CN115260146A - 氧杂蒽酮酯类与糖类衍生物及其制备与抗菌用途 - Google Patents
氧杂蒽酮酯类与糖类衍生物及其制备与抗菌用途 Download PDFInfo
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- CN115260146A CN115260146A CN202210872955.0A CN202210872955A CN115260146A CN 115260146 A CN115260146 A CN 115260146A CN 202210872955 A CN202210872955 A CN 202210872955A CN 115260146 A CN115260146 A CN 115260146A
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- Prior art keywords
- derivative
- alpha
- mangostin
- xanthone
- compound
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- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 20
- -1 Xanthone ester Chemical class 0.000 title claims description 29
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- 238000000034 method Methods 0.000 claims abstract description 19
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- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims abstract description 8
- 241000192125 Firmicutes Species 0.000 claims abstract description 7
- 239000007858 starting material Substances 0.000 claims abstract description 3
- GNRIZKKCNOBBMO-UHFFFAOYSA-N alpha-mangostin Chemical class OC1=C(CC=C(C)C)C(O)=C2C(=O)C3=C(CC=C(C)C)C(OC)=C(O)C=C3OC2=C1 GNRIZKKCNOBBMO-UHFFFAOYSA-N 0.000 claims description 123
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 70
- QTDMGAWIBXJNRR-UHFFFAOYSA-N Mangostin Natural products CC(=CCc1c(O)cc2Oc3cc(C)c(O)c(CC=C(C)C)c3C(=O)c2c1O)C QTDMGAWIBXJNRR-UHFFFAOYSA-N 0.000 claims description 70
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 6
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
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- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 claims description 3
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
- C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
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Abstract
Description
技术领域
本发明属于生物医药领域,涉及一种氧杂蒽酮酯类与糖类衍生物及其制备与抗菌用途,具体涉及新型天然氧杂蒽酮α-倒捻子素酯类与糖类衍生物及其合成方法,和其在抗菌药物研发中的应用。
背景技术
抗生素在临床和养殖业中的大量应用以及不合理地使用,造成细菌多重耐药。细菌耐药性已成为21世纪人类健康面临的重大威胁。动物养殖业是细菌耐药性产生的主要源头之一,耐药基因和耐药菌能在“动物、食品、环境和人群”链条内流通,加剧威胁人类健康。当前面对细菌耐药性带来的挑战,全球主要的应对策略有:加强耐药监测、合理使用抗生素、开发新型抗菌药物和恢复或增强现有抗生素的抗菌活性等。开发新型抗生素和恢复或增强耐药菌对现有抗生素的敏感性是控制细菌耐药性持续发展的有效措施。
山竹(莽吉柿,Garcinia mangostana L.),为藤黄科(Guttiferae)藤黄属(Garcinia)常绿乔木,是东南亚地区的传统药物,含有氧杂蒽酮类化合物最多,在体内外证明具有显著的生物活性,包括抗肿瘤作用(倒捻子素衍生物A,其制备方法及其抗肿瘤的用途,中国发明专利(CN 106188089 A))、抗氧化活性(新型α-和γ-倒捻子素Mannich碱:合成和抗氧化和膜保护活性评价,欧洲药物化学,152(2018)10-20)、抗菌活性、神经保护活性(α-倒捻子素衍生物及其应用,中国发明专利,CN 111253412A)。α-倒捻子素(α-mangostin,α-MG)是山竹中含量最高的氧杂蒽酮衍生物,具有三环芳香体系(C6-C3-C6)独特的化学结构,其中异戊二烯、甲氧基和羟基位于A环和B环上的不同位置,其独特的抗菌活性引起药物学家关注,然而目前针对α-MG结构修饰主要采取拟肽原理制备两性分子,α-倒捻子素氧杂蒽醌部分为亲脂,对称引入的含氮侧链增加极性,携带电荷的N原子与细菌膜上负电荷发生静电作用,分子量增大,结构特征违反类药5原则(Rule of 5),结果活性提高不明显(两性非肽氧杂蒽酮衍生物:构效关系和膜靶向性,药物化学,59(2016)1,171-193),进一步研究发现A环和B环的异戊二烯是α-MG抗菌活性的必需基团(氧杂蒽酮氨基酸衍生物:新颖且富有前景广阔的治疗多药耐药革兰氏阳性细菌感染的膜活性抗菌剂,药物化学,58(2015)739-752),因此,过去研究主要集中靶向识别并结合细菌膜过程而进行结构改造,忽视氧杂蒽酮类化合物成药性所需物化性质,往往其衍生物分子量大、水溶性差、生物利用度低等缺陷,导致很难发现基于氧杂蒽酮结构的小分子药物。本发明进一步挖掘氧杂蒽酮α-MG上不同含氧基团对抗菌活性贡献,选择性地引入低分子量取代基,控制α-MG活性氧产生避免作用的非特异性,同时,采用对称性或非对称性方式,引入具有靶向性、高水溶性的简单糖,包括细菌源糖,合理改构氧杂蒽酮α-MG,提高其成药性概率,研发一系列抑制革兰氏阳性菌或者逆转耐药性革兰氏阳性菌的全新结构α-MG衍生物。
发明内容
本发明的目的在于克服上述现有技术存在的不足,提供一种新型抗菌α-MG衍生物及其制备方法与应用,具体是以α-mangostin(α-MG)为先导,集中在氧杂蒽酮α-MG的C-1,C-3,C-6,C-9进行对称性与非对称性改构,合成一系列α-MG衍生物,进行抗菌活性筛选,得到新型具有良好抗菌活性的衍生物,或者可以逆转常规抗菌药物对多重耐药菌株的耐药性的衍生物(如图1所示)。本发明所述的α-MG衍生物设计独特,所述的合成条件温和,反应试剂易得,反应路线短,所述衍生物具有靶向破坏细胞壁生物合成、损伤细胞膜结构,导致通透性增强,内容物外流,阻断生物膜形成,可作为新型抗革兰氏阳性菌化合物以及致敏临床耐药株的辅助剂。
