CN113730391A - 桃金娘酮类化合物在制备抗新型冠状病毒SARS-CoV-2药物中的应用 - Google Patents
桃金娘酮类化合物在制备抗新型冠状病毒SARS-CoV-2药物中的应用 Download PDFInfo
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- CN113730391A CN113730391A CN202010476418.5A CN202010476418A CN113730391A CN 113730391 A CN113730391 A CN 113730391A CN 202010476418 A CN202010476418 A CN 202010476418A CN 113730391 A CN113730391 A CN 113730391A
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- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- GOMNOOKGLZYEJT-UHFFFAOYSA-N isoflavone Chemical compound C=1OC2=CC=CC=C2C(=O)C=1C1=CC=CC=C1 GOMNOOKGLZYEJT-UHFFFAOYSA-N 0.000 description 1
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 description 1
- 235000008696 isoflavones Nutrition 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Abstract
本发明公开了桃金娘酮类化合物在制备抗新型冠状病毒SARS‑CoV‑2药物中的应用。本发明的桃金娘酮类化合物对新型冠状病毒SARS‑CoV‑2具有明显的抑制作用,其作用机理包括(但不限于)抑制新型冠状病毒SARS‑CoV‑2进入细胞,阻止新型冠状病毒SARS‑CoV‑2在宿主细胞中的复制,适时调控受感染细胞的凋亡程序。本发明提供的桃金娘酮类化合物对新型冠状病毒SARS‑CoV‑2有显著抑制作用,且细胞毒性相对较小,因此可以用于预防或治疗新冠肺炎。本发明有望为临床治疗新冠肺炎提供新的候选药物分子。
Description
技术领域
本发明属于医学和药学技术领域,具体涉及桃金娘酮类化合物在制备抗新型冠状病毒SARS-CoV-2药物中的应用。
背景技术:
新冠肺炎(COVID-19)是由新冠病毒SARS-CoV-2(早期曾叫2019-nCoV)感染所致的烈性传染性流行病,具有较高的死亡率。目前疫情已经扩散至全球200多个国家和地区,给全人类造成了前所未有的威胁。有研究表明新冠病毒无症状感染者具有传染性,可能要做好新冠肺炎成为季节性疾病的准备。疫苗被公认为是抑制新冠肺炎的最后解决方案,世界很多国家都在研发预防新冠肺炎的疫苗,并且取得了一定的进展,但目前仍没有预防新冠肺炎的疫苗上市,且由于RNA病毒极易变异,也有可能使疫苗失效。由此,寻找治疗新冠肺炎有效的药物是目前最有效和现实的选择。
桃金娘为Rhodomyrtus tomentosa(Ait.)Hass桃金娘科(Mytaceae)桃金娘属Rhodomyrtus(DC.)Reich植物,别名哆尼、岗菍、山菍、多莲、当梨根、稔子树、豆稔、仲尼、乌肚子、桃舅娘、当泥,主要分布于中国的南部和东南部,尤其盛产于岭南地区,为广东常用地产药材。桃金娘其性味甘涩平,以根、叶、花和果入药或食用,具有清热、解毒、养血、止血、涩肠、固精、暖腹脏、益肌肉之功效,因而是一种非常具有潜在开发利用价值的经济植物。此外,它的使用历史悠久,唐刘恂《岭表录异》已有记载:“倒捻子……食之甜软,甚暖腹,兼益肌肉。”
目前已有文献和专利报道桃金娘中的桃金娘酮化合物及其衍生物具有抗菌作用(专利申请号:CN 104761565 A桃金娘酮化合物及其在制备抗菌药物中的应用;CN108752305 A闭环桃金娘酮类似物及在抗菌药物中的应用;CN 105859537 A开环桃金娘酮类似物及其制备方法和在抗菌药物中的应用),但在本专利之前未发现任何与桃金娘及其活性成分抗病毒有关的研究报道。
发明内容:
本发明的目的是提供一类桃金娘酮类化合物、或其立体异构体、差向异构体、构型异构体或其药学上可以接受的盐、或它们的水合物在制备抗新型冠状病毒SARS-CoV-2药物中的应用。
所述的桃金娘酮类化合物,其结构如式I所示:
其中,虚线部分表示任选的C-C单键,当虚线不存在时即形成C-C单键,当虚线存在时形成C=X双键;
当虚线存在时,形成C=X双键,R4、R5和R6各自独立选O、S或者NR1’,R1’为氢、或C1-C15直链、支链环烷基或含有苯环的芳香基团;
R1为氢、或C1-C15直链、支链环烷基或含有苯环的芳香基团;
R2和R3、R7各自独立选氢、或者自下面取代基团;
其中n=0-15的任何数字,R8和R9各自独立选氢、或C1-C15直链,支链环烷基或含有苯环的芳香基团,或R8和R9形成环烷基,杂环。
优选地,所述的n=1-8。
优选地,所述的R1为C3-C10的直链、支链或环烷基。
优选,所述的桃金娘酮类化合物如式II所示:
其中R3为H,R1为C3-C4的直链或支链烷基,R2为氢、或者自下面取代基团;
其中n=0-15的任何数字,R8和R9各自独立选氢、或C1-C15直链,支链环烷基或含有苯环的芳香基团,或R8和R9形成环烷基或杂环。
进一步优选,所述的桃金娘酮类化合物如下所示:
进一步优选,所述的桃金娘酮类化合物为化合物2-h,18或21。
本发明桃金娘酮类化合物作为植物来源的天然产物,可以从桃金娘科植物桃金娘的全株植物的任何部位中通过物理和/或者化学方法提取,还可以从其他桃金娘科植物中提取获得,或用半合成和全合成化学方法实现,用于预防或治疗新型冠状病毒SARS-CoV-2的药物中的用途。
本发明的桃金娘酮类化合物对新型冠状病毒SARS-CoV-2具有明显的抑制作用,其作用机理包括(但不限于)抑制新型冠状病毒SARS-CoV-2进入细胞,阻止新型冠状病毒SARS-CoV-2在宿主细胞中的复制,适时调控受感染细胞的凋亡程序。本发明提供的桃金娘酮类化合物对新型冠状病毒SARS-CoV-2有显著抑制作用,且细胞毒性相对较小,因此可以用于预防或治疗新冠肺炎。本发明有望为临床治疗新冠肺炎提供新的候选药物分子。
