CN115181112B - Synthesis of 3,4-diketone Derivatives of 6-Bromocyclo-Epimedium Chroman and Its Antitumor Application - Google Patents
Synthesis of 3,4-diketone Derivatives of 6-Bromocyclo-Epimedium Chroman and Its Antitumor Application Download PDFInfo
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- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 230000015572 biosynthetic process Effects 0.000 title claims description 5
- 238000003786 synthesis reaction Methods 0.000 title claims description 5
- 230000000259 anti-tumor effect Effects 0.000 title description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 238000001308 synthesis method Methods 0.000 claims abstract description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 150000001298 alcohols Chemical class 0.000 claims abstract 2
- 238000002360 preparation method Methods 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 4
- 238000010189 synthetic method Methods 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 3
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 3
- YCUQJKHDFXAMBE-BQYQJAHWSA-N (e)-2,3-dibromo-3-phenylprop-2-enoic acid Chemical compound OC(=O)C(\Br)=C(/Br)C1=CC=CC=C1 YCUQJKHDFXAMBE-BQYQJAHWSA-N 0.000 claims description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 2
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- TUUXBSASAQJECY-UHFFFAOYSA-N 3,5,7-trihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-enyl)chromen-4-one Chemical compound C1=CC(OC)=CC=C1C1=C(O)C(=O)C2=C(O)C=C(O)C(CC=C(C)C)=C2O1 TUUXBSASAQJECY-UHFFFAOYSA-N 0.000 claims 4
- 150000003938 benzyl alcohols Chemical class 0.000 claims 1
- 238000005893 bromination reaction Methods 0.000 abstract description 4
- 230000031709 bromination Effects 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 2
- 125000002723 alicyclic group Chemical group 0.000 abstract 1
- 125000003342 alkenyl group Chemical group 0.000 abstract 1
- 125000000304 alkynyl group Chemical group 0.000 abstract 1
- 230000001093 anti-cancer Effects 0.000 abstract 1
- 238000000338 in vitro Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 16
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical group BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- 201000007270 liver cancer Diseases 0.000 description 5
- 208000014018 liver neoplasm Diseases 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- TZJALUIVHRYQQB-XFDQAQKOSA-N Icariin Natural products O(C)c1ccc(C2=C(O[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@H](C)O3)C(=O)c3c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O4)c(C/C=C(\C)/C)c3O2)cc1 TZJALUIVHRYQQB-XFDQAQKOSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- TZJALUIVHRYQQB-XLRXWWTNSA-N icariin Chemical compound C1=CC(OC)=CC=C1C1=C(O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)C(=O)C2=C(O)C=C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C(CC=C(C)C)=C2O1 TZJALUIVHRYQQB-XLRXWWTNSA-N 0.000 description 3
- TZJALUIVHRYQQB-UHFFFAOYSA-N icariine Natural products C1=CC(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(C)O2)O)C(=O)C2=C(O)C=C(OC3C(C(O)C(O)C(CO)O3)O)C(CC=C(C)C)=C2O1 TZJALUIVHRYQQB-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 241000893536 Epimedium Species 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 235000018905 epimedium Nutrition 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004224 protection Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000020395 negative regulation of osteoclast differentiation Effects 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000009818 osteogenic differentiation Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007447 staining method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- 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
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本申请公开了结构式如式I所示的6‑溴代环淫羊藿素色满3,4‑二酮类衍生物，
Description
技术领域technical field
本发明属于新药设计与合成领域，具体涉及一类6-溴代环淫羊藿素色满3,4-二酮类衍生物的合成及其抗肿瘤应用。The invention belongs to the field of new drug design and synthesis, and specifically relates to the synthesis of a class of chroman 3,4-diketone derivatives of 6-bromocyclic epimedium and its antitumor application.
背景技术Background technique
淫羊藿苷是黄酮类化合物之一，具有多种药理和生物学活性，如神经保护作用、促进成骨分化、抑制破骨细胞分化以及抗肿瘤活性。Icariin, one of the flavonoids, has various pharmacological and biological activities, such as neuroprotection, promotion of osteogenic differentiation, inhibition of osteoclast differentiation, and antitumor activity.
卤化是经典的有机化学反应，卤素基团作为良好的药效基团，能有效改变药物分子的亲油性，还能增加药物活性。基于上述原因，申请人设计：利用溴化反应在淫羊藿素的C-6位引入卤素基团，以提高淫羊藿素的亲脂性。据此，合成制备得到了一系列新型6-溴代淫羊藿素色满3,4-二酮类衍生物。Halogenation is a classic organic chemical reaction. As a good pharmacophore, the halogen group can effectively change the lipophilicity of drug molecules and increase drug activity. Based on the above reasons, the applicant designed: using a bromination reaction to introduce a halogen group at the C-6 position of icariin to improve the lipophilicity of icariin. Accordingly, a series of new chroman 3,4-diketone derivatives of 6-bromo-epmedium were synthesized and prepared.