本发明的目的是通过以下技术方案来实现的:
第一方面,本发明涉及一种氧杂蒽酮α-MG衍生物,结构通式I所代表的化合物,
其中,X=O或H;R=OH、OR3或OCOR3;R1=H、R5、-Y-R4或COR5;R2=H、R7、-Z-R6或COR7;R3为1-6个碳原子的烷烃或不饱和烃(烯烃);R4和R6为甘露糖、半乳糖、鼠李糖、岩藻糖、葡萄糖、古洛糖、红霉胺糖等及其醛酸或不同位置糖胺取代物;R5和R7为1-3个碳烷烃;Y和Z为0-6个碳链或含氧碳链。这些化合物可以抗革兰氏阳性菌以及致敏临床耐药菌株,也可以作为分子探针揭示氧杂蒽醌类化合物抗菌作用机制。
优选的,所述烷烃包括直链饱和烃和支链饱和烃,所述不饱和烃包括直链不饱和烃与支链不饱和烃,所述不饱和烃包括烯烃、共轭烯烃或炔烃。优选的,所选0-6个含氧碳链包括乙二醇或二聚乙二醚。
优选的,所述简单糖包括甘露糖、半乳糖、葡萄糖、古洛糖、鼠李糖、红霉胺糖、博来霉素二糖。
优选的,所述不同位置糖胺取代物包括简单糖的一个或多个氨基取代物。
第二方面,本发明氧杂蒽酮α-MG衍生物制备方法,以α-MG为起始原料,经不同化学反应组合得结构式I所代表化合物。
优选的,所述合成方法,制备路线示意图如图2和图3,具体包括如下步骤:
S1、在氮气保护下,在0-5℃下,将α-MG溶于无水醚类溶剂中,加入1-8倍氢化铝锂,40-75℃下反应半小时得9-亚甲基倒捻子素A。
优选的,所述无水醚类试剂包括四氢呋喃和乙醚,所选氢化铝锂与α-MG的物质的量之比2-4:1,所选反应温度为60-75℃。
S2、在氮气保护下,在0-5℃下,将α-MG溶于无水溶剂中,加入2-10倍有机碱与催化量的N,N-二甲基吡啶(DMAP),然后再加入2-8倍酰化试剂,在20-35℃下搅拌数小时得3,6-二酰基倒捻子素类似物B。
优选的,所述无水溶剂试剂包括四氢呋喃和二氯甲烷,所选有机碱为三乙胺、吡啶、N,N-二异丙基乙胺等,α-MG、有机碱、DMAP与酰化试剂的物质的量之比1:2.5-6:0.1-0.5:2.0-5.0;所选反应温度为20-35℃,更优选室温。
优选的,所述酰化试剂为酸酐或酰氯,具体包括乙酸酐、乙酰氯、异丁酸酐、异丁酰氯等。
S3、在氮气保护下,将α-MG溶于有机碱中,加入催化量的碱,半小时后,加入3-10倍当量酰化试剂,在40-60℃反应过夜得1,3,6-三酰基或醚基倒捻子素衍生物C。
优选的,所选生成酰基的碱为碳酸钾、三乙胺、吡啶等,所选生成醚基的碱为钠氢、甲醇钠等,所选α-MG、碱与酰化试剂的物质的量之比1:0.1-0.5:3-6;所选反应温度为45-55℃。
优选的,所述酰化试剂为酰氯或卤代烃,具体包括乙酰氯、丙酰氯、异丁酰氯以及氯乙烷、溴乙烷、溴苄等。
S4、在氮气保护下,将α-MG溶于丙酮中,加入5倍当量无机碱,在常温下,通过控制卤代烯丙基量,反应数小时选择性地得到3,6-二烯丙基倒捻子素衍生物D或6-烯丙基倒捻子衍生物E。
优选的,所述无机碱包括碳酸钾、碳酸铯等,对衍生物D而言,所选α-MG、无机碱、卤代烯丙基的物质的量之比1:2-5:2-3,对衍生物E而言,所选α-MG、无机碱、卤代烯丙基的物质的量之比1:2-5:1-1.5。
S5、在氮气保护下,将化合物D或E溶于无水有机溶剂,加入适量有机碱,0-5℃反应10分钟后,相同温度下滴加1-3倍当量的酰化试剂,常温下反应数小时得3,6-二烯丙基-1-单酰化倒捻子素衍生物F与6-烯丙基-1,4-二酰化倒捻子素衍生物G。
优选的,所述无水溶剂为四氢呋喃、乙醚、二氯甲烷、二氯乙烷,所选有机碱为三乙胺、碳酸钾、吡啶等,所述酰化试剂为酰氯,所选α-MG、有机碱、酰化试剂的物质的量之比1:1.5-4.0:1.2-2.5。
S6、在氮气保护下,将化合物F或G溶于无水二氯甲烷中,加入催化量三苯基膦钯(Pd(PPh3)4)和3-8倍当量的无机碱,20-35℃反应数小时得1-单酰化倒捻子素衍生物H与1,4-二酰化倒捻子素衍生物I。
优选的,所述无机碱为碳酸钾、碳酸铯等,所选α-MG、无机碱、Pd(PPh3)4的物质的量之比1:3-5:0.1-0.3,所选反应温度为20-35℃,更优选为常温。
S7、在氮气保护下,将α-MG溶于丙酮中,加入5倍当量无机碱,在40-70℃下,通过严格控制不同长度卤代醇的反应量,反应数小时选择性地得到3,6-二取代醚倒捻子素衍生物J或6-取代醚倒捻子衍生物K。
优选的,所述无机碱为碳水铯、碳酸钾等;所述卤代醇包括溴乙醇、溴戊醇、溴己醇等。对衍生物J而言,所选α-MG、无机碱、卤代醇的物质的量之比1:2.5-5:2.2-3,对衍生物K而言,所选α-MG、无机碱、卤代醇的物质的量之比1:1.5-3:1.0-1.5,所选反应温度为45-55℃。
S8、在氮气保护下,在0-5℃下,将化合物J或K溶于无水溶剂中,加入4A分子筛粉末,滴加1.0-5倍当量的三氯乙酰亚胺活化的全酰化简单糖,同时加入催化量三氟化硼乙醚复合物,低温反应数小时得3,6-二全乙酰化糖倒捻子素衍生物L与6-全乙酰化糖倒捻子衍生物M。
优选的,所述无水溶剂为二氯甲烷、N,N-二甲基甲酰胺。对化合物L而言,所选化合物J、三氯乙酰亚胺活化的全酰化简单糖、三氟化硼乙醚复合物的物质的量之比1:2.5-3.0:0.1-0.3;对化合物M而言,所选化合物M、三氯乙酰亚胺活化的全酰化简单糖、三氟化硼乙醚复合物的物质的量之比1:1.2-1.5:0.1-0.3;所选反应温度(低温)为-10-5℃。
所述三氯乙酰亚胺活化的全酰化简单糖包括甘露糖、阿拉伯糖、庚糖酸、红霉胺糖等。
S9、在氮气保护下,常温下,将化合物L和M溶于无水甲醇中,加入催化量的甲醇钠,反应适当时间后经酸性树脂Amberlite IR120H型或Amberlyst 35等处理得3,6-二糖基化倒捻子素衍生物N与6-糖基化倒捻子衍生物O。
优选的,所选合物L或M:甲醇钠的物质的量之比1:0.05-0.2,所选反应温度为20-35℃。
第三方面,本发明涉及一种所述的氧杂蒽酮α-MG酯类或糖类衍生物的作用机制,通过靶向抑制细胞壁生物合成、破坏膜结构,导致其通透性增强,内容物外流,进而抑制革兰氏阳性菌如金黄色葡萄菌(Staphylococcus aureus)等生长。
第四方面,本发明涉及一种所述的氧杂蒽酮α-MG酯类或糖类衍生物的用途,用于抗革兰氏阳性菌或对青霉素、阿莫西林等临床抗生素具有协同增效作用,用于临床耐药菌株的致敏剂。
第五方面,本发明涉及一种所述氧杂蒽酮α-MG酯类或糖类衍生物的用途,可用于动物养殖业中减少抗生素甚至代替抗生素;或作为用于揭示氧杂蒽醌类的化合物抗菌作用机制的分子探针。
与现有技术相比,本发明具有如下有益效果:
1)本发明所有合成α-MG酯类或糖类衍生物侧重于其类药特性,通过控制分子量大小、对称或非对称地引入靶向细菌简单糖等策略实现。
2)本发明所有合成路线短、产率高、反应过程绿色清洁、对环境友好,易大规模生产。
3)本发明涉及的具有抗菌活性氧杂蒽醌类化合物,其机制独特,是一种通过抑制细菌胞壁生物合成、破坏细胞膜结构进而增强细胞通透性,造成细菌内容物外流而阻碍细胞生长,不易耐药。
4)本发明涉及的氧杂蒽醌类化合物能够逆转临床抗生素如青霉素等耐药抵抗,可以作为临床抗菌药的辅助剂,克服与延缓临床耐药性。
附图说明
通过阅读参照以下附图对非限制性实施例所作的详细描述,本发明的其它特征、目的和优点将会变得更明显:
图1为氧杂蒽酮α-MG衍生物的结构示意图;
图2为不同程度酰化的氧杂蒽酮衍生物合成示意图;其中,i),base,R1X(Cl、Br),40-60℃6ii)base,R1X(Cl、Br)or(R1CO)2O,r.t.6iii)base,CH2CHCH2X(X=Cl,Br),r.t.6iv)base,R1COCl,r.t.6v)base,Pd(PPh3)4;
