H,J=18.7Hz),2.66(dd,1H,J=19.0,7.4Hz),2.57(d,1H,J=18.7Hz),1.56-1.47(m,4H),1.38(sextet,4H,J=7.3Hz),1.20(s,3H),0.86(t,6H,J=7.3Hz);ESI-MS?m/z:465.2[M-1] -.
6,7-bis(n-Hexylthio)1-Deoxy-6-demethoxybostrycin18：
Yield:55%;red?solid(MeOH);mp:170–172℃; 1H?NMR(400MHz,DMSO-d 6):δ13.11(s,2H),4.79(br?s,1H),4.45(s,1H),3.62(brt,1H),3.23(t,4H,J=7.2Hz),2.82(dd,1H,J=19.2,5.4Hz),2.77(d,1H,J=18.7Hz),2.65(dd,1H,J=19.2,7.3Hz),2.56(d,1H,J=18.7Hz),1.57–1.47(m,4H),1.40–1.33(m,4H),1.27–1.21(m,8H),1.20(s,3H),0.87–0.80(m,6H);ESI-MS?m/z:521.1[M-1] -.
6,7-(Ethan-1′,2′-yl-dithio)1-Deoxy-6-demethoxybostrycin19：
Yield:47%;red?solid(MeOH);mp:226–227℃; 1H?NMR(400MHz,DMSO-d 6):δ12.64(s,2H),4.80(d,1H,J=5.2Hz),4.45(s,1H),3.64(dt,1H,J=7.5,5.2Hz),3.34(s,4H),2.85(dd,1H,J=18.9,5.4Hz),2.80(d,1H,J=18.4Hz),2.66(dd,1H,J=18.9,7.7Hz),2.59(d,1H,J=18.4Hz),1.21(s,3H);ESI-MS?m/z:379.1[M-1] -.
6,7-(Butan-2′,3′-yl-dithio)1-Deoxy-6-demethoxybostrycin20：
Yield:78%;red?solid(MeOH);mp:225–227℃; 1H?NMR(400MHz,DMSO-d 6):δ12.68(s,1H),12.66(s,1H),4.79(d,1H,J=5.2Hz),4.44(s,1H),3.68–3.44(m,3H),2.84(dd,1H,J=18.6,5.2Hz),2.80(d,1H,J=18.5Hz),2.66(dd,1H,J=18.6,7.7Hz),2.58(d,1H,J=18.5Hz),1.32and1.30(each?d,3H,J=6.0Hz),1.21(s,3H);ESI-MS?m/z:407.1[M-1] -.
Embodiment 3: 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 MDA-MB-435, human hepatoma cell line HepG2, CCL188 HCT-116.
A. the cold pipe of depositing of taking-up MCF-7 MDA-MB-435, human hepatoma cell line HepG2, CCL188 HCT-116 from liquid nitrogen container is inserted rapidly in 37 ℃ of water baths, does not stop to shake to make it to dissolve rapidly, and aseptic technique moves in the centrifuge tube;
B. add the DMEM complete culture solution to 10mL, 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 4/ mL.
1.4 natural product deoxybostrycin derivative solution configuration:
Get natural product deoxybostrycin 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.96 add MCF-7 MDA-MB-435, human hepatoma cell line HepG2, CCL188 HCT-116 100 μ L (1 * 10 in each hole of orifice plate 4/ 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 1 is the extracorporeal anti-tumor cytoactive result (IC of The compounds of this invention 50, μ M)
Figure BDA00002052139900111
Figure BDA00002052139900121
Figure BDA00002052139900131
Epirubicin:Used?as?a?positive?control。

Claims (9)