发明内容Contents of the invention
本发明针对现有技术的不足，研究并设计一系列新型6-溴代淫羊藿素色满3,4-二酮类衍生物，活性研究表明该类新衍生物对肝癌和乳腺癌有较好的抑制作用。Aiming at the deficiencies in the prior art, the present invention researches and designs a series of novel 6-bromo-eparidin chroman 3,4-diketone derivatives, and the activity research shows that these new derivatives have a better effect on liver cancer and breast cancer. Good inhibitory effect.
本发明的目的之一是提供6-溴代环淫羊藿素色满3,4-二酮类衍生物，其结构式如式I所示，One of the objects of the present invention is to provide 6-bromocycloicariin chroman 3,4-dione derivatives, the structural formula of which is shown in formula I,
其中R选自饱和烷基或取代的烷基。wherein R is selected from saturated alkyl or substituted alkyl.
优选地，6-溴代环淫羊藿素色满3,4-二酮类衍生物I，R选自C1-C5的饱和烷基或苄基。Preferably, in the 6-bromocycloicariin chroman 3,4-diketone derivative I, R is selected from C1-C5 saturated alkyl or benzyl.
另一方面，本发明提供了如上所述的6-溴代环淫羊藿素色满3,4-二酮类衍生物I的合成方法，合成路线为：On the other hand, the present invention provides a method for synthesizing the above-mentioned 6-bromocycloicariin chroman 3,4-diketone derivative I, and the synthetic route is:
具体为：以环淫羊藿素为原料，与溴化试剂在适当的醇试剂下在适当条件下反应得到6-溴代环淫羊藿素色满3,4-二酮类衍生物I。Specifically, cycloicariin is used as a raw material to react with a brominating reagent under appropriate alcohol reagents under appropriate conditions to obtain 6-bromocycloicariin chroman 3,4-diketone derivative I.
如上所述的6-溴代环淫羊藿素色满3,4-二酮类衍生物I的合成方法，其中，溴化试剂选自N-溴代丁二酰亚胺(简称NBS)、液溴(简称Br2)、氢溴酸(HBr)，NaBr/H2O2、NBS/AIBN或α,β-二溴肉桂酸；优选为NBS。As mentioned above, the synthetic method of 6-bromocycloicariin chroman 3,4-diketone derivative I, wherein the bromination reagent is selected from N-bromosuccinimide (abbreviated as NBS), Liquid bromine (abbreviated as Br 2 ), hydrobromic acid (HBr), NaBr/H 2 O 2 , NBS/AIBN or α,β-dibromocinnamic acid; preferably NBS.
如上所述的I的合成方法，其中，适合的醇选自饱和烷基醇或取代的烷基醇；优选为，C1-C5的饱和烷基醇或苄基醇。The synthesis method of I as above, wherein the suitable alcohol is selected from saturated alkyl alcohol or substituted alkyl alcohol; preferably, C1-C5 saturated alkyl alcohol or benzyl alcohol.
如上所述的I的合成方法，其中，适当条件包括反应时间为1～48小时，反应温度为0℃至所用醇试剂的回流温度；优选地，反应时间为2～6小时，反应温度为0℃至室温。The synthesis method of I as above, wherein, suitable conditions include a reaction time of 1 to 48 hours, a reaction temperature of 0° C. to the reflux temperature of the alcohol reagent used; preferably, a reaction time of 2 to 6 hours, and a reaction temperature of 0 °C to room temperature.
如上所述的I的合成方法，其中，适当条件还包括反应中环淫羊藿素：溴化试剂的投摩尔比为1:1～1:8，环淫羊藿素：醇试剂的投摩尔比为1:1～1：100。The synthetic method of I as above, wherein, appropriate conditions also include cycloicariin in the reaction: the molar ratio of bromination reagent is 1:1～1:8, cycloicariin: the molar ratio of alcoholic reagent 1:1～1:100.
进一步的，本发明还提供了6-溴代环淫羊藿素色满3,4-二酮类衍生物在制备抗肿瘤药物中的用途。优选的，具体是在制备人肝癌和人乳腺癌两种抗肿瘤药物中的用途。Further, the present invention also provides the use of the 6-bromocyclo-icariin chroman 3,4-diketone derivatives in the preparation of antitumor drugs. Preferably, it is specifically used in the preparation of two antitumor drugs for human liver cancer and human breast cancer.