图3为亚甲基化或糖基化氧杂蒽酮类化合物合成示意图;其中,i)base,X(CH2)nOH(X=Br or Cl),40-70℃6ii)BF3OEt,sugar donor6 iii),CH3ONa/CH3OH,acid resin,r.t.6iv),LiAlH4,40-75℃;
图4为不同程度乙酰与异戊酰化的氧杂蒽酮衍生物以及三苄基化α倒捻子素衍生物合成示意图;其中,i),K2CO3 and CH3COCl for 2a,Py,DMAP and(CH3)2CHCOCl for 2b,NaH and BnBr for 2c,40-60℃6ii)Py,CH3COCl for 3a or(CH2CH3)3and(CH3)2CHCOCl for3b,r.t.6iii)K2CO3,CH2CHCH2X(X=Cl,Br),40-70℃6iv),N(CH2CH3)3,R1Cl,r.t.6v),K2CO3,Pd(PPh3)4;
图5为亚甲基化和甘露糖化氧杂蒽酮类化合物合成示意图;其中,i)base,X(CH2)6OH(X=Br or Cl),40-70℃6ii)BF3OEt,sugar donor F46 iii),CH3ONa dissolved inanhydrous CH3OH,acid resin,r.t.6iv),LiAlH4,40-75℃;
图6为三氯乙酰亚胺活化甘露糖衍生物供体F1-F4合成示意图;
图7为α-MG及其衍生物对金黄色葡萄球菌多重耐药菌株MRSA2的杀菌曲线;其中,A:α-MG;B:衍生物8a;C:衍生物9a;
图8为透射电镜下观察经α-MG或衍生物8a孵育后金黄色葡萄球菌形态变化示意图;
图9为经α-MG或衍生物8a孵育后S.aureus ATCC29213细胞壁厚度变化示意图;其中,A:α-MG;B:衍生物8a;
图10为α-MG及其衍生物对S.aureus ATCC29213细胞膜质子势的影响示意图;其中,A:α-MG;B:衍生物8a;C:衍生物9a;
图11为α-MG及其衍生物在金黄葡萄球菌多重耐药株小鼠皮肤脓肿感染模型实验中的皮肤脓肿体积统计图,其中,A:第1天;B:第3天。
图12为α-MG及其衍生物在金黄葡萄球菌多重耐药株小鼠皮肤脓肿感染模型实验中的皮肤细菌数量统计图,其中,A:第1天;B:第3天。
具体实施方式
下面结合实施例对本发明进行详细说明。以下实施例在以本发明技术方案为前提下,进行实施,以α-倒捻子素为先导物,对其进行乙酰化、异丁酰化、甘露糖化制备倒捻子素酯类或糖类衍生物,给出了详细的实施方式和具体的操作过程,将有助于本领域的技术人员进一步理解本发明,但不以任何形式限制发明。应当指出的是,对本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干调整与改进。这些属于本发明保护范围。
实施例1、不同位置酰化或醚化α-倒捻子素衍生物的合成
本实施例具体涉及乙酰化α倒捻子素衍生物、异丁酰化α倒捻子素衍生物以及苄基化α倒捻子素衍生物合成,反应路线图如图4。
1)1,3,6-三乙酰化α-倒捻子素衍生物(2a)的合成
将α-倒捻子素(1,1mmoL,410mg)和无水碳酸钾(6mmoL,828mg)溶解于无水20mLDMF中,氮气保护下加入乙酸酐(6mmoL,612mg),加热至60℃,反应过夜。反应结束后,加入100mL乙酸乙酯稀释,后用50mL水加入分层,有机层用100mL水和50mL饱和食盐水先后洗涤,有机层经无水硫酸钠干燥,减压旋干,粗品过200~300目硅胶柱层析得到402.5mg黄色固体化合物2a,产率75%。1H NMR(400MHz,CDCl3)δ7.13(s,1H),7.10(s,1H),5.24–5.15(m,1H),5.09–4.99(m,1H),4.07(d,J=6.4Hz,2H),3.76(s,3H),3.27(s,2H),2.46(s,3H),2.35(d,J=16.8Hz,6H),1.79(d,J=28.8Hz,12H).13C NMR(100MHz,CDCl3)δ176.17,169.30,168.20,168.15,154.60,153.31,153.22,148.89,148.60,146.85,139.12,132.55,131.82,123.69,123.08,121.04,119.01,113.67,110.37,109.07,61.70,26.33,25.89,25.71,23.60,21.30,21.07,21.00,18.29,18.00.
2)1,3,6-三异丁酰化α-倒捻子素衍生物(2b)的合成
将α-倒捻子素(1,1mmoL,410mg)和4-二甲胺基吡啶(DMAP)(0.2mmoL,24.4mg)溶解于无水20mL吡啶中,氮气保护下加入异丁酰氯(6mmoL,639.6mg),加热至60℃,反应过夜。反应结束后,加入100mL乙酸乙酯稀释,后用50mL水加入分层,有机层用100mL水和50mL饱和食盐水先后洗涤,有机层经无水硫酸钠干燥,减压旋干,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=14/1,V/V)得到558.6mg黄色固体化合物2b,产率90%。1H NMR(400MHz,CDCl3)δ7.11(s,1H),7.06(s,1H),5.20-5.17(m,1H),5.04-5.00(m,1H),4.05(Bs,2H),3.73(s,3H),3.28(d,J=8.0Hz,2H),3.07-3.05(m,1H),2.91-3.87(m,2H),1.80(s,3H),1.71(s,3H),1.66(s,6H),1.41(s,3H),1.39(s,3H),1.38(s,3H),1.36(s,3H),1.35(s,3H),1.33(s,3H).13C NMR(100MHz,CDCl3)δ176.08,175.03,174.33,174.26,154.60,153.28,153.24,148.92,148.69,146.75,138.93,132.37,131.40,123.73,118.84,113.61,110.20,108.60,61.78,61.73,34.31,34.24,34.20,26.13,25.70,25.50,23.18,18.86,18.82,18.15,18.01.
3)1,3,6-三苄基α-倒捻子素衍生物(2c)的合成
将α-倒捻子素(1,1mmoL,410mg)和60%NaH(6mmoL,240mg)溶解于无水15mL DMF中,氮气保护下加入溴苄(6mmoL,942mg),加热至50℃,反应过夜。反应结束后,加入100mL乙酸乙酯稀释,后用50mL水加入分层,有机层用100mL水和50mL饱和食盐水先后洗涤,有机层经无水硫酸钠干燥,减压旋干,粗品过200~300目硅胶柱层析得到531.0mg黄色固体化合物2c,产率78%。1H NMR(400MHz,CDCl3)δ7.65-7.56(m,2H),7.51-7.29(m,13H),6.77(s,1H),6.63(s,1H),5.38-5.30(m,1H),5.21(s,2H),5.17-5.09(m,3H),5.01(s,2H),4.19(d,J=6.6Hz,2H),3.37(d,J=6.8Hz,2H),1.86(d,J=1.6Hz,3H),1.67-1.59(m,6H),1.54(d,J=1.6Hz,3H).13C NMR(100MHz,CDCl3)δ176.38,161.29,157.30,156.58,156.07,154.20,144.32,137.78,137.62,136.23,136.11,131.53,131.42,129.00,128.87,128.75,128.43,128.38,128.27,128.00,127.49,127.39,124.00,122.99,121.21,115.10,111.33,99.23,95.62,70.69,70.48,61.07,26.17,26.00,25.85,22.94,18.38,18.00.