具体实施方式:
以下实施例是对本发明的进一步说明,而不是对本发明的限制。
实施例1:
以下参照具体的实施例来说明本发明。本领域技术人员能够理解,这些实施例仅用于说明本发明,其不以任何方式限制本发明的范围。
下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的药材原料、试剂材料等,如无特殊说明,均为市售购买产品。
实施例1从桃金娘科植物种分离获得桃金娘酮类化合物
1.1植物材料
以桃金娘科桃金娘属植物桃金娘为实验原料,该植物在我国南部特别是岭南地区分布广泛。本实验的植物材料采自于江西省赣州市南康县(区),干燥后共20kg,由中国科学院华南植物园王发国研究员鉴定为桃金娘科桃金娘属植物桃金娘(R.tomentosa)。植物标本现存放于中国科学院华南植物园天然产物与化学生物学研究实验室。
1.2实验仪器与试剂
旋光数据采用Perkin-Elmer 341 polarimeter(美国Perkin-Elmer公司)测定。紫外光谱由Perkin-Elmer Lambda 35 UV-vis spectrophotometer(美国Perkin-Elmer公司)测定,溶剂为甲醇或氯仿。红外光谱由BrukerVertex 33 infrared spectrophotometer(德国Bruker公司)测定,测定前需要压片。核磁共振氢谱、碳谱、DEPT-135谱以及二维谱由Bruker公司的BrukerAVIII500型超导核磁共振仪测定,TMS为内标,δ为ppm,J为Hz。制备型HPLC为L3000型HPLC(北京创新通恒科技有限公司),色谱柱为C18柱(ALLTIMA C18 10U,250nm×10nm,3mL/min),并配有单波长紫外检测器。高分辨质谱由Bruker公司的BrukerBio TOF IIIQ mass spectrometer测定。100~200、200~300、300~400目硅胶和薄层色谱板由青岛谱科分离材料有限公司生产。MCI凝胶(CHP20P,75-150mm)由日本三菱化学公司生产。Sephadex LH-20凝胶由瑞典Amersham生物科学公司生产。有机溶剂来自于上海化学材料有限公司。薄层色谱显色剂为5%浓硫酸-乙醇溶液,有紫外吸收的化合物需要在紫外灯下观测。实验过程中所用的混合溶剂的配比皆为体积比。
1.3获得提取物
对干燥桃金娘叶进行充分粉粹(20KG),用体积分数95%乙醇水溶液提取3次(30L×3),合并的溶剂在减压下旋蒸,得到棕色糖浆状残余物为乙醇部(2.5KG),将其悬浮于水中(1:1,重量比),用正己烷萃取(3L×3),萃取部分经溶剂旋干得正己烷部;再用乙酸乙酯萃取(3L×3),萃取部分经溶剂旋干得乙酸乙酯部,剩余水部旋干为水部。
1.4分离获得单体化合物
本实验选取桃金娘叶的正己烷部和/或乙酸乙酯部用尽量少的氯仿在拌样锅里溶解完全,之后用500g硅胶(80~100目)进行拌样,搅拌均匀,待溶剂挥发完全后干法上样,用正己烷-乙酸乙酯体系10:1、5:1、2:1、1:1、0:1v/v进行梯度洗脱,最后用甲醇冲柱,经过TLC薄层色谱检测后合并主点相同的流分,收集TLC检测(展开溶剂正己烷:乙酸乙酯=5:1v/v)为紫外灯下显蓝色荧光;硫酸-乙醇显色剂作用下显橘红色的组分Fr.C,再经过MCI柱层析脱去色素,然后经过Sephadex LH-20凝胶柱层析,以正己烷-乙酸乙酯体系(8:1→1:1v/v)进行梯度洗脱,收集经TLC检测(展开溶剂正己烷:乙酸乙酯=5:1v/v)为紫外灯下显蓝色荧光;硫酸-乙醇显色剂作用下显橘红色的部位Fr.C2。Fr.C2经过Sephadex LH-20凝胶柱层析,以氯仿:甲醇(1:1v/v)进行洗脱,得到化合物2-h、3和4。TLC检测(展开溶剂正己烷:乙酸乙酯:=4:1v/v),化合物2-h、3和4的Rf分别为0.4,0.35,0.42。
化合物2-h为化合物桃金娘酮,淡黄色针状晶体,易溶于氯仿;核磁数据:1HNMR(CDCl3,500MHz):δH 6.12(1H,s,H-5),4.27(1H,t,J=5.6Hz,H-9),2.99(3H,m,H-1”,H-2”),2.28(1H,dp,J=13.3,6.6Hz,H-3'),1.55,1.43,1.41,1.37(each 3H,s,H-11,H-12,H-13,H-14),0.98(6H,d,J=6.7,Hz,H-4',H-5'),0.87,0.83(each 3H,d,J=6.0Hz,H-3”,H-4”);13C NMR(CDCl3,125MHz):δC 212.2(C-3),206.7(C-1'),198.3(C-1),167.5(C-4a),162.8(C-8),158.7(C-6),155.7(C-10a),114.3(C-9a),107.7(C-7),106.4(C-8a),94.7(C-5),56.1(C-2),53.2(C-2'),46.4(C-4),45.8(C-1”),25.5(C-9),25.5(C-2”),25.2,25.1(C-13,C-14),24.7,24.6(C-11,C-12),24.2(C-3'),23.5,23.2(C-3”,C-4”),22.8,22.8(C-4',C-5')。化合物2-h的结构式如下所示:
化合物3为桃金娘异酮,黄色胶状物,易溶于氯仿;核磁数据:1HNMR(CDCl3,500MHz):δH 0.85(d,J=6.3Hz,3H,4”-CH3),0.86(d,J=6.3Hz,3H,3”-CH3),0.99(d,J=6.6Hz,3H,5'-CH3),1.01(d,J=6.6Hz,3H,4'-CH3),1.38(s,10-CH3),1.41(s,11-CH3),1.46(s,13-CH3),1.62(s,12-CH3),1.35(obscured,1H,2”-H),1.35(obscured,2H,1”-H),2.35(qqdd,J=6.8,6.8,6.6,6.6Hz,1H,3'-H),2.93(dd,J=17.2,6.1Hz,1H,2'-Ha),3.17(dd,J=17.2,7.3Hz,1H,2'-Hb),4.29(t,J=6.1Hz,1H,9-H),6.25(s,1H,7-H),8.08(s,1H,OH),13.49(s,1H,OH);13C NMR(CDCl3,126MHz):δC 211.8(C-3),203.9(C-1'),198.5(C-1),167.4(C-4a),159.8(C-6),159.7(C-8),153.1(C-4b),114.6(C-9a),106.0(C-5),105.5(C-8a),100.2(C-7),56.1(C-2),53.4(C-2'),47.3(C-4),46.9(C-1”),25.4(C-13),25.0(C-9),24.8(C-2”),24.7(C-12),24.5(C-3'),24.5(C-11),24.2(C-10),23.4(C-3”),23.1(C-4”),22.9(C-4'),22.6(C-5')。化合物3的结构式如下所示:
化合物4为myrciaroneA,黄色无定形粉末,易溶于氯仿;光谱数据:.UVλmax299nm,『a』D+7.5°(c=0.24,CHCl3),HR-MS;m/z 429.2282[M+H]+(calcd.for C25H33O6,429.2268).核磁数据:1HNMR(CDCl3,500MHz):6.07(1H,s,H-5),4.24(1H,t,J=5.9Hz,H-9),3.88(1H,m,J=6.6,H-2’),1.41-1.44(2H,obscure,H-1”),1.36-1.46(2H,obscure,H-2”),1.36(3H,s,2-Me),1.39(3H,s,2-Me),1.42(3H,s,4-Me),1.54(3H,s,4-Me),1,20(3H,d,J=5.5Hz,2’-Me),1.19(3H,d,J=6,6Hz,2’-Me),0.83(3H,d,J=6.0Hz,2”-Me),0.87(3H,d,J=6.0Hz,2”-Me).13C NMR(CDCl3,126MHz):197.5(C-1),56.1(C-2),212.1(C-3),47.1(C-4),166.8(C-4a),94.5(C-5),158.0(C-6),106.7(C-7),158.0(C-8),106.7(C-8a),25.2(C-9),114.2(C-9a),155.6(C-10a),210.9(C-1’),39.8(C-2’),45.9(C-1”),25.1(C-2”),24.2(2-Me),24.5(2-Me),24.6(4-Me),24.7(4-Me),19.1(2’-Me),19.2(2’-Me),23.1(2”-Me),23.5(2”-Me).化合物4的结构式如下所示:
实施例2全合成桃金娘酮类化合物
2.1化学部分的材料和实验仪器
除非另有说明,否则所有化学反应均在无水条件下、在干燥的溶剂中和氮气保护下进行。试剂以高商业质量购买,可不经进一步纯化而使用。所有溶剂均为分析级(上海化工厂,中国上海)。用0.25mm青岛硅胶板(60F-254)进行薄层色谱法(TLC),并通过暴露于UV光(254nm)或用高锰酸钾染色显影。用于快速柱色谱的硅胶(ZCX-II,200-300目)购自中国青岛海洋化学工业有限公司。核磁共振氢谱、碳谱、DEPT-135谱以及二维谱由Bruker公司的BrukerAVIII500型超导核磁共振仪测定,TMS为内标,δ为ppm,J为Hz。制备型HPLC为L3000型HPLC(北京创新通恒科技有限公司),色谱柱为C18柱(ALLTIMA C18 10U,250nm×10nm,3mL/min),并配有单波长紫外检测器。高分辨质谱用Bruker公司的Bruker Bio TOF IIIQ massspectrometer测定。合成过程如下:
2.2合成Acylphloroglucinol(6)
在含有240mL二氯甲烷和240mL硝基甲烷混合液的悬浮搅拌器中加入30.0g化合物ph loroglucinol(5)(0.238mol)后在混合液中加入127.0g三氯化铝(0.952mol,4倍当量),室温搅拌三十分钟。后用注射器在黑色的反应瓶中加入17mL乙酰氯(0.238mol,1当量)。加入完全后,反应回流三小时,同时用薄层检测反应进程。随后,反应物冷却至室温,减压蒸发掉挥发成分后加入400mL冰水,用500mL乙酸乙酯萃取三次。混合物溶液用饱和度氯化钠溶液洗涤一次,用无水硫酸钠吸水,过滤,真空浓缩。石油醚:乙酸乙酯(2:1)快速柱层析得到化合物6,化合物6为淡黄色晶体,可以在甲苯中重结晶。Rf=0.26(petroleum ether/ethylacetate,2:1);1H NMR(400MHz,DMSO-d6):d 2.53(s,3H,CH3),5.78(s,2H,Ar),10.39(br s,1H,OH),12.23(br s,2H,OH);13C NMR(100MHz,DMSO-d6):d 32.5(CH3),94.6(C-3,C-5),104.1(C-1),164.4(C-2,C-6),164.8(C-4),202.6(C=O).
2.3合成4-Acetyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(acylsyncarpic a cid)(7)
甲醇钠的制备:30.6g钠(1.33mol,8.16equiv)分几次加入1L的无水甲醇溶液中。室温搅拌直到完全溶解。加入142mL碘甲烷(2.28mol,14equiv)后,加入27.46g化合物6(0.163mol),混合液回流6h,(期间用薄层板检测,石油/醚乙酸乙酯2:1v/v展开),冷却到室温。减压浓缩,剩余部分用水溶解,用300Ml乙醚萃取四次,后加1M盐酸酸化。将有机相用400mL饱和的亚硫酸钠溶液酸化,后加入3M的盐酸,直到有白色出现为止。用100mL乙醚萃取三次。合并所有化合物合并,加入硫酸镁,过滤、浓缩、真空干燥。得到黄色固体,可以由石油醚重结晶得到化合物7(30.6g、84%)。1H NMR(400MHz,CDCl3):d 1.33(s,6H,2CH3),1.42(s,6H,2CH3),2.57(s,3H,COCH3);13C NMR(100MHz,CDCl3):d 23.8(2CH3),24.3(2CH3),27.4(COCH3),52.0(C-6),56.7(C-2),109.4(C-4),196.7(C-5),199.1(C-3),201.7(CH3 C=O),210.0(C-1).