本发明的有益效果：合成方法中采用的原料、试剂以及溶剂价廉易得；合成方法条件温和，易于实施操作。本发明合成得到的6-溴代淫羊藿素色满3,4-二酮类衍生物对HepG2和MCF-7肿瘤细胞具有较好的抑制作用。The beneficial effect of the present invention is that the raw materials, reagents and solvents used in the synthesis method are cheap and easy to obtain; the synthesis method has mild conditions and is easy to operate. The 6-bromo-icariin chroman 3,4-diketone derivative synthesized by the present invention has better inhibitory effect on HepG2 and MCF-7 tumor cells.
具体实施方式Detailed ways
下面通过具体实施方式进一步详细说明：The following is further described in detail through specific implementation methods:
下述实施例中，除非另有说明，所述的试验方法通常按照常规条件或制造厂商建议的条件实施；所示的原料、试剂均可通过市售购买的方式获得。In the following examples, unless otherwise specified, the test methods are generally implemented under conventional conditions or conditions suggested by the manufacturer; the raw materials and reagents shown can all be obtained through commercially available means.
实施例1化合物Ia-j的制备The preparation of embodiment 1 compound Ia-j
(1)6-溴代淫羊藿素色满3,4-二酮类化合物(Ia)的制备(1) Preparation of 6-Bromo-Epimedium Chroman 3,4-Diketone Compound (Ia)
在氮气氛围下，往圆底烧瓶中加入环淫羊藿素(50mg，0.135mmol)和甲醇(2mL)。然后将混合物冷却至0℃，并分批加入NBS(48mg，2eq.)。然后将反应混合物加热到室温并搅拌4小时。通过TLC检测，当原料消失后，将反应溶剂减压浓缩。剩余物加入CH2Cl2(10mL)和水(2mL)以稀释混合物。有机相萃取分离，硫酸镁干燥。使用石油醚：乙酸乙酯＝6：1洗脱机通过色谱柱纯化残留物，得到标题化合物Ia,收率65％，浅黄色固体。M.p.149.5-150.2℃,Rf＝0.34(石油醚:乙酸乙酯＝2:1).1H NMR(400MHz,CDCl3)δ＝11.30(s,1H),7.67(dd,J＝18.7,8.7Hz,2H),6.98(dd,J＝14.6,8.8Hz,2H),4.71(d,J＝49.1Hz,1H),3.84(dd,J＝4.3,1.4Hz,3H),3.06(s,1H),3.01(s,3H),2.89–2.77(m,1H),2.71–2.63(m,1H),1.87(q,J＝6.9Hz,2H),1.42(s,6H)。13C NMR(100MHz,CDCl3)δ：192.33,160.39,160.10,157.44,154.08,129.97,129.76,125.16,113.80,113.31,106.12,102.97,99.77,92.87,55.26,50.51,50.11,31.59,27.27,26.36,16.41。HRMS-ESI(m/z):分子式为C22H21BrO7Na，[M+Na]+:计算值499.0363,测得值499.0362.Cycloicariin (50 mg, 0.135 mmol) and methanol (2 mL) were added to a round bottom flask under nitrogen atmosphere. The mixture was then cooled to 0 °C and NBS (48 mg, 2 eq.) was added portionwise. The reaction mixture was then warmed to room temperature and stirred for 4 hours. Through TLC detection, when the starting material disappeared, the reaction solvent was concentrated under reduced pressure. The residue was added CH2Cl2 ( 10 mL) and water (2 mL) to dilute the mixture. The organic phase was separated by extraction and dried over magnesium sulfate. The residue was purified by chromatographic column using petroleum ether:ethyl acetate=6:1 eluent to obtain the title compound Ia in a yield of 65% as a light yellow solid. Mp149.5-150.2℃, R f =0.34 (petroleum ether: ethyl acetate = 2:1). 1 H NMR (400MHz, CDCl 3 ) δ = 11.30 (s, 1H), 7.67 (dd, J = 18.7, 8.7Hz, 2H), 6.98(dd, J＝14.6, 8.8Hz, 2H), 4.71(d, J＝49.1Hz, 1H), 3.84(dd, J＝4.3, 1.4Hz, 3H), 3.06(s, 1H), 3.01(s, 3H), 2.89–2.77(m, 1H), 2.71–2.63(m, 1H), 1.87(q, J=6.9Hz, 2H), 1.42(s, 6H). 13 C NMR (100MHz, CDCl 3 ) δ: 192.33, 160.39, 160.10, 157.44, 154.08, 129.97, 129.76, 125.16, 113.80, 113.31, 106.12, 102.97, 99.77, 92.87, 55.26, 50.51, 50.11, 31.59, 27.27, 26.36 ,16.41. HRMS-ESI (m/z): Molecular formula is C 22 H 21 BrO 7 Na, [M+Na] + : calculated value 499.0363, measured value 499.0362.