4)3,6-二乙酰化α-倒捻子素衍生物(3a)的合成
将α-倒捻子素(1,1mmoL,410mg)溶解于无水20mL二氯甲烷中,氮气保护下加入乙酸酐(6mmoL,612mg),然后滴加10滴吡啶,常温反应2小时。反应结束后,加入100mL乙酸乙酯稀释,后用50mL水加入分层,有机层用100mL水和50mL饱和食盐水先后洗涤,有机层经无水硫酸钠干燥,减压旋干,粗品过200~300目硅胶柱层析得到272.0mg黄色固体化合物2a,产率55%。1H NMR(400MHz,CDCl3)δ14.04(d,J=1.6Hz,1H),7.75(d,J=2.0Hz,1H),7.26(s,1H),5.84–5.76(m,2H),4.76(d,J=6.4Hz,2H),4.40(d,J=1.6Hz,3H),3.94(d,J=7.2Hz,2H),2.98(dd,J=20.8,1.8Hz,6H),2.43(d,J=22.4Hz,6H).13C NMR(100MHz,CDCl3)δ183.00,168.51,168.06,161.14,155.01,154.18,153.82,149.55,146.88,139.25,132.42,132.35,122.77,121.46,116.97,116.34,110.72,107.23,100.45,61.78,26.59,25.93,25.82,22.43,21.07,20.99,18.31,17.94.
5)3,6-二异丁酰化α-倒捻子素衍生物(3b)的合成
将α-倒捻子素(1,1mmoL,410mg)和4-二甲胺基吡啶(DMAP)(1.8mmoL,219.6mg)溶解于20mL无水四氢呋喃和1mL三乙胺中,氮气保护下加入异丁酰氯(4mmoL,426.4mg),加热至50℃,反应过夜。反应结束后,加入100mL乙酸乙酯稀释,后用50mL水加入分层,有机层用100mL水和50mL饱和食盐水先后洗涤,有机层经无水硫酸钠干燥,减压旋干,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=14/1,V/V)得到523.6mg黄色固体化合物3b,产率95%。1H NMR(400MHz,CDCl3)δ13.44(d,J=4.0Hz,1H),7.10(s,1H),6.61(s,1H),5.20(d,J=8.0Hz,2H),5.14(d,J=8.0Hz,2H),4.13(d,J=4.0Hz,2H),4.13(d,J=4.0Hz,2H),3.76(s,3H),3.31(d,J=4.0Hz,2H),2.98-2.84(m,2H),1.84(s,3H),1.77(s,3H),1.69(s,6H),1.39(s,3H),1.37(s,3H),1.36(s,3H),1.34(s,3H).13C NMR(100MHz,CDCl3)δ182.85,174.59,174.16,160.96,155.07,154.09,153.68,149.67,146.81,139.06,132.37,132.24,122.66,121.44,116.75,116.31,110.58,107.01,100.21,100.11,61.85,61.75,34.32,34.23,26.44,25.83,25.80,25.70,25.68,22.16,18.87,18.84,18.22,18.18,17.89,17.86.
6)3,6-二烯丙基α-倒捻子素衍生物(4)的合成
将α-倒捻子素(1,1mmoL,410mg)和无水碳酸钾(4.0mmoL,552mg)溶解于20mL无水丙酮中,氮气保护下加入溴代烯丙基(3.0mmoL,306.0mg),常温反应过夜。反应结束后,过滤,蒸干,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=8/1,V/V)得到407.2mg黄色固体化合物4,产率83%.1H NMR(400MHz,CDCl3)δ13.48(s,1H),6.65(s,1H),6.22(s,1H),6.16-5.99(m,2H),5.54-5.09(m,6H),4.65(d,J=4.0Hz,2H),4.59(d,d,J=4.0Hz,2H),4.12(d,J=8.0Hz,2H),3.81(s,3H),3.36(d,J=8.0Hz,2H),1.85(s,3H),1.80(s,3H),1.68(s,6H).13C NMR(100MHz,CDCl3)δ182.02,162.27,159.94,156.93,155.18,155.05,144.17,137.31,132.62,132.08,131.75,123.51,122.57,122.38,118.52,117.83,112.14,111.71,104.02,99.34,89.74,69.50,69.11,60.98,60.81,26.18,25.92,21.57,18.24,17.95.
7)6-烯丙基α-倒捻子素衍生物(5)的合成
将α-倒捻子素(1,1mmoL,410mg)和无水碳酸钾(2.0mmoL,276mg)溶解于20mL无水丙酮中,氮气保护下加入溴代烯丙基(1.5mmoL,153.0mg),常温反应过夜。反应结束后,过滤,蒸干,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=6/1,V/V)得到193.7mg黄色固体化合物5,产率43%.1H NMR(400MHz,CDCl3)δ13.82(s,1H),6.68(s,1H),6.37(s,1H),6.27(s,1H),6.25(s,1H),6.14-6.04(m,1H),5.52(d,J=16.0Hz,1H),5.38-5.23(m,3H),4.65(d,J=8.0Hz,2H),4.13(d,J=8.0Hz,2H),3.82(s,3H),3.43(d,J=8.0Hz,2H),1.85(s,3H),1.83(s,3H),1.76(s,3H),1.68(s,3H).13C NMR(100MHz,CDCl3)δ182.15,161.58,160.71,157.05,155.33,155.07,144.15,137.46,135.46,132.14,123.45,121.80,118.48,112.04,108.75,103.82,99.47,93.34,69.57,61.07,26.33,25.99,25.91,21.56,18.35,18.25,17.97.
8)1-乙酰基-3,6-二烯丙基α-倒捻子素衍生物(6a)的合成
将3,6-烯丙基-α-倒捻子素衍生物(4,1mmoL,490.6mg)溶解于15mL无水吡啶中,在氮气保护下先后加入乙酰酐(1.5mmoL,153.0mg)和DMAP(0.2mmoL,24.5mg),加热至50℃,反应2小时。反应结束后,60℃下减压蒸馏去吡啶,加入30mL乙酸乙酯稀释,用30mL水和30mL饱和食盐水洗涤,然后无水硫酸钠干燥,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=10/1,V/V)得到511.3mg淡黄色固体化合物6a,产率96%。
1H NMR(400MHz,CDCl3)δ6.68(s,1H),6.64(s,1H),6.14-6.07(m,1H),5.47(t,J=12.0Hz,2H),5.37(t,J=12.0Hz,2H),5.24(t,J=8.0,1H),5.13(t,J=8.0,1H),5.65-4.61(m,4H),4.03(s,2H),3.82(s,3H),3.33(s,2H),2.47(s,3H),1.84(s,3H),1.84(s,3H),1.78-1.73(s,3H),1.68(s,6H).13C NMR(100MHz,CDCl3)δ175.73,169.68,160.58,156.04,155.78,154.30,148.19,144.16,137.52,132.14,131.88,131.14,123.64,123.56,120.29,118.29,118.15,118.08,114.25,109.47,98.97,96.95,69.36,26.04,25.85,25.71,22.72,21.36,18.18,17.89.
9)1-异丁酰基-3,6-二烯丙基α-倒捻子素衍生物(6b)的合成
将3,6-烯丙基-α-倒捻子素衍生物(4,1mmoL,490.6mg)溶解于15mL无水吡啶中,在氮气保护下先后加入异丁酰氯(1.5mmoL,151.1mg)和DMAP(0.2mmoL,24.5mg),加热至60℃,反应2小时。反应结束后,60℃下减压蒸馏去吡啶,加入50mL乙酸乙酯稀释,用50mL水和50mL饱和食盐水洗涤,然后无水硫酸钠干燥,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=10/1,V/V)得到493.4mg淡黄色固体化合物6b,产率88%.
1H NMR(400MHz,CDCl3)δ6.68(s,1H),6.63(s,1H),6.10-6.02(m,2H),5.50(t,J=16.0Hz,2H),5.37(t,J=16.0Hz,2H),5.26(t,J=4.0Hz,1H),5.11(t,J=4.0Hz,1H),4.66-4.61(m,4H),4.13(d,J=44.0Hz,2H),3.80(d,J=4.0Hz,3H),3.38(d,J=44.0Hz,2H),3.08(m,1H),1.82(s,3H),1.74(s,3H),1.65(s,6H),1.43(s,3H),1.41(s 3H).13C NMR(100MHz,CDCl3)δ175.70,175.40,160.52,155.96,155.72,154.25,148.38,144.05,137.45,132.19,132.15,131.88,130.90,123.79,123.69,121.76,121.63,118.23,118.16,118.13,118.05,114.27,109.68,98.95,98.87,96.81,96.72,69.40,69.34,69.31,60.82,60.73,34.29,34.26,25.97,25.80,25.77,25.70,25.68,19.16,18.47,18.16,17.99,17.96.