2.4合成5-Hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(syncarpic acid)(8)
用3M盐酸约1.4L溶解化合物7,搅拌回流6h,直到全部溶解(薄层监测)。随后,反应液冷却到室温,用400mL乙酸乙酯萃取四次。用水洗两次提取液,加硫酸钠吸水,过滤,真空干燥。初品用甲苯重结晶。得到18.3g淡黄色化合物8。R f1/40.37(petroleum ether/ethylacetate,1:1);1H NMR(400MHz,CDCl3),mixture of keto and enol tautomers in aratio of 2:1;keto tautomer:d 1.31(s,12H,4CH 3),3.61(s,2H,CH 2);enol tautomer:d 1.40(s,12H,4CH 3),5.74(br d,J1/42.3Hz,1H,CH),8.00(br s,1H,OH);13C NMR(100MHz,CDCl3):keto tautomer:d 21.8(4CH 3),50.2(CH 2),59.1(2C(CH3)2),204.3(2CO),208.9(CO);enol tautomer:d 24.6(4CH3),51.2(C-6),59.1(CH3),101.7(C-4),191.9(C-5),204.3(C-3),212.6(C-1).
2.5合成2,2,4,4-tetramethyl-6-(3-methylbutylidene)cyclohexane-1,3,5-trione(9)
在加有6.76g化合物8(0.037mol)的110mL二氯甲烷中加入7.4mL哌啶(0.075mol,2equiv)后再加入6mL异戊醛(0.056mol,1.5equiv)。开始搅拌之前的十分钟,反应液用50mL1M的盐酸淬灭、加入饱和的氯化铵溶液,剧烈搅拌一小时。反应液用150mL二氯甲烷萃取三次.加入硫酸钠吸水,过滤,真空干燥。化合物9的初品以二氯甲烷为溶剂用5厘米的薄层硅胶板制备。容易异构,需要现做现用。
2.6合成6,8-Dihydroxy-9-isobutyl-2,2,4,4-tetramethyl-4,9-dihydro-1H-xanthene-1,3(2H)-dione(10)
在含有化合物9(5.94mmol,1.5equiv)的15mLTHF混合物中,加入间苯三酚(0.5g,3.97mmol)和p-TsOH.H2O(2.263g,11.9mmol,3equiv),回流两小时(薄层检测)。室温下间苯三酚几分钟就消耗尽,中间产物慢慢转化成化合物10。反应混合液缓慢降低至室温,用水淬灭反应。用50mL乙醚萃取四次。用硫酸镁干燥后,过滤,真空干燥。硅胶柱层析(石油醚:乙酸乙酯=2:1)后用甲苯重结晶,得到化合物10。
2.7合成桃金娘酮类化合物2-R1
用25mL二氯甲烷悬浮溶解化合物10(400mg,1.116mmol),加入四氯化钛,室温搅拌十分钟。之后加入R1ClO(0.145mL,1.19mmol,1.07equiv),室温搅拌26小时。直到主产物形成后反应液用40mL水淬灭。之后用50mL二氯甲烷萃取四次,饱和氯化钠溶液洗涤,硫酸钠干燥。过滤,真空浓缩。褐色的油状物,用乙醚乙酸乙酯4:1柱层析。R1=H(b),CH3(c),C2H5(d),n-C3H7(e),i-C3H7(f),n-C4H9(g),i-C4H9(h),n-C5H11(i),n-C6H13(j),n-C7H15(k),n-C8H17(l),n-C9H19(m),n-C10H21(n),n-C11H23(o),n-C13H27(p),n-C15H31(q),c-C4H7(r),c-C5H9(s),c-C6H11(t),CH2Ph(u,C2H4Ph(v).
当R1=i-C4H9(h)时,结构式如下:
化合物2-h为化合物rhodomyrthone,淡黄色针状晶体,易溶于氯仿;核磁数据:1HNMR(CDCl3,500MHz):δH 6.12(1H,s,H-5),4.27(1H,t,J=5.6Hz,H-9),2.99(3H,m,H-1”,H-2”),2.28(1H,dp,J=13.3,6.6Hz,H-3'),1.55,1.43,1.41,1.37(each 3H,s,H-11,H-12,H-13,H-14),0.98(6H,d,J=6.7,Hz,H-4',H-5'),0.87,0.83(each 3H,d,J=6.0Hz,H-3”,H-4”);13C NMR(CDCl3,125MHz):δC 212.2(C-3),206.7(C-1'),198.3(C-1),167.5(C-4a),162.8(C-8),158.7(C-6),155.7(C-10a),114.3(C-9a),107.7(C-7),106.4(C-8a),94.7(C-5),56.1(C-2),53.2(C-2'),46.4(C-4),45.8(C-1”),25.5(C-9),25.5(C-2”),25.2,25.1(C-13,C-14),24.7,24.6(C-11,C-12),24.2(C-3'),23.5,23.2(C-3”,C-4”),22.8,22.8(C-4',C-5')。化合物2-h的结构式如下所示:
实施例3在实施例1或实施例2获得桃金娘酮类化合物的基础上进一步合成相关的衍生物
合成过程如下:
3.1化学部分的材料和实验仪器,
同实施例2.1部分
3.2 8-hydroxy-9-isobutyl-6-methoxy-2,2,4,4-tetramethyl-7-(3-methylbutanoyl)-4,9-dihydro-1H-xanthene-1,3(2H)-dione的合成(11)
在N,N-二甲基甲酰胺(DMF)中,向桃金娘酮(化合物2-h)(22.7mg,0.0513mmol)和K2CO3(12mg,0.1026mmol)的搅拌溶液中加入碘甲烷(1mL)。将反应混合物在室温下搅拌,直到转化率可接受为止。用蒸馏水(50ml)搅拌混合物,用氯化氢(3×50ml)萃取。用蒸馏水(100mL)洗涤结合的有机层,在无水硫酸钠上干燥,并蒸发至干燥。粗品用100:0到84:16的正己烷-二氯甲烷进行柱层析纯化,得到黄色无定形化合物11(5.5mg,23%)。1H NMR(CDCl3):δ0.80(d,J=5.8Hz,3H,CH3-3″),0.84(d,J=5.9Hz,3H,CH3-4″),0.95(d,J=6.6Hz,6H,CH3-4′and CH3-5′),1.34,1.37(each s,2×3H,C(CH3)2),1.42,1.54(each s,2×3H,C(CH3)2),2.19(m,1H,H-3′),2.83(dd,J=6.7,15.4Hz,1H,H-2a′),2.90(dd,J=6.6,15.4Hz,1H,H-2b′),3.88(s,3H,OCH3),4.25(t,J=5.5Hz,1H,H-9),6.09(s,1H,H-5),14.1(br s,1H,8-OH);MS(ES):m/z:455([M-H]-,100%).