(2)化合物Ib的制备(2) Preparation of compound Ib
参照以上合成方法，采用乙醇作为反应试剂和溶剂，得到化合物Ib,收率67％，浅黄色固体。M.p.153.5-154℃,Rf＝0.45(石油醚:乙酸乙酯＝2:1),1H NMR(400MHz,CDCl3)δ＝11.31(s,1H),7.68(dd,J＝18.4,8.8Hz,2H),7.02–6.90(m,2H),3.84(d,J＝5.2Hz,3H),3.43–3.32(m,1H),3.24–3.10(m,1H),3.01(s,1H),2.81(ddt,J＝16.8,8.2,6.4Hz,1H),2.63(dq,J＝17.4,6.1Hz,1H),1.87(dt,J＝13.3,6.5Hz,1H),1.46–1.34(m,6H),0.97(dt,J＝11.6,7.1Hz,3H)。13C NMR(100MHz,CDCl3)δ＝191.47,160.77,160.14,157.58,154.25,129.82,124.71,113.70,106.37,102.93,99.64,91.93,89.76,59.72,55.34,31.56,27.24,26.31,16.46,14.98。HRMS-ESI(m/z):分子式为C23H23BrO7Na，[M+Na]+:计算值513.0519,测得值513.0519.Referring to the above synthesis method, ethanol was used as the reaction reagent and solvent to obtain compound Ib with a yield of 67% as a light yellow solid. Mp153.5-154℃, R f =0.45 (petroleum ether: ethyl acetate = 2:1), 1 H NMR (400MHz, CDCl 3 ) δ = 11.31 (s, 1H), 7.68 (dd, J = 18.4, 8.8Hz, 2H), 7.02–6.90(m, 2H), 3.84(d, J=5.2Hz, 3H), 3.43–3.32(m, 1H), 3.24–3.10(m, 1H), 3.01(s, 1H ), 2.81(ddt, J＝16.8, 8.2, 6.4Hz, 1H), 2.63(dq, J＝17.4, 6.1Hz, 1H), 1.87(dt, J＝13.3, 6.5Hz, 1H), 1.46–1.34( m, 6H), 0.97 (dt, J = 11.6, 7.1 Hz, 3H). 13 C NMR (100MHz, CDCl 3 ) δ＝191.47, 160.77, 160.14, 157.58, 154.25, 129.82, 124.71, 113.70, 106.37, 102.93, 99.64, 91.93, 89.76, 59.72, 55.34, 31 .56, 27.24, 26.31, 16.46, 14.98 . HRMS-ESI (m/z): Molecular formula is C 23 H 23 BrO 7 Na, [M+Na] + : calculated value 513.0519, measured value 513.0519.
(3)化合物Ic的制备(3) Preparation of compound Ic
参照以上合成方法，采用丙醇作为反应试剂和溶剂，得到化合物Ic,收率61％，浅黄色固体,M.p.163-164℃,Rf＝0.5(石油醚:乙酸乙酯＝2:1).1H NMR(400MHz,CDCl3)δ11.31(s,1H),7.69(d,J＝8.7Hz,2H),6.98(d,J＝8.6Hz,2H),3.84(s,3H),3.31(dt,J＝9.3,6.6Hz,1H),3.06(dt,J＝9.3,6.8Hz,1H),2.78(q,J＝3.6,2.9Hz,1H),2.70–2.61(m,1H),1.89–1.79(m,2H),1.41(d,J＝2.5Hz,6H),1.36(qd,J＝6.8,2.0Hz,2H),0.63(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3)δ191.48,160.77,160.12,157.57,154.25,129.89,124.57,113.69,106.14,103.00,99.65,91.90,89.80,65.56,55.34,31.57,27.18,26.33,22.55,16.50,10.45。HRMS-ESI(m/z):分子式为C24H25BrO7K[M+K]+:计算值543.0415,测得值543.0821.Referring to the above synthesis method, using propanol as the reaction reagent and solvent, compound Ic was obtained with a yield of 61%, light yellow solid, Mp163-164°C, R f =0.5 (petroleum ether: ethyl acetate = 2:1). 1 H NMR (400MHz, CDCl 3 ) δ11.31(s, 1H), 7.69(d, J=8.7Hz, 2H), 6.98(d, J=8.6Hz, 2H), 3.84(s, 3H), 3.31( dt,J=9.3,6.6Hz,1H),3.06(dt,J=9.3,6.8Hz,1H),2.78(q,J=3.6,2.9Hz,1H),2.70–2.61(m,1H),1.89 -1.79 (m, 2H), 1.41 (d, J=2.5Hz, 6H), 1.36 (qd, J=6.8, 2.0Hz, 2H), 0.63 (t, J=7.4Hz, 3H). 13 C NMR (100MHz, CDCl 3 ) δ191.48, 160.77, 160.12, 157.57, 154.25, 129.89, 124.57, 113.69, 106.14, 103.00, 99.65, 91.90, 89.80, 65.56, 55.34, 31. 57, 27.18, 26.33, 22.55, 16.50, 10.45 . HRMS-ESI(m/z): Molecular formula is C 24 H 25 BrO 7 K[M+K] + : Calculated value 543.0415, found value 543.0821.