10)3-乙酰基-6-烯丙基α-倒捻子素衍生物(7a)的合成
将6-烯丙基-α-倒捻子素衍生物(5,1mmoL,450.5mg)和三乙胺(4.0mmoL,404mg)溶解于20mL无水四氢呋喃中,在氮气保护下先后加入乙酰氯(1.5mmoL,117.8mg)和DMAP(0.2mmoL,24.5mg),常温反应过夜。反应结束后,加入50mL乙酸乙酯稀释,用50mL水和50mL饱和食盐水洗涤,然后无水硫酸钠干燥,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=10/1,V/V)得到479.0mg淡黄色固体化合物7a,产率92%.1HNMR(400MHz,CDCl3)δ13.68(s,1H),6.72(s,1H),6.58(s,1H),6.13-6.05(m,1H),5.52(d,J=12.0Hz,1H),5.38(d,J=12.0Hz,1H),5.22(t,J=8.0Hz,1H),5.13(t,J=8.0Hz,1H),4.68(d,J=4.0Hz,2H),4.16-4.09(m,2H),3.82(s,3H),3.30(d,J=8.0Hz,2H),2.87-2.82(m,1H),1.85(s,3H),1.77(s,3H),1.68(s,6H),1.36(s,3H),1.34(s,3H).13CNMR(100MHz,CDCl3)δ182.57,174.68,160.93,155.46,154.49,153.58,144.27,137.51,132.25,131.93,131.81,122.99,122.89,121.59,121.46,118.57,118.51,116.01,112.00,106.94,99.92,99.82,99.31,99.24,69.52,60.91,60.82,34.32,26.22,25.90,25.88,25.70,22.14,18.19,18.15,17.86.
11)3-异丁酰基-6-烯丙基α-倒捻子素衍生物(7b)的合成
将6-烯丙基-α-倒捻子素衍生物(5,1mmoL,450.5mg)和三乙胺(4.0mmoL,404mg)溶解于20mL无水四氢呋喃中,在氮气保护下先后加入异丁酰氯(1.5mmoL,151.1mg)和DMAP(0.2mmoL,24.5mg),常温反应过夜。反应结束后,加入50mL乙酸乙酯稀释,用50mL水和50mL饱和食盐水洗涤,然后无水硫酸钠干燥,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=10/1,V/V)得到446.6mg淡黄色固体化合物7b,产率85%.TOF-MS,m/z:[M+H+],calcd forC31H37O7 +,521.2534,found:521.2540.
12)1-乙酰基-α-倒捻子素衍生物(8a)的合成
将536mg(1mmoL)1,3,6-三乙酰化α-倒捻子素衍生物的(2a)溶解于THF中,0℃下加入228mg NaBH4(6mmoL),搅拌反应过夜,反应结束后,加入60mL乙酸乙酯稀释,加入50mL水分层,有机层先后用50mL水与100mL饱和食盐水洗涤洗,无水硫酸钠干燥,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=8/1,V/V)得到235.3mg,产率52%。1H NMR(400MHz,CDCl3)δ7.19(s,1H),6.53(d,J=2.2Hz,2H),6.44(d,J=1.2Hz,1H),5.28-5.09(m,2H),4.04(s,2H),3.76(d,J=1.4Hz,3H),3.27(d,J=7.2Hz,2H),2.50(s,3H),1.80(s,3H),1.75(d,J=1.6Hz,3H),1.67(dd,J=10.2,1.7Hz,6H).13C NMR(100MHz,CDCl3)δ176.22,171.11,159.84,159.81,155.64,154.89,153.99,153.97,148.14,142.80,137.23,131.59,123.65,121.24,118.63,114.24,109.15,101.48,100.71,61.90,61.87,26.43,25.86,25.82,22.89,21.57,18.32,17.97.
13)1-异丁酰基-α-倒捻子素衍生物(8b)的合成
将620mg(1mmoL)1,3,6-三乙酰化α-倒捻子素衍生物的(2b)溶解于THF中,0℃下加入228mg NaBH4(6mmoL),搅拌反应过夜,反应结束后,加入60mL乙酸乙酯稀释,加入50mL水分层,有机层先后用50mL水与100mL饱和食盐水洗涤洗,无水硫酸钠干燥,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=8/1,V/V)得到225.7mg,产率47%。TOF-MS,m/z:[M+Na+],calcd for C28H32NaO7 +,503.2040,found:503.2035.
14)3-乙酰基-α-倒捻子素衍生物(9a)的合成
将3-乙酰基-6-烯丙基-α-倒捻子素衍生物(7b,1mmoL,492.6mg)和碳酸钾(5.0mmoL,690mg)溶解于20mL无水二氯甲烷中,在氮气保护下先后加入Pd(PPh3)4(0.5mmoL,577.8mg),常温反应8h。反应结束后,加入50mL乙酸乙酯稀释,用50mL水和50mL饱和食盐水洗涤,然后无水硫酸钠干燥,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=4/1,V/V)得到294.1mg淡黄色固体化合物9a,产率65.0%。
1H NMR(400MHz,CDCl3)δ13.62(s,1H),6.78(s,1H),6.59(s,1H),5.26-5.14(m,2H),4.11-4.01(m,2H),3.77(s,3H),3.34-3.27(m,2H),2.34(s,3H),1.81(d,J=18.6Hz,7H),1.69(s,7H).13C NMR(100MHz,CDCl3)δ182.62,168.93,161.14,156.05,155.30,154.47,153.76,143.01,137.40,132.36,132.22,123.09,121.66,116.07,112.27,107.07,101.80,100.30,62.09,26.73,25.93,25.85,22.44,21.12,18.36,17.97.
15)3-异丁酰基α-倒捻子素衍生物(9b)的合成
将3-异丁酰基-6-烯丙基-α-倒捻子素衍生物(7b,1mmoL,520.6mg)和碳酸钾(5.0mmoL,690mg)溶解于20mL无水二氯甲烷中,在氮气保护下先后加入Pd(PPh3)4(0.5mmoL,577.8mg),常温反应10h。反应结束后,加入50mL乙酸乙酯稀释,用50mL水和50mL饱和食盐水洗涤,然后无水硫酸钠干燥,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=3/1,V/V)得到240.0mg淡黄色固体化合物9b,产率50.0%.1H NMR(400MHz,CDCl3)δ13.62(s,1H),6.73(s,1H),6.61(s,1H),6.55(s,1H),5.22(t,J=4.0Hz,1H),5.15(d,J=4.0Hz,1H),4.03(d,J=4.0Hz,1H),3.75(s,3H),3.30(d,J=4.0Hz,2H),2.88-2.85(m,1H),1.83(s,3H),1.77(s,3H),1.68(s,6H),1.36(s,3H),1.35(s,3H).13C NMR(100MHz,CDCl3)δ182.42,175.11,160.95,155.80,155.74,155.14,154.49,153.58,142.82,137.20,132.24,132.18,122.99,122.91,121.51,116.05,112.01,106.79,101.67,101.62,99.96,61.90,61.83,34.33,26.54,25.81,25.71,22.13,18.89,18.21,17.88.