1. natural product deoxybostrycin verivate is characterized in that having the structure of logical formula I,
Figure 718527DEST_PATH_IMAGE001
Work as R 2During=H, R 1=NHR 3Or
Figure 47877DEST_PATH_IMAGE002
Wherein: R 3=direct-connected or branched-chain alkyl, undersaturated alkyl, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl, the alkyl that contains hydroxyl and oxygen containing alkyl;
R 4=H, direct-connected or branched-chain alkyl, undersaturated alkyl, replacement or unsubstituted phenyl, replacement or substituted benzyl not;
Y?=?C、O、N;
During as
Figure 810559DEST_PATH_IMAGE003
R 6The straight chained alkyl of=H, C1-C5, replacement or unsubstituted phenyl;
R 7The straight chained alkyl of=H, C1-C5, replacement or unsubstituted phenyl.
2. according to the described natural product deoxybostrycin of claim 1 verivate, it is characterized in that having down
The compound of array structure 2– 15,
Figure 541754DEST_PATH_IMAGE004
。
3. according to the described natural product deoxybostrycin of claim 1 verivate, it is characterized in that having down
The compound of array structure 16– 20,
Figure 535118DEST_PATH_IMAGE005
。
4. the preparation method of claim 1 or 2 said natural product deoxybostrycin verivates,
It is characterized in that adopting deoxybostrycin is raw material, in acid or do not have under the acid catalysis with the aminated compounds reaction and obtain corresponding compounds.
5. the preparation method of claim 1 or 3 said natural product deoxybostrycin verivates,
It is characterized in that adopting deoxybostrycin is raw material, under the catalysis of alkali, obtains corresponding compounds with the sulfur alcohol compound reaction.
6. according to the preparation method of the said natural product deoxybostrycin of claim 4 verivate, it is characterized in that said acid is tosic acid.
7. according to the preparation method of the said natural product deoxybostrycin of claim 5 verivate, it is characterized in that said alkali is triethylamine.
8. the application of the said natural product deoxybostrycin of claim 1 verivate in the anticancer disease drug of preparation.
9. application according to claim 8 is characterized in that said cancer is mammary cancer, liver cancer or colorectal carcinoma.
CN2012103066995A 2012-08-24 2012-08-24 Natural product deoxybostrycin derivatives and preparation method and application thereof Pending CN102796017A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2012103066995A CN102796017A (en) 2012-08-24 2012-08-24 Natural product deoxybostrycin derivatives and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2012103066995A CN102796017A (en) 2012-08-24 2012-08-24 Natural product deoxybostrycin derivatives and preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN102796017A true CN102796017A (en) 2012-11-28

Family

ID=47195357

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2012103066995A Pending CN102796017A (en) 2012-08-24 2012-08-24 Natural product deoxybostrycin derivatives and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN102796017A (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104262130A (en) * 2014-09-05 2015-01-07 大丰海洋生物医药研究所 Naphthaquinone compound derived from marine microbes, and preparation method and application thereof
CN104744226A (en) * 2014-07-25 2015-07-01 华南师范大学 Naphthazarin derivative and preparation method and application thereof
CN105152901A (en) * 2015-09-28 2015-12-16 三峡大学 Preparation method for anthraquinone compound and application of anthraquinone compound as receptor tyrosine kinase inhibitor
CN104744226B (en) * 2014-07-25 2016-11-30 华南师范大学 A kind of naphthazarin derivant and its preparation method and application

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102531933A (en) * 2012-01-16 2012-07-04 中山大学 Natural product Bostrycin derivates II and preparation method and application thereof
CN102558143A (en) * 2012-01-16 2012-07-11 中山大学 Derivant III of natural product Bostrycin and preparation method and purpose thereof
CN102603524A (en) * 2012-01-05 2012-07-25 中国海洋大学 Quinones derivative as well as preparation method of quinones derivative and application of quinones derivative as antibacterial agent