(4)化合物Id的制备(4) Preparation of Compound Id
参照以上合成方法，采用异丙醇作为反应试剂和溶剂，得到化合物Id,收率54％，浅黄色固体,M.p.186.5-188℃,Rf＝0.34(石油醚:乙酸乙酯＝2:1).1H NMR(400MHz,CDCl3)δ＝11.28(s,1H),7.79(d,J＝8.8Hz,2H),6.98(d,J＝8.9Hz,2H),3.85(s,3H),3.82(d,J＝4.6Hz,1H),2.87–2.80(m,1H),2.72–2.65(m,1H),1.90–1.85(m,1H),1.81(d,J＝7.3Hz,1H),1.41(d,J＝11.8Hz,6H),1.02(d,J＝6.2Hz,3H),0.75(d,J＝6.2Hz,3H).13C NMR(100MHz,CDCl3)δ＝160.91,160.29,157.67,154.86,130.40,125.46,106.83,102.84,99.54,91.84,90.01,26.97,26.76,23.86,22.94,16.99.HRMS-ESI(m/z):分子式为C24H25BrO7Na，[M+Na]+:计算值527.0676,测得值527.0675.Referring to the above synthesis method, using isopropanol as the reaction reagent and solvent, the compound Id was obtained with a yield of 54%, light yellow solid, Mp186.5-188°C, R f =0.34 (petroleum ether:ethyl acetate=2:1 ). 1 H NMR (400MHz, CDCl 3 )δ=11.28(s,1H),7.79(d,J=8.8Hz,2H),6.98(d,J=8.9Hz,2H),3.85(s,3H) ,3.82(d,J＝4.6Hz,1H),2.87–2.80(m,1H),2.72–2.65(m,1H),1.90–1.85(m,1H),1.81(d,J＝7.3Hz,1H ), 1.41(d, J=11.8Hz, 6H), 1.02(d, J=6.2Hz, 3H), 0.75(d, J=6.2Hz, 3H). 13 C NMR(100MHz, CDCl 3 )δ=160.91 , 160.29, 157.67 , 154.86 , 130.40, 125.46, 106.83, 102.84, 99.54, 91.84, 90.01, 26.97, 26.76, 23.86, 22.94, 16.99. BrO 7 Na, [M+Na] + : calculated value 527.0676, measured value 527.0675.
(5)化合物Ie的制备(5) Preparation of compound Ie
参照以上合成方法，采用正丁基醇作为反应试剂和溶剂，得到化合物Ie,收率60％，浅黄色固体,M.p.158.5-160℃,Rf＝0.36(石油醚:乙酸乙酯＝2:1).1H NMR(400MHz,CDCl3)δ11.31(s,1H),7.70(d,J＝8.5Hz,2H),6.99(d,J＝8.5Hz,2H),3.84(d,J＝8.6Hz,3H),3.34(dd,J＝9.5,6.6Hz,1H),3.16–3.10(m,1H),2.84–2.77(m,1H),2.68–2.63(m,1H),1.86(q,J＝6.8,6.4Hz,1H),1.83–1.77(m,1H),1.41(s,6H),1.35–1.29(m,2H),1.12–1.03(m,2H),0.70(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3)δ191.45,160.79,160.12,157.57,154.23,129.87,128.91,124.54,113.98,113.71,106.16,102.96,99.63,91.90,89.79,63.61,55.34,31.59,31.27,27.13,26.37,19.02,16.51,13.60。HRMS-ESI(m/z):分子式为C25H27BrO7Na，[M+Na]+:计算值541.0832,测得值541.0832。Referring to the above synthesis method, n-butyl alcohol was used as the reaction reagent and solvent to obtain compound Ie with a yield of 60%, light yellow solid, Mp 158.5-160°C, R f =0.36 (petroleum ether: ethyl acetate = 2: 1). 1 H NMR (400MHz, CDCl 3 ) δ11.31(s, 1H), 7.70(d, J=8.5Hz, 2H), 6.99(d, J=8.5Hz, 2H), 3.84(d, J ＝8.6Hz, 3H), 3.34(dd, J＝9.5, 6.6Hz, 1H), 3.16–3.10(m, 1H), 2.84–2.77(m, 1H), 2.68–2.63(m, 1H), 1.86( q,J＝6.8,6.4Hz,1H),1.83–1.77(m,1H),1.41(s,6H),1.35–1.29(m,2H),1.12–1.03(m,2H),0.70(t, J=7.4Hz, 3H). 13 C NMR (100MHz, CDCl 3 ) δ191.45, 160.79, 160.12, 157.57, 154.23, 129.87, 128.91, 124.54, 113.98, 113.71, 106.16, 102.96, 99.63, 91.90, 89.79, 6 3.61, 55.34, 31.59, 31.27, 27.13, 26.37 , 19.02, 16.51, 13.60. HRMS-ESI (m/z): Molecular formula is C 25 H 27 BrO 7 Na, [M+Na] + : calculated value 541.0832, found value 541.0832.