实施例2、本实施例具体涉及亚甲基化和甘露糖化α-倒捻子素衍生物的合成
本实施例涉及亚甲基化和甘露糖化α-倒捻子素衍生物的合成,合成路线如图5所示。
1)亚甲基α-倒捻子素衍生物(A,10)合成
将α-倒捻子素衍生物(1,1mmoL,410mg)溶于30mL无水四氢呋喃溶液中,氮气保护下加入氢化铝锂(5.0mmoL,190.0mg),70℃反应3小时。反应结束后,过滤,加入20mL饱和氯化铵溶液和50mL乙酸乙酯,有机层水洗和饱和食盐水洗涤,无水硫酸钠干燥,旋转蒸干,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=8/1,V/V)得到400.1mg黄色固体化合物10,产率62%。
1H NMR(400MHz,CDCl3)δ6.50(s,1H),6.09(s,1H),5.30-5.22(m,1H),5.07(d,J=6.8Hz,1H),3.75(d,J=1.6Hz,3H),3.67(s,2H),3.38(d,J=6.8Hz,4H),1.90-1.66(m,12H).13C NMR(100MHz,CDCl3)δ153.43,152.92,150.33,148.25,148.00,141.12,136.06,133.41,132.92,121.86,110.64,107.24,101.65,101.56,100.42,95.65,61.93,29.85,29.48,26.00,25.82,22.52,20.04,18.22.
图6为三氯乙酰亚胺活化甘露糖衍生物供体F1-F4合成示意图;F2、F3、F4的合成例如下:
2)五乙酰甘露糖(F2)合成
在室温下,将D-甘露糖(5g,27.8mmoL)溶于10mL吡啶溶液,在0℃下,滴加6mLAc2O,相同稳定下搅拌30min后,升至室温继续搅拌5h,TLC监测反应完全后,加入50mL乙酸乙酯稀释,用60mL水洗涤有机层三次,稀盐酸洗涤2次,再依次用饱和NaHCO3小心洗涤和饱和食盐水洗涤,然后,用无水Na2SO4干燥,直接浓缩即得10.8g白色固体化合物F2,产率97%。1HNMR(400MHz,CDCl3)δ6.08(d,J=3.6Hz,1H),5.35(d,J=4.0Hz,1H),5.34(s,1H),4.30-4.25(m,1H),4.12-4.03(m,2H),2.17(s,3H),2.16(s,3H),2.08(s,3H),2.05(s,3H),2.0(s,3H).13C NMR(100MHz,CDCl3)δ170.75,170.10,169.85,168.17,90.75,70.75,68.87,68.48,65.59,62.24,20.98,20.89,20.83,20.78,20.76.
3)四乙酰甘露糖(F3)合成
在室温下,将化合物F2(5g,12.8mmoL)溶于20mL N,N-二甲基甲酰胺溶液中,搅拌后加入1.2g醋酸肼(13.5mmoL),继续搅拌2h,TLC监测反应完全后,加入50mL乙酸乙酯稀释,依次用饱和50mL饱和NaHCO3小心洗涤、100mL水和50mL饱和食盐水洗涤,然后,用无水Na2SO4干燥,浓缩干燥,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=4/1,V/V)得到3.97g化合物F3,产率89%。1H NMR(400MHz,CDCl3)δ5.44-5.39(m,1H),5.30-5.19(m,1H),4.27-4.10(m,3H),2.15(s,3H),2.08(s,3H),2.03(s,3H),1.98(s,3H).
4)三氯乙酰亚胺活化四乙酰甘露糖供体(F4)合成
将化合物F3(3.48g,10.0mmoL)溶于20mL无水二氯甲烷,在0℃下,滴加1.58g三氯乙腈(11.0mmoL)和催化量DBU(按质量比10%)滴入反应液中,相同温度搅拌2小时后,低温旋干直接上柱,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=3/1,V/V)得到4.33g油状物F4,产率88%。1H NMR(400MHz,CDCl3)δ8.17(s,1H),6.26(s,1H),5.44-5.36(m,2H),4.25-4.06(m,4H),2.17(s,3H),2.05(s,3H),2.04(s,3H),1.98(s,3H).
5)3,6-二己醇α-倒捻子素衍生物(11)合成
将α-倒捻子素(1,1mmoL,410mg)和无水碳酸钾(5.0mmoL,690mg)溶解于20mL无水丙酮中,氮气保护下加入6溴1-已醇(4.0mmoL,724.0mg),70℃反应6h。反应结束后,过滤,蒸干,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=8/1,V/V)得到531.4mg黄色固体化合物11,产率87%。1H NMR(400MHz,CDCl3)δ13.49(s,1H),6.66(s,1H),6.24(s,1H),5.29-5.19(m,2H),4.11(d,J=6.8Hz,2H),4.03(dt,J=18.0,6.4Hz,4H),3.78(s,3H),3.66(t,J=6.4Hz,4H),3.33(d,J=7.2Hz,2H),1.96-1.44(m,28H).13C NMR(100MHz,CDCl3)δ182.06,162.89,159.86,157.51,155.37,155.21,144.07,137.18,131.76,131.41,123.53,123.35,122.74,122.55,111.95,111.51,103.91,98.86,98.73,89.42,89.23,68.79,68.39,63.11,63.04,62.94,62.87,62.78,62.71,61.01,60.84,32.76,32.67,29.20,29.00,26.28,26.04,25.98,25.94,25.65,25.58,21.56,18.33,18.26,17.97,17.90.
6)6-已醇α-倒捻子素衍生物(12)合成
将α-倒捻子素(1,1mmoL,410mg)和无水碳酸钾(5.0mmoL,690mg)溶解于20mL无水丙酮中,氮气保护下加入6溴1-已醇(3.0mmoL,543.0mg),60℃反应3h。反应结束后,过滤,蒸干,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=8/1,V/V)得到383.2mg黄色固体化合物12,产率75%。1H NMR(400MHz,CDCl3)δ13.82(s,1H),6.67(s,1H),6.23(s,1H),5.33-5.19(m,2H),4.14-4.00(m,4H),3.79(s,3H),3.69(t,J=6.4Hz,2H),3.42(dd,J=7.0,4.0Hz,2H),1.87(d,J=28.8Hz,8H),1.77-1.47(m,12H).13C NMR(100MHz,CDCl3)δ182.16,161.62,160.72,157.62,155.47,155.05,144.00,137.24,135.22,131.90,123.37,123.33,121.76,111.76,108.86,103.77,98.90,98.85,93.16,93.11,68.82,62.97,61.00,60.95,32.61,28.96,26.31,26.05,26.01,25.99,25.54,21.57,18.31,18.05,18.03.
7)3,6-二全乙酰甘露糖基-α-倒捻子素衍生物(13a)合成
分别称取糖供体F4(118.4mg,0.24mmoL)和α-倒捻子素(41.0mg,0.1mmoL)溶于20mL无水二氯甲烷中,并加入粉末4A分子筛,移至0℃搅拌,滴加42.6mg三氟化硼乙醚(0.3mmoL),0℃下继续反应,TLC反应检测完全后,过滤分子筛,用饱和NaHCO3溶液中和,分层后,有机层用水和饱和食盐水洗涤,无水Na2SO4干燥,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=4/1,V/V)得到338.9mg黄色固体化合物13a,产率32%。TOF-MS,m/z:[M+Na+],calcd.for C50H58NO24Na+,1065.3210,found:1065.3218.
8)3,6-二全乙酰葡萄糖基-α-倒捻子素衍生物(13b)合成
合成过程与操作步骤如7)所示,四乙酰葡萄糖供体代替F4,得到396.0mg黄色固体化合物13b,产率38%。TOF-MS,m/z:[M+Na+],calcd.for C50H58NO24Na+,1065.3210,found:1065.3231.
9)3,6-二全乙酰-葡萄糖胺-α-倒捻子素衍生物(13c)合成
合成过程与操作步骤如7)所示,3,4,6-三乙酰-2-N,N-二甲基葡萄糖胺供体代替F4,得到273.5mg黄色固体化合物13c,产率27%。TOF-MS,m/z:[M+Na+],calcd.forC50H64O20N2Na+,1035.3945,found:1035.3963.