3.3 9-isobutyl-2,2,4,4-tetramethyl-7-(3-methylbutanoyl)-1,3-dioxo-2,3,4,9-tetrahydro-1H-xanthene-6,8-diyl diacetate的合成(12)
向含桃金娘酮(化合物2-h)(21.1mg,0.0477mmol)的吡啶(2mL)搅拌溶液中逐滴添加醋酸酐(0.5mL)和4-二甲氨基吡啶(10mg,0.0818mmol)。用薄层色谱法对反应进行监测,直到转化率合格为止。加入蒸馏水(50ml)并用乙酸乙酯(3×50ml)提取混合物。用蒸馏水(100mL)洗涤组合的乙酸乙酯提取物,在无水硫酸钠上干燥,并蒸发至干燥。以正己烷丙酮(98:2)为洗脱溶剂,经柱层析纯化得到无色无定形化合物12(5.2mg,21%)。1HNMR(CDCl3):δ0.79(d,J=6.2Hz,3H,H-3″),0.89(d,J=6.1Hz,3H,H-4″),0.93(d,J=6.6Hz,6H,H-4′andH-5′),1.33,1.36(each s,2×3H,C(CH3)2),1.42,1.52(each s,2×3H,C(CH3)2),2.18(m,1H,H-3′),2.26,2.90(each s,6H,2×OAc),2.56(dd,J=6.9,17.6Hz,1H,H-2a′),2.63(dd,J=6.8,17.6Hz,1H,H-2b′),3.99(t,J=6.0Hz,1H,H-9),6.91(s,1H,H-5);MS(ES):m/z:483([M-H]-,100%).
3.4 6,8-dihydroxy-9-isobutyl-2,2,4,4-tetramethyl-7-(3-methylbutanoyl)-4,9-dihydro-1H-xanthene-1,3(2H)-dione的合成(13)
向含化合物2-h(20.1mg,0.0454mmol)的二氯甲烷/甲醇(2mL)的搅拌溶液中滴加乙酸(0.5mL)。然后在室温下添加苯肼(0.1mL)。用薄层色谱法监测反应进展。加入蒸馏水(50ml),并用乙酸乙酯(3×50ml)萃取,得到反应物。用蒸馏水(100毫升)洗涤有机相,在无水硫酸钠上干燥,并在减压下浓缩。用柱层析法以二氯甲烷为洗脱溶剂对粗混合物进行纯化,得到淡黄色无定形化合物13(2.8mg,11%)。1HNMR(CDCl3):δ0.84(d,J=6.1Hz,3H,H-3″),0.88(d,J=6.1Hz,3H,H-4″),1.00(d,J=6.6Hz,3H,CH3-4′),1.03(d,J=6.6Hz,3H,CH3-5′),1.36,1.41(each s,2×3H,C(CH3)2),1.43,1.56(each s,2×3H,C(CH3)2),2.20(m,1H,H-3′),2.95(dd,J=7.5,13.8Hz,1H,H-2a′),3.03(dd,J=6.9,13.8Hz,1H,H-2b′),4.35(t,J=6.3Hz,1H,H-9),5.77(br s,1H,6-OH),6.99(s,1H,H-5),7.31(t,J=7.4Hz,1H,Ar-H),7.51(t,J=7.9Hz,2H,Ar-H),7.66(d,J=7.4Hz,2H,Ar-H);MS(ES):m/z:533([M-H]-,60%).
3.5 6,8-dihydroxy-7-(1-hydroxy-3-methylbutyl)-9-isobutyl-2,2,4,4-tetramethyl-4,9-dihydro-1H-xanthene-1,3(2H)-dione的合成(14)
将含桃金娘酮(化合物2-h)(19.8mg,0.0447mmol)在甲醇(2ml)的搅拌溶液中逐滴加入乙酸(1ml)和硼氢化钠(4mg,0.1056mmol)。在室温下搅拌反应混合物。反应混合物用蒸馏水(50ml)稀释,然后用乙酸乙酯(3×50ml)萃取。用蒸馏水(100mL)洗涤得到的乙酸乙酯提取物,在无水硫酸钠上干燥,并蒸发至干燥。粗品经柱层析法纯化,以二氯甲烷-甲醇(99:1)为洗脱溶剂,得到橙色无定形化合物14(7.9mg,40%)。1H NMR(CDCl3):δ0.77(d,J=6.1Hz,3H,H-3″),0.83(d,J=6.1Hz,3H,H-4″),0.95(d,J=6.6Hz,6H,CH3-4′and CH3-5′),1.34,1.37(each s,2×3H,C(CH3)2),1.41,1.52(each s,2×3H,C(CH3)2),1.62(m,1H,H-3′),2.57(m,2H,H-2′),4.15(t,J=5.8Hz,1H,H-9),4.82(m,1H,H-1′),4.95(br s,1H,OH),6.19(s,1H,H-5);MS(ES):m/z:455.3([M-H]-,100%).
3.6化合物15和16的合成
将盐酸羟胺(6mg,0.086mmol)加入到含的桃金娘酮(化合物2-h)(18.9mg,0.0427mmol)的二氯甲烷/甲醇搅拌溶液中,然后加入N,N-二异丙基乙胺(0.2mL)。将反应混合物在室温下搅拌,直到转化率可接受为止。加入蒸馏水(50ml)制成混合物,用乙醇酸乙酯(3×50ml)提取。用蒸馏水(100毫升)洗涤有机相,在无水硫酸钠上干燥,并在减压下浓缩。粗品用柱层析法,以二氯甲烷/甲醇为洗脱溶剂,随着甲醇浓度的逐渐增加,得到黄色无定形化合物15(0.9mg,4.6%)和化合物16(11.9mg,60.9%)。
化合物15.1H NMR(CDCl3):δ0.76(d,J=6.1Hz,3H,H-3″),0.82(d,J=6.1Hz,3H,H-4″),0.85(d,J=6.6Hz,3H,CH3-4′)0.86(d,J=6.6Hz,3H,CH3-5′),1.35,1.38(each s,2×3H,C(CH3)2),1.41,1.52(each s,2×3H,C(CH3)2),1.89(m,1H,H-3′),2.92(dd,J=7.5,13.8Hz,1H,H-2a′),2.98(dd,J=6.9,13.8Hz,1H,H-2b′),4.22(t,J=5.2Hz,1H,H-9),6.23(s,1H,H-5);MS(ES):m/z:915([2M-H]-,100%).