(6)化合物If的制备(6) Preparation of Compound If
参照以上合成方法，采用正戊醇作为反应试剂和溶剂，得到化合物If,收率50％，浅黄色固体,M.p.121-123℃,Rf＝0.48(石油醚:乙酸乙酯＝2:1),1H NMR(400MHz,CDCl3)δ11.31(s,1H),7.68(d,J＝8.8Hz,2H),6.98(d,J＝8.9Hz,2H),3.84(s,3H),3.33(dd,J＝9.5,6.4Hz,1H),3.11(dt,J＝9.4,6.8Hz,1H),2.83–2.76(m,1H),2.69–2.62(m,1H),1.90–1.77(m,2H),1.41(s,6H),1.37–1.31(m,2H),1.07(ddd,J＝13.0,7.9,5.0Hz,2H),1.03–0.96(m,2H),0.71(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝191.65,160.70,160.09,157.55,154.25,129.89,124.57,113.64,106.17,103.03,99.70,91.88,89.88,78.07,63.78,55.32,31.58,28.89,28.02,27.12,26.42,22.15,16.51,13.94.HRMS-ESI(m/z):分子式为C26H29BrO7Na，[M+Na]+:计算值555.0989,测得值555.0988。Referring to the above synthesis method, using n-pentanol as the reaction reagent and solvent, the compound If was obtained with a yield of 50%, light yellow solid, Mp121-123°C, R f =0.48 (petroleum ether: ethyl acetate = 2:1), 1 H NMR (400MHz, CDCl 3 ) δ11.31(s, 1H), 7.68(d, J=8.8Hz, 2H), 6.98(d, J=8.9Hz, 2H), 3.84(s, 3H), 3.33 (dd,J＝9.5,6.4Hz,1H),3.11(dt,J＝9.4,6.8Hz,1H),2.83–2.76(m,1H),2.69–2.62(m,1H),1.90–1.77(m ,2H),1.41(s,6H),1.37–1.31(m,2H),1.07(ddd,J＝13.0,7.9,5.0Hz,2H),1.03–0.96(m,2H),0.71(t,J ＝7.1Hz, 3H). 13 C NMR (100MHz, CDCl 3 ) δ＝191.65, 160.70, 160.09, 157.55, 154.25, 129.89, 124.57, 113.64, 106.17, 103.03, 99.70, 91.88, 89.88, 78. 07,63.78,55.32, 31.58, 28.89, 28.02, 27.12, 26.42, 22.15, 16.51, 13.94. HRMS-ESI (m/z): Molecular formula is C 26 H 29 BrO 7 Na, [M+Na] + : calculated value 555.0989, measured value 555.0988 .
(7)化合物Ig的制备(7) Preparation of Compound Ig
参照以上合成方法，采用3-甲基-1-丁醇作为反应试剂和溶剂，得到化合物Ig,收率55％，浅黄色固体,M.p.108-110℃,Rf＝0.56(石油醚:乙酸乙酯＝2:1).1H NMR(400MHz,CDCl3)δ11.30(s,1H),7.68(d,J＝8.5Hz,2H),6.98(d,J＝8.6Hz,2H),3.84(s,3H),3.37–3.30(m,1H),3.20–3.13(m,1H),2.86–2.77(m,2H),2.69–2.61(m,1H),1.90–1.84(m,1H),1.83–1.76(m,1H),1.40(s,6H),1.22(d,J＝7.4Hz,2H),0.69(d,J＝6.6Hz,3H),0.61(d,J＝6.6Hz,3H).13C NMR(100MHz,CDCl3)δ191.52,160.76,160.11,157.56,154.22,129.86,124.54,113.70,106.18,102.95,99.63,91.90,89.81,62.19,55.34,38.00,31.59,27.05,26.89,26.44,24.68,22.49,22.04,16.53.HRMS-ESI(m/z):分子式为C26H29BrO7Na，[M+Na]+:计算值555.0989,测得值555.0988.With reference to the above synthesis method, using 3-methyl-1-butanol as the reaction reagent and solvent, compound Ig was obtained with a yield of 55%, light yellow solid, Mp108-110°C, Rf =0.56 (petroleum ether: ethyl acetate =2:1). 1 H NMR (400MHz, CDCl 3 ) δ11.30(s, 1H), 7.68(d, J=8.5Hz, 2H), 6.98(d, J=8.6Hz, 2H), 3.84( s,3H),3.37–3.30(m,1H),3.20–3.13(m,1H),2.86–2.77(m,2H),2.69–2.61(m,1H),1.90–1.84(m,1H), 1.83–1.76(m,1H),1.40(s,6H),1.22(d,J＝7.4Hz,2H),0.69(d,J＝6.6Hz,3H),0.61(d,J＝6.6Hz,3H ). 13 C NMR (100MHz, CDCl 3 ) δ191.52, 160.76, 160.11, 157.56, 154.22, 129.86, 124.54, 113.70, 106.18, 102.95, 99.63, 91.90, 89.81, 62.19, 55.34, 38.00, 31.59, 27.05, 26.89, 26.44 ,24.68,22.49,22.04,16.53. HRMS-ESI(m/z): Molecular formula is C 26 H 29 BrO 7 Na, [M+Na] + : calculated value 555.0989, measured value 555.0988.