10)3,6-甘露糖基-α-倒捻子素衍生物(15a)合成
称取104.2mg 3,6-二全乙酰甘露糖基α-倒捻子素衍生物(13a,0.1mmoL)溶液5mL无水甲醇中,加入催化量的甲醇钠(0.5%m/m),室温反应30min,TLC检测完全后,用酸性树脂Amberlyst 35中和过滤,蒸干,得53.0mg淡黄色固体15a产率75%。TOF-MS,m/z:[M+Na+],calcd.for C34H42O16Na+,729.2365,found:729.2378.
11)3,6-葡萄糖基-α-倒捻子素衍生物(15b)合成
合成过程与操作步骤如10)所示,衍生物13b替代13a,得到60.7mg黄色固体化合物15b,产率86%。TOF-MS,m/z:[M+Na+],calcd.for C34H42O16Na+,729.2365,found:729.2372.
12)3,6-二(2’-N,N-二甲基葡萄糖胺)-α-倒捻子素衍生物(15c)合成
合成过程与操作步骤如10)所示,衍生物13c替代13c,得到547.8mg黄色固体化合物14c,产率72%。TOF-MS,m/z:[M+Na+],calcd.for C38H52N2O14Na+,783.3311,found:788.3335.
13)3-全乙酰甘露糖基-6-烯丙基-α-倒捻子素衍生物(14a)合成
分别称取糖供体F4(59.2mg,0.12mmoL)和化合物5(45.1mg,0.1mmoL)溶于20mL无水二氯甲烷中,并加入粉末4A分子筛,移至0℃搅拌,滴加14.2mg三氟化硼乙醚(0.1mmoL),0℃下继续反应,TLC反应检测完全后,过滤分子筛,用饱和NaHCO3溶液中和,分层后,有机层用水和饱和食盐水洗涤,无水Na2SO4干燥,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=3/1,V/V)得到351.1mg黄色固体化合物14a,产率45%。
1H NMR(400MHz,CDCl3)δ13.59(s,1H),6.67(s,1H),6.62(s,1H),6.13-5.99(m,1H),5.65(d,J=4.0Hz,2H),5.57-5.48(m,2H),5.42-5.33(m,2H),4.69(d,J=4.0Hz,2H),4.15-4.08(m,4H),3.87(s,2H),3.81(s,3H),3.44-3.37(m,3H),2.23(s,3H),2.07(s,3H),2.04(s,6H),1.85(s,3H),1.79(s,3H),1.69(s,3H),1.67(s,3H).TOF-MS,m/z:[M+Na+],calcd.for C40H46O15Na+,789.2729,found:789.2732.
13)3-全乙酰葡萄糖基-6-烯丙基-α-倒捻子素衍生物(14b)合成
如同制备14a样,用四乙酰葡萄供体替代F4,得到414.0mg黄色固体化合物14b,产率54%。TOF-MS,m/z:[M+Na+],calcd.for C40H46O15Na+,789.2729,found:789.2753.
14)3-(3’,4’,6’-三乙酰基-2’-N,N-二甲基葡萄糖胺)-6-烯丙基-α-倒捻子素衍生物(14c)合成
如同制备14a样,用3’,4’,6’-三乙酰基-2’-N,N-二甲基葡萄糖胺供体替代F4,得到308.2mg黄色固体化合物14a,产率41%。TOF-MS,m/z:[M+Na+],calcd.for C40H49O13NNa+,774.3096,found:774.3082.
15)3-全乙酰甘露糖基α-倒捻子素衍生物(16a)合成
将3-全乙酰甘露糖基-6-烯丙基-α-倒捻子素衍生物(14a,0.1mmoL,78.1mg)和碳酸钾(0.5mmoL,79mg)溶解于10mL无水二氯甲烷中,在氮气保护下先后加入Pd(PPh3)4(0.05mmoL,57.7mg),常温反应6h。反应结束后,加入20mL乙酸乙酯稀释,用20mL水和20mL饱和食盐水洗涤,然后无水硫酸钠干燥,粗品过200~300目硅胶柱层析(石油醚/乙酸乙酯=2/1,V/V)得到55.6mg淡黄色固体化合物16a,产率75.0%.
1H NMR(400MHz,CDCl3)δ13.61(s,1H),7.09(s,1H),6.20(s,1H),6.13-5.99(m,1H),5.64(d,J=4.0Hz,1H),5.60(dd,J=4.0,8.0Hz,1H),5.53-5.51(m,1H),5.42-5.37(m,1H),5.23(d,J=4.0Hz,1H),4.33-4.31(m,1H),4.15-4.07(m,4H),3.87(s,3H),2.72(t,J=4.0Hz,2H),2.21(s,3H),2.07(s,3H),2.05(s,3H),2.04(s,3H),1.85(s,3H),1.69(s,3H),1.35(s,6H).13C NMR(100MHz,CDCl3)δ182.18,170.43,169.88,169.65,169.54,160.41,158.66,155.27,154.62,144.34,137.51,132.39,131.87,123.03,122.13,118.51,112.62,105.61,99.24,95.35,91.86,69.51,69.14,68.79,65.78,62.03,60.84,26.19,25.85,25.60,21.60,20.79,20.58,18.14,17.96.
16)3-全乙酰葡萄糖基α-倒捻子素衍生物(16b)合成
如同制备16a样,用衍生物14b替代衍生物14a,得到63.0mg黄色固体化合物16b,产率85%。TOF-MS,m/z:[M+Na+],calcd.for C37H42O15NNa+,749.2416,found:749.2437.
17)3-(3’,4’,6’-三乙酰基-2’-N,N-二甲基葡萄糖胺)-α-倒捻子素衍生物(16c)合成
如同制备16a样,用衍生物14c替代衍生物14a,得到46.3mg黄色固体化合物16c,产率65%。TOF-MS,m/z:[M+Na+],calcd.for C37H45O13NNa+,734.2783,found:734.2796.
18)3-甘露糖基-α-倒捻子素衍生物(17a)合成
称取74.1mg 3-全乙酰甘露糖基α-倒捻子素衍生物(16a,0.1mmoL)溶液5mL无水甲醇中,加入催化量的甲醇钠(0.5%m/m),室温反应30min,TLC检测完全后,用酸性树脂Amberlyst 35中和过滤,蒸干,得45.8mg淡黄色固体17a产率80%。1H NMR(400MHz,CD3OD)δ7.13(s,1H),6.19(s,1H),5.65(d,J=4.0Hz,1H),5.20(d,J=8.0Hz,2H),4.13(m,1H),4.04(d,J=8.0Hz,2H),4.0(d,J=4.0Hz,1H),3.98(d,J=8.0Hz,1H),3.86-3.80(m,2H),3.87(s,3H),3.75-3.72(m,1H),3.63-3.50(m,2H),3.24(d,J=8.0Hz,2H),1.82(s,3H),1.77(s,3H),1.67(s,3H),1.65(s,3H).13C NMR(100MHz,CDCl3)δ182.98,163.76,161.45,156.04,155.69,155.27,145.50,138.44,131.90,131.73,124.74,123.65,113.87,111.58,103.82,103.38,103.32,100.32,76.09,72.38,71.67,65.57,61.76,61.58,25.97,22.23,18.39,17.916TOF-MS,m/z:[M+Na+],calcd.for C29H34O11Na+,581.1993,found:581.1980.
19)3-葡萄糖-α-倒捻子素衍生物(17b)合成
如同制备17a样,用衍生物16b替代衍生物16a,得到46.3mg黄色固体化合物17b,产率83%。TOF-MS,m/z:[M+Na+],calcd.for C29H34O11Na+,581.1993,found:581.2004.
20)3-(2-N,N-二甲基葡萄糖胺)-α-倒捻子素衍生物(17c)合成
如同制备17a样,用衍生物16b替代衍生物16c,得到43.3mg黄色固体化合物17c,产率74%。TOF-MS,m/z:[M+Na+],calcd.for C31H39O10NNa+,608.2466,found:608.2478.