化合物16.1H NMR(CDCl3):δ0.75-0.85(m,12H,H-3″,H-4″,CH3-4′,CH3-5′),1.35,1.38(each s,2×3H,C(CH3)2),1.41,1.53(each s,2×3H,C(CH3)2),1.61(m,1H,H-3′),2.62(dd,J=7.5,13.8Hz,1H,H-2a′),2.72(dd,J=6.9,13.8Hz,1H,H-2b′),4.29(t,J=5.3Hz,1H,H-9),6.33(s,1H,H-5);MS(ES):m/z:915([2M-H]-,100%).
3.7 6-(3-bromopropoxy)-8-hydroxy-9-isobutyl-2,2,4,4-tetramethyl-7-(3-methylbutanoyl)-4,9-dihydro-1H-xanthene-1,3(2H)-dione的合成(17)
向桃金娘酮(化合物2-h)(42mg,0.0949mmol)的DMF(2mL)搅拌溶液中添加碳酸钾(14mg,0.1013mmol)和1.3-二溴丙烷(0.1mL)。在室温下搅拌混合物,直到可以接受的转化。用蒸馏水(50ml)进行反应,用乙酸乙酯(3×50mL)萃取。用蒸馏水(50ml)洗涤组合有机层,在无水硫酸钠上干燥,并在减压下浓缩至干燥。以100:0~95:5的正己烷-乙酸乙酯为洗脱剂,柱层析纯化得到无色无定形化合物17(27.7mg,52%)。1H NMR(CDCl3):δ0.80(d,J=5.7Hz,3H,H-3″),0.83(d,J=5.8Hz,3H,H-4″),0.94(d,J=6.6Hz,6H,H-4′and H-5′),1.33,1.36(each s,2×3H,C(CH3)2),1.41,1.53(each s,2×3H,C(CH3)2),2.22(m,1H,H-3′),2.40(m,2H,H-2″′),2.86(dd,J=7.1,16.4Hz,1H,H-2a′),2.92(dd,J=7.0,16.4Hz,1H,H-2b′),3.59(t,J=6.3Hz,2H,H-3″′),4.19(t,J=5.3Hz,2H,H-1″′),4.24(t,J=5.4Hz,1H,H-9),6.12(s,1H,H-5),14.1(br s,1H,8-OH);MS(ES):m/z:563([M-H]-,80%),565([M-H]-,100%).
3.8 8-hydroxy-9-isobutyl-2,2,4,4-tetramethyl-7-(3-methylbutanoyl)-6-(3-mor pholinopropoxy)-4,9-dihydro-1H-xanthene-1,3(2H)-dione的合成(18)
将吗啉(0.2ml)添加到含化合物17(6.4mg,0.0011mmol)的DMF(0.5ml)的搅拌溶液中。将反应在室温下搅拌至可接受的转化率,并通过添加蒸馏水(25毫升)进行。用乙酸乙酯(3×50mL)萃取混合物。用蒸馏水(50ml)洗涤有机相,无水硫酸钠上干燥,并蒸发至干燥。以二氯甲烷/甲醇(98:2)为洗脱溶剂,经柱层析纯化得到无色无定形化合物18(4.1mg,63%)。1H NMR(CDCl3):δ0.80(d,J=5.5Hz,3H,H-3″),0.84(d,J=5.7Hz,3H,H-4″),0.95(d,J=6.6Hz,6H,H-4′and H-5′),1.33,1.37(each s,2×3H,C(CH3)2),1.42,1.53(each s,2×3H,C(CH3)2),2.07(m,2H,H-2″′),2.24(m,1H,H-3′),2.49(m,4H,H-1″″),2.57(m,J=6.3Hz,2H,H-3″′),2.88(dd,J=6.8,16.1Hz,1H,H-2a′),2.95(dd,J=6.8,16.1Hz,1H,H-2b′),3.74(m,4H,H-2″″),4.10(t,J=5.2Hz,2H,H-1″′),4.25(t,J=5.2Hz,1H,H-9),6.10(s,1H,H-5),14.1(br s,1H,8-OH);MS(ES):m/z:570([M-H]-,100%).
3.9 8-hydroxy-9-isobutyl-2,2,4,4-tetramethyl-7-(3-methylbutanoyl)-6-(3-(piperi din-1-yl)propoxy)-4,9-dihydro-1H-xanthene-1,3(2H)-dione的合成(19)
向含化合物17(3.5mg,0.0062mmol)的DMF(0.5mL)搅拌溶液中逐滴添加哌啶(0.2mL)。混合物在室温下搅拌。用薄层色谱法监测反应过程,直至转化率合格。在反应混合物中加入蒸馏水(25ml),然后用乙醇酸乙酯(3×50mL)萃取。用蒸馏水(50ml)洗涤有机相,在无水硫酸钠上干燥,并在减压下浓缩至干燥。以二氯甲烷/甲醇(98:2))为洗脱溶剂,采用柱层析法纯化粗品,得到无色无定形化合物19(2.6mg,74%)。1H NMR(CDCl3):δ0.80(d,J=5.5Hz,3H,H-3″),0.84(d,J=5.6Hz,3H,H-4″),0.95(d,J=6.5Hz,6H,H-4′and H-5′),1.33,1.37(each s,2×3H,C(CH3)2),1.41,1.53(each s,2×3H,C(CH3)2),1.46(m,2H,H-4″″),1.63(m,4H,H-3″″and H-5″″),2.09(m,2H,H-2″′),2.24(m,1H,H-3′),2.47(m,4H,H-2″″and H-6″″),2.56(t,J=6.7Hz,2H,H-3″′),2.89(dd,J=6.8,16.1Hz,1H,H-2a′),2.95(dd,J=6.8,16.1Hz,1H,H-2b′),4.09(m,2H,H-1″′),4.25(t,J=5.4Hz,1H,H-9),6.10(s,1H,H-5),14.1(br s,1H,8-OH);MS(ES):m/z:568([M-H]-,100%).