(3)化合物Ih的制备(3) Preparation of compound Ih
参照以上合成方法，采用苄醇作为反应试剂和溶剂，得到化合物Ih,收率35％，浅黄色固体,M.p.98-100℃,Rf＝0.38(石油醚:乙酸乙酯＝2:1).1H NMR(400MHz,CDCl3)δ＝11.32(s,1H),7.78(d,J＝8.9Hz,2H),7.17(dd,J＝4.9,1.8Hz,3H),7.02(d,J＝8.9Hz,2H),6.97(q,J＝2.9,2.3Hz,2H),4.46(d,J＝12.1Hz,1H),4.24(d,J＝12.2Hz,1H),3.86(d,J＝5.3Hz,3H),2.73(ddd,J＝14.9,8.6,6.3Hz,2H),2.53–2.46(m,1H),1.83–1.77(m,1H),1.36(d,J＝3.5Hz,6H).13C NMR(100MHz,CDCl3)δ：160.35,157.75,128.37,127.72,114.03,103.21,31.61,29.84,16.53.HRMS-ESI(m/z):分子式为C28H25BrO7Na，[M+Na]+:计算值575.0676,测得值575.0675.Referring to the above synthesis method, using benzyl alcohol as the reaction reagent and solvent, the compound Ih was obtained with a yield of 35%, light yellow solid, Mp98-100°C, R f =0.38 (petroleum ether: ethyl acetate = 2:1). 1 H NMR (400MHz, CDCl 3 )δ=11.32(s,1H),7.78(d,J=8.9Hz,2H),7.17(dd,J=4.9,1.8Hz,3H),7.02(d,J=8.9 Hz, 2H), 6.97(q, J=2.9, 2.3Hz, 2H), 4.46(d, J=12.1Hz, 1H), 4.24(d, J=12.2Hz, 1H), 3.86(d, J=5.3 Hz, 3H), 2.73(ddd, J＝14.9, 8.6, 6.3Hz, 2H), 2.53–2.46(m, 1H), 1.83–1.77(m, 1H), 1.36(d, J＝3.5Hz, 6H) . 13 C NMR (100MHz, CDCl 3 ) δ: 160.35, 157.75, 128.37, 127.72, 114.03, 103.21, 31.61, 29.84, 16.53. HRMS-ESI (m/z): The molecular formula is C 28 H 25 BrO 7 Na, [ M+Na] + : calculated value 575.0676, measured value 575.0675.
实施例2 6-溴代环淫羊藿素色满3,4-二酮类化合物的抗肿瘤活性测试Example 2 Antitumor activity test of 6-bromocycloicariin chroman 3,4-diketone compound
细胞株和溶剂采用：人肝癌细胞HepG2；人乳腺癌细胞MCF-7；肿瘤细胞培养于含10％胎牛血清的DMEM培养基中；溶剂为二甲亚砜(简称DMSO)。Cell lines and solvents are: human liver cancer cell HepG2; human breast cancer cell MCF-7; tumor cells are cultured in DMEM medium containing 10% fetal bovine serum; solvent is dimethyl sulfoxide (DMSO for short).