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102603524A (en) * 2012-01-05 2012-07-25 中国海洋大学 Quinones derivative as well as preparation method of quinones derivative and application of quinones derivative as antibacterial agent
CN102531933A (en) * 2012-01-16 2012-07-04 中山大学 Natural product Bostrycin derivates II and preparation method and application thereof
CN102558143A (en) * 2012-01-16 2012-07-11 中山大学 Derivant III of natural product Bostrycin and preparation method and purpose thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
H. M. GE ET AL.: "New and Cytotoxic Anthraquinones from Pleospora sp. IFB-E006, an Endophytic Fungus in Imperata cylindrical", 《PLANTA MEDICA》 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104744226A (en) * 2014-07-25 2015-07-01 华南师范大学 Naphthazarin derivative and preparation method and application thereof
CN104744226B (en) * 2014-07-25 2016-11-30 华南师范大学 A kind of naphthazarin derivant and its preparation method and application
CN104262130A (en) * 2014-09-05 2015-01-07 大丰海洋生物医药研究所 Naphthaquinone compound derived from marine microbes, and preparation method and application thereof
CN104262130B (en) * 2014-09-05 2016-03-30 大丰海洋生物医药研究所 A kind of naphthoquinone compound of ocean microorganism, preparation method and its usage
CN105152901A (en) * 2015-09-28 2015-12-16 三峡大学 Preparation method for anthraquinone compound and application of anthraquinone compound as receptor tyrosine kinase inhibitor

Similar Documents

Publication Publication Date Title
CN108358973A (en) Naphthalimide tetravalence platinum-like compounds, preparation method and its application in preparation of anti-tumor drugs
CN103951566B (en) N-alkyl-1,2,3,4,5,6-hexahydro-1,1,5,5-tetramethyl-7H-2,4 alpha-methanonaphthalene-7-amine compound as well as synthetic method and application thereof
CN106967024B (en) A kind of α-pyrone derivative and its preparation method and application
CN102796017A (en) Natural product deoxybostrycin derivatives and preparation method and application thereof
CN102250150B (en) Organic hydridized tetra-core platinum complex and preparation method thereof as well as application in antitumor medicament preparation
CN106349160B (en) A kind of 8-aminoquinoline derivatives and its preparation and application
CN111808117A (en) Artemisinin-anilinoquinazoline D-type derivative, and pharmaceutical composition and application thereof
CN104288160B (en) The application in preparing anti-acute gout medicine of O-(piperazinyl) ethyl derivative of Cleistanone
CN105294639B (en) A kind of asymmetric New cyclobutane derivative and its preparation method and application
CN104829619A (en) Substituted aryl matrine compounds, preparation method and applications thereof
CN102558143B (en) Derivant III of natural product Bostrycin and preparation method and purpose thereof
CN105367575B (en) A kind of folacin compound, its preparation method and medical usage
CN107540680A (en) A kind of lappaconitine acetal analog derivative and its synthetic method with antitumor activity
CN102531933B (en) Natural product Bostrycin derivates II and preparation method and application thereof
CN103613600A (en) Anilino podophyllotoxin derivative with anti-tumor activity and preparation method and application thereof
CN103396400B (en) Pyrazole amide compounds, and preparation method and application thereof
BR112021004094A2 (en) crystalline forms of a phosphoinositide 3-kinase (pi3k) inhibitor
CN104825470A (en) Application of cleistanone O-(benzimidazolyl) ethyl derivative in preparation of drugs for treating acute gout
CN105906539B (en) Raphanin anticancer derivative compound and preparation method thereof
CN104628772A (en) Antitumor prodrug, activator, composition, and application thereof
CN108822120A (en) FL118 amino acid hydrochloride salt and the preparation method and application thereof
CN104788498A (en) Platinum (II) complex using chiral bicyclodiamine as carrier ligand and preparation method and application of platinum (II) complex
CN107445859B (en) Fluorine-containing gossypol derivative with anti-tumor activity and preparation method and application thereof
CN104119343A (en) 2-trifluoromethyl thiadiazole compound and application thereof
CN115557889A (en) 2-aryl-3, 4-dihydroisoquinoline derivative and application thereof in preparing antitumor drugs

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20121128