3.108-hydroxy-9-isobutyl-2,2,4,4-tetramethyl-7-(3-methylbutanoyl)-6-(3-(pipe razin-1-yl)propoxy)-4,9-dihydro-1H-xanthene-1,3(2H)-dione的合成(20)
将哌嗪(1mg,0.0116mmol)添加到含化合物17(3.8mg,0.0067mmol)的DMF(0.5mL搅拌溶液中。在室温下搅拌反应直到可接受的转化。将蒸馏水(25ml)加入反应混合物中,用乙醇酸乙酯(3×50mL)萃取。用蒸馏水(50ml)洗涤组合的乙酸乙酯提取物,在无水硫酸钠上干燥,并蒸发至干燥。用100:0到87:13用二氯甲烷/甲柱层析法醇纯化原料混合物,得到无色无定形化合物20(1.4mg,37%)。1H NMR(CDCl3):δ0.80(d,J=5.7Hz,3H,H-3″),0.83(d,J=5.8Hz,3H,H-4″),0.94(d,J=6.6Hz,6H,H-4′and H-5′),1.33,1.37(each s,2×3H,C(CH3)2),1.41,1.53(each s,2×3H,C(CH3)2),2.04(m,2H,H-2″′),2.23(m,1H,H-3′),2.56(m,6H,H-1″″and H-3″′),2.87(dd,J=6.8,16.0Hz,1H,H-2a′),2.94(dd,J=6.8,16.0Hz,1H,H-2b′),3.02(m,4H,H-2″″),4.08(t,J=5.3Hz,2H,H-1″′),4.25(t,J=5.4Hz,1H,H-9),6.08(s,1H,H-5),14.1(br s,1H,8-OH);MS(ES):m/z:569([M-H]-,100%).
3.11 6-(3-(diethylamino)propoxy)-8-hydroxy-9-isobutyl-2,2-dimethyl-7-(3-methyl butanoyl)-4,9-dihydro-1H-xanthene-1,3(2H)-dione的合成(21)
将0.2mL二乙胺添加到含化合物17(3.8mg,0.0067mmol)的DMF(0.5mL搅拌溶液中。在室温下搅拌反应直到可接受的转化。将蒸馏水(25ml)加入反应混合物中,用乙醇酸乙酯(3×50mL)萃取。用蒸馏水(50ml)洗涤组合的乙酸乙酯提取物,在无水硫酸钠上干燥,并蒸发至干燥。用100:0到87:13用二氯甲烷/甲柱层析法醇纯化原料混合物,得到无色无定形化合物21(2.6mg,72%)。1H NMR(CDCl3):δ0.80(d,J=5.7Hz,3H,H-3″),0.83(d,J=5.8Hz,3H,H-4″),0.94(d,J=6.6Hz,6H,H-4′and H-5′),1.33,1.37(each s,2×3H,C(CH3)2),1.41,1.53(each s,2×3H,C(CH3)2),2.04(m,2H,H-2″′),2.23(m,1H,H-3′),2.56(m,6H,H-1″″andH-3″′),2.87(dd,J=6.8,16.0Hz,1H,H-2a′),2.94(dd,J=6.8,16.0Hz,1H,H-2b′),3.02(m,4H,H-2″″),4.08(t,J=5.3Hz,2H,H-1″′),4.25(t,J=5.4Hz,1H,H-9),6.08(s,1H,H-5),14.1(br s,1H,8-OH);MS(ES):m/z:527([M-H]-,100%).
实施例4桃金娘酮类化合物抗新型冠状病毒SARS-CoV-2活性分析
4.1细胞和病毒
非洲绿猴肾细胞Vero-E6按照常规传代培养,调整细胞密度为1×105个/mL接种到96孔板中,待孔内细胞生长为完整单层备用。新型冠状病毒SARS-CoV-2为中国科学院武汉病毒所保存的病毒。细胞培养液为含10%FBS、1%青链霉素混合液的DEME培养液,细胞维持液、病毒维持液为含3%FBS、1%青链霉素混合液的DEME培养液。
4.2化合物细胞毒性的测定
将化合物用细胞维持液连续2倍倍比稀释后,加入到细胞长成单层的96孔培养板上,100μL/孔,每个稀释度重复3孔,另设不加化合物的细胞对照组,置5%CO2培养箱37℃培养72h,每天观察记录细胞病变(CPE)情况。待培养到72h后,弃上清,用PBS缓冲液清洗2遍,每孔加入20μLMTT,继续培养4h后,弃MTT上清,每孔加入150μLDMSO,震荡5-10min,待结晶完全溶解后用酶标仪测OD570。以CPE程度和所测得OD值为依据,计算药物致细胞的病变率,CC50是使得50%的细胞发生病变时的药物浓度。
4.3化合物对新型冠状病毒SARS-CoV-2病毒复制的抑制作用
96孔板中的MDCK细胞长成单层后,吸去培养液,用0.01MOI的SARS-CoV-2病毒100μL吸附细胞,37℃孵育1h,洗去游离病毒,加入用细胞维持液倍比稀释的化合物100μL,每个稀释度重复3孔,同时设不加化合物和病毒的细胞对照组、不加化合物加病毒的病毒对照组,37℃、5%CO2继续培养,观察细胞病变,确定细胞病变是否为SARS-CoV-2病毒引起的特异性病变,培养72h,按MTT方法测定各药物浓度组的存活细胞。用以下公式计算样品对病毒的抑制率。以CPE和抑制率结果确定样品抑制半数细胞感染病毒的浓度(IC50)。最后计算出选择指数SI=CC50/IC50
表1 2-h等3个桃金娘酮类化合物对新型冠状病毒SARS-CoV-2的抗病毒效果
结果表明桃金娘酮类化合物2-h,18,21对新型冠状病毒SARS-CoV-2均有显著的抑制活性,以化合物2-h为例,对Vero-E6细胞毒性CC50为4.58±0.76μM,抑制新型冠状病毒SARS-CoV-2复制的IC50为0.32±0.09μM,选择性系数SI为14.31,数据说明化合物2-h能够显著抑制SARS-CoV-2复制,且细胞毒性相对较弱,有作为抗新型冠状病毒药物的基础。通过改变桃金娘酮化合物的侧链,能够得到系列桃金娘酮类化合物,其中化合物21对Vero-E6细胞毒性CC50为4.87±0.82μM,抑制新型冠状病毒SARS-CoV-2复制的IC50为0.21±0.06μM,选择性系数SI为23.19,数据说明通过结构改造获得的桃金娘酮类化合物21能够增强抗病毒活性,同时进一步减弱了细胞毒性,可以用于预防或治疗新冠肺炎,有望为临床治疗新冠肺炎提供新的候选药物分子。
总之,本发明提供了具有结构式I的化合物及其在抗新型冠状病毒SARS-CoV-2药物中的应用。
以上对本发明具体实施方式的描述并不限制本发明,本领域技术人员可以根据本发明作出各种改变或变形,只要不脱离本发明的精神,均应属于本发明所附权利要求的范围。
Claims (6)