CCK-8染色法检测细胞抗肿瘤活性实施方案：取对数生长期细胞进行实验。细胞经消化、计数、制成细胞悬液，接种于96孔板中(100μL/孔)，置于37℃，5％CO2培养箱中培养24小时；每孔加入含相应浓度的受试物，同时设立阴性对照组及空白组，每5复孔；将板置于培养箱中培养72小时后，显微镜下观察各组细胞形态，每孔加入10μL CCK-8溶液，在细胞培养箱内继续孵育4小时，450nm下测定吸光值，计算细胞的抑制率。设定浓度梯度，得出IC 50值(μM)，实验结果详见表1。CCK-8 staining method for detection of anti-tumor activity of cells Embodiment: Take cells in logarithmic growth phase for experiment. The cells were digested, counted, and made into a cell suspension, inoculated in a 96-well plate (100 μL/well), and placed in a 37°C, 5% CO 2 incubator for 24 hours; each well was added with a corresponding concentration of the test substance At the same time, a negative control group and a blank group were set up, with 5 replicate wells; after the plate was placed in the incubator for 72 hours, the cell morphology of each group was observed under a microscope, and 10 μL of CCK-8 solution was added to each well, and continued in the cell incubator. After incubation for 4 hours, the absorbance value was measured at 450 nm, and the inhibition rate of the cells was calculated. The concentration gradient was set to obtain the IC 50 value (μM). The experimental results are shown in Table 1.
表1 6-溴代环淫羊藿素色满3,4-二酮Ia-h对肿瘤细胞的抑制率和IC50值(μM)Table 1 Inhibitory rate and IC 50 value of 6-bromocycloicariin chroman 3,4-diketone Ia-h on tumor cells (μM)
从表1的实验结果看出，本发明设计并合成的如I式所示的6-溴代环淫羊藿素色满3,4-二酮对人肝癌和人乳腺癌都具有很好的抗肿瘤效果。该类化合物新型衍生物可用于制备抗肿瘤药物，尤其是用于肝癌和乳腺癌药物的制备中。Find out from the experimental result of table 1, the 6-bromocyclic epimedium chroman 3,4-dione that the present invention designs and synthesizes as shown in formula I all has very good effect on human liver cancer and human breast cancer. Antitumor effect. The novel derivatives of the compound can be used in the preparation of antitumor drugs, especially in the preparation of liver cancer and breast cancer drugs.
以上所述的仅是本发明的实施例，方案中公知的具体结构及特性等常识在此未作过多描述。应当指出，对于本领域的技术人员来说，在不脱离本发明结构的前提下，还可以作出若干变形和改进，这些也应该视为本发明的保护范围，这些都不会影响本发明实施的效果和专利的实用性。本申请要求的保护范围应当以其权利要求的内容为准，说明书中的具体实施方式等记载可以用于解释权利要求的内容。What is described above is only an embodiment of the present invention, and common knowledge such as specific structures and characteristics known in the scheme are not described here too much. It should be pointed out that for those skilled in the art, under the premise of not departing from the structure of the present invention, some modifications and improvements can also be made, which should also be regarded as the protection scope of the present invention, and these will not affect the implementation of the present invention. Effects and utility of patents. The scope of protection required by this application shall be based on the content of the claims, and the specific implementation methods and other records in the specification may be used to interpret the content of the claims.
Claims (9)
- The 1, 6-bromo-cycloicaritin chromane 3, 4-diketone derivative is characterized in that the structural formula is shown in a formula I,；
wherein R is selected from saturated alkyl or benzyl of C1-C5. - 2. The synthetic method of the 6-bromo-cycloicaritin chroman 3, 4-diketone derivative I according to claim 1, wherein the synthetic route is as follows:；
the method comprises the following steps: the method is characterized in that the cycloicaritin is used as a raw material, and reacts with a brominating reagent under proper alcohol reagent and under proper conditions to obtain the 6-bromo cycloicaritin chroman 3, 4-diketone derivative I. - 3. The synthesis method according to claim 2, characterized in that: the brominating reagent is selected from NBS, br 2 、HBr、NaBr/H 2 O 2 NBS/AIBN or alpha, beta-dibromocinnamic acid.
- 4. The synthesis method according to claim 2, characterized in that: suitable conditions include a reaction time of 1 to 48 hours and a reaction temperature of 0℃to the reflux temperature of the alcohol reagent used.
- 5. The synthesis method according to claim 2, characterized in that: suitable conditions include in-reaction cycloicaritin: the mole ratio of the brominating reagent is 1:1-1:8, and the cycloicaritin: the molar ratio of the alcohol reagent is 1:1-1: 100.
- 6. the synthetic method according to any one of claims 2 to 5, wherein: the brominating reagent is selected from NBS.
- 7. The method of synthesis according to claim 6, wherein: suitable alcohols are selected from the group consisting of C1-C5 saturated alkyl alcohols and benzyl alcohols.
- 8. The method of synthesis according to claim 7, wherein: suitable conditions include a reaction time of 2 to 6 hours and a reaction temperature of 0℃to room temperature.
- 9. The use of the 6-bromo-cycloicaritin chromane 3, 4-dione derivative in preparation of antitumor drugs according to claim 1.
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