1.桃金娘酮类化合物、或其立体异构体、差向异构体、构型异构体或其药学上可以接受的盐、或它们的水合物,或桃金娘的部分或者全株(包括但不限于叶、茎、花、果、根、内生菌)的提取物,提取溶剂可以是水或者(更有效)有机溶剂包括但是不限于乙醇、丙酮、甲醇、乙酸乙酯、正己烷等或者以上溶剂不同比例的混合物)和CO2超临界或者亚临界提取、或者以上提取物经过物理和化学方法浓缩、分配、富集和部分和纯化的馏分或者部位在制备抗新型冠状病毒SARS-CoV-2药物中的应用,所述的桃金娘酮类化合物,其结构如式I所示:
其中,虚线部分表示任选的C-C单键,当虚线不存在时即形成C-C单键,当虚线存在时形成C=X双键;
当虚线存在时,形成C=X双键,R4、R5和R6各自独立选O、S或者NR1’,R1’为氢、或C1-C15直链、支链环烷基或含有苯环的芳香基团;
R1为氢、或C1-C15直链、支链环烷基或含有苯环的芳香基团;
R2和R3、R7各自独立选氢、或者自下面取代基团;
其中n=0-15的任何数字,R8和R9各自独立选氢、或C1-C15直链,支链环烷基或含有苯环的芳香基团,或R8和R9形成环烷基或杂环。
2.根据权利要求1所述的应用,其特征在于,所述的R1为C3-C10的直链、支链或环烷基。
5.根据权利要求1所述的应用,其特征在于,所述的n=1-8。
6.根据权利要求4所述的应用,其特征在于,所述的桃金娘酮类化合物2-h、18或21。
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112516134A (zh) * | 2019-09-18 | 2021-03-19 | 上海医药集团股份有限公司 | 一种含羟基的化合物在制备药物中的应用 |
CN112741831A (zh) * | 2020-08-11 | 2021-05-04 | 暨南大学 | 一类多环聚酮化合物在制备抗新型冠状病毒药物中的应用 |
CN114558020A (zh) * | 2022-04-24 | 2022-05-31 | 中国科学院华南植物园 | 一种天然抗病毒液及其制备方法和应用 |
CN114948936A (zh) * | 2022-05-05 | 2022-08-30 | 中国科学院华南植物园 | 一种天然抗病毒雾化液及其制备方法和应用 |
CN115626906A (zh) * | 2022-10-25 | 2023-01-20 | 中国科学院华南植物园 | 一种高纯度桃金娘酮的工业化提取方法 |
WO2023070373A1 (zh) * | 2021-10-27 | 2023-05-04 | 暨南大学 | 一类多环聚酮化合物在制备抗新型冠状病毒药物中的应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010041703A1 (ja) * | 2008-10-08 | 2010-04-15 | 株式会社 ポッカコーポレーション | 抗sarsコロナウイルス剤及び抗sarsコロナウイルス剤含有製品 |
CN104761565A (zh) * | 2015-04-16 | 2015-07-08 | 中国科学院华南植物园 | 桃金娘酮化合物及其在制备抗菌药物中的应用 |
CN108752305A (zh) * | 2018-08-24 | 2018-11-06 | 中国科学院华南植物园 | 闭环桃金娘酮类似物及在抗菌药物中的应用 |
CN110279688A (zh) * | 2019-06-26 | 2019-09-27 | 暨南大学 | 一类多环聚酮化合物在制备抗疱疹病毒药物中的应用 |
-
2020
- 2020-05-29 CN CN202010476418.5A patent/CN113730391B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010041703A1 (ja) * | 2008-10-08 | 2010-04-15 | 株式会社 ポッカコーポレーション | 抗sarsコロナウイルス剤及び抗sarsコロナウイルス剤含有製品 |
CN104761565A (zh) * | 2015-04-16 | 2015-07-08 | 中国科学院华南植物园 | 桃金娘酮化合物及其在制备抗菌药物中的应用 |
CN108752305A (zh) * | 2018-08-24 | 2018-11-06 | 中国科学院华南植物园 | 闭环桃金娘酮类似物及在抗菌药物中的应用 |
CN110279688A (zh) * | 2019-06-26 | 2019-09-27 | 暨南大学 | 一类多环聚酮化合物在制备抗疱疹病毒药物中的应用 |
Non-Patent Citations (4)
Title |
---|
LI-YUN ZHAO ET AL.: "《Rhodomyrtosone B, a membrane-targeting anti-MRSA natural acylgphloroglucinol from Rhodomyrtus tomentosa》", 《JOURNAL OF ETHNOPHARMACOLOGY》 * |
ROSARIO ET AL.: "《Structures and Bioactive Properties of Myrtucommulones and Related Acylphloroglucinols from Myrtaceae》", 《MOLECULES》 * |
肖婷 等: "《桃金娘的化学成分、药理作用和临床应用研究进展》", 《现代药物与临床》 * |
黄儒强等: "《山稔子黄酮类提取物抗自由基作用及体内抗氧化功能的研究》", 《食品科学》 * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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CN112516134B (zh) * | 2019-09-18 | 2023-06-06 | 上海医药集团股份有限公司 | 一种含羟基的化合物在制备药物中的应用 |
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WO2023070373A1 (zh) * | 2021-10-27 | 2023-05-04 | 暨南大学 | 一类多环聚酮化合物在制备抗新型冠状病毒药物中的应用 |
CN114558020A (zh) * | 2022-04-24 | 2022-05-31 | 中国科学院华南植物园 | 一种天然抗病毒液及其制备方法和应用 |
CN114948936A (zh) * | 2022-05-05 | 2022-08-30 | 中国科学院华南植物园 | 一种天然抗病毒雾化液及其制备方法和应用 |
CN115626906A (zh) * | 2022-10-25 | 2023-01-20 | 中国科学院华南植物园 | 一种高纯度桃金娘酮的工业化提取方法 |
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