实施例3、α-倒捻子素及其衍生物最小抑菌浓度试验
1)实验原理
本实验基于细菌在96孔板MH(Mueller-Hinton Broth)培养基中生长,过段时间由于量大会产生白色沉淀,很容易区别有无细菌生长,将抑菌剂倍比稀释,加入菌悬液培养一段时间后,无沉淀的最后一个孔即为最小抑菌浓度(Minimal Inhibitory Concentration,MIC)。
2)实验方法
按照NCCLS实验操作要求,使用菌株包括E.coli ATCC25922、S.aureus ATCC29213和临床分离多重耐药株MRSA 2(ATCC33591),将菌株复苏后培养至对数生长期备用。将α-MG及其衍生物用二甲基亚砜溶解至2mg/mL,取出96孔板,在第一列加入25.6μL,加入MH(B)培养基至200μL,2倍比稀释至第10列。第11列是培养基(阴性)对照,第12列是菌液(阳性)对照。青霉素和阿莫西林作为药物对照,37℃培养18-24h观察结果。药物对照的最小抑菌浓度应该在参考范围之内,认为同批次的实验结果可靠。
3)实验结果
通过微量稀释法检测了α-MG及其19个衍生物对大肠杆菌和金黄色葡萄球菌标准株和多重耐药株的抗菌活性,结果如表1所示。
4)实验结论
从表1的数据可以看出,先导化合物α-MG和衍生物9a、10、8a、2a、15对金黄色葡萄球菌的标准株和临床分离的多重耐药株均有一定的抑菌活性,其中α-MG和8a、9a的抑菌活性较强,且1位或3位酰基引入有利于活性保持,简单糖引入不同程度增强蒽醌类化合物抗菌活性。从构效关系角度分析可知,酮基还原活性降低,1位羟基修饰不影响药效,甘露糖(17a)与葡萄糖胺(17c)引入有利于活性增强以及水溶性增加。
表1α-MG及其衍生物对细菌的最小抑菌浓度
实施例4、体外联合抑菌实验--微量棋盘稀释法
1)实验原理
微量棋盘稀释法基于两种抗菌药物对细菌的作用部位不同,同时使用两种抗菌药物呈现的最小抑菌浓度(MIC),与单独使用一种抗菌药物相比,会出现抗菌活性增强或减弱的现象。从单独的MIC值和联合的MIC值可以计算出fractional inhibitoryconcentration(FIC),FIC=联合用药时甲药MIC/单独应用甲药时MIC+联合应用乙药时MIC/单独应用乙药时MIC。FIC≤0.5为具有协同作用,0.5<FIC≤1为具有相加作用,1<FIC≤2为具有无关作用,FIC﹥2为具有拮抗作用。
2)实验方法
采用棋盘法考察α-MG以及合成的衍生物与β-内酰胺类化合物的协同作用,具体方法为:菌液准备同最小抑菌浓度(MIC),常规药物选择β-内酰胺类抗生素、大环内酯类抗生素、氨基甙类抗生素、四环素类抗生素和多肽类抗生素等类型中的代表性药物,在96孔板中的第一列加入常规药物,2倍比稀释至第10列,横向加入不同浓度的α-MG或合成的衍生物,加入菌液后37℃培养18-24h观察结果,同时测定最小抑菌浓度。
3)实验结果
化合物α-MG和选取衍生物10、8a、9a与青霉素、阿莫西林呈现出协同作用,结果见表2至表5。
4)实验结论
从表2至表5可以看出,α-MG和选取衍生物10、8a、9a与青霉素或阿莫西林在抑制金黄色葡萄球菌的多重耐药菌MRSA 2中表现出协同或相加作用,说明这一类化合物能够恢复β-内酰胺类药物对多重耐药菌的抑制作用。
表2α-MG与β-内酰胺类药物对S.aureus MRSA 2的协同作用
a每孔的α-MG和青霉素/阿莫西林用量都不同;α-MG(0.25ug/ml)和青霉素(4ug/ml)/阿莫西林(2ug/ml)组合的孔中协同作用最明显。
表3α-MG衍生物10与β-内酰胺类药物对S.aureus MRSA 2的协同作用
表4α-MG衍生物8a与β-内酰胺类药物对S.aureus MRSA 2的协同作用
表5α-MG衍生物9a与β-内酰胺类药物对S.aureus MRSA 2的协同作用
实施例5、α-MG及其衍生物对细菌的杀菌曲线检测试验
1)实验原理
细菌生长曲线反映了单细胞微生物在一定环境条件下于液体培养时所表现出的群体生长规律。当细菌与抗菌药物一起孵育时,细菌的繁殖可能会受到影响,其生长和繁殖的速率与不加药物的状态相比会有所不同。因此通过检测微生物的生长曲线,能够了解抗菌药物对细菌生长状态的影响,直接反映出药物对细菌的抑制活性。
2)实验方法
将细菌培养至对数生长期,使得最终菌液浓度为106-107CFU/ml,将不同浓度的受试化合物加入到菌液中,37℃200rpm/min培养,分别于不同的时间点取样,10倍比稀释至适当浓度,取适量稀释液涂至培养板上,37℃静置培养18-24h,菌落计数,制作杀菌曲线。
3)实验结果
α-MG及其衍生物对金黄色葡萄球菌多重耐药菌株MRSA 2的杀菌曲线见图7。从结果可以看出,未经化合物处理的对照组(图7中0MIC对应的曲线),菌落数在60min内的趋势是持续增加的,但是经α-MG及其衍生物8a、9a处理时,菌落数都呈现出明显的减少,60min内已经将菌落数降低了99.99%。
4)实验结论:由α-MG及其衍生物对金黄色葡萄球菌多重耐药菌株MRSA 2的杀菌曲线实验结果可以得出结论,该类化合物对多重耐药菌MRSA 2具有明显抑制效果。
实施例6、透射电镜下观察α-MG及其衍生物对细菌形态的影响
1)实验原理
基于透射电子显微镜可以观察样品组织的形貌,通过超薄切片技术制作厚度在10~100nm的超薄切片,透射电子显微镜下观察经α-MG及其衍生物孵育后的细菌形态的变化。
2)实验方法
将复苏至对数生长期的金黄色葡萄球菌与不同浓度的α-MG及其衍生物孵育2h,离心将培养基弃去,PBS清洗2-3次,2.5%戊二醛固定,经过脱水,喷金,透射电镜下观察,并测量细胞壁的厚度。
3)实验结果
金黄色葡萄球菌经α-MG以及衍生物8a孵育后,细胞壁外出现很多圆形阴影(图8)。通过测量细胞壁的厚度发现(图9),经α-MG或8a处理后,细菌的细胞壁明显增厚。
4)实验结论
从实验结果可以看出,α-MG及其衍生物与细菌作用一定时间后,导致细菌的细胞壁明显增厚,细胞组分明显外溢。推测化合物的作用靶点在细胞壁,与细胞壁组分结合导致细胞壁松动,细胞疏水性组分外溢,导致观察到细胞壁外侧附近有圆形阴影出现。
实施例7、α-MG衍生物对细菌细胞膜电位的影响试验
1)实验原理
DiOC2(3)属膜电位慢反应探针,常常用于细菌的膜电位检测。DiOC2(3)在所有细胞中都呈绿色,当膜电位升高时,染料分子之间自聚合产生红色荧光;当膜电位降低时,则染料分子不能聚合,而是以单体形式存在于胞质中,只能发出绿色荧光。故用试剂产生的红色和绿色荧光比来判断细菌给药后膜电位变化,若荧光比下降则表示细胞膜去极化。
2)实验方法
菌液准备:取-80℃保存的菌株,复苏,随后传代孵育至对数生长期。
化合物与细菌孵育:将菌液4500rpm离心10min,弃去上清,沉淀稀释成1ml待用。再在此5ml体系中加入4ml 1XPBS以及化合物,设置去极化对照组、blank组和阴性对照DIO组,孵育。
测试前处理:将体系离心4500rpm,10min,沉淀用PBS洗(此过程重复两次),最后再用PBS稀释菌液至浓度为1×106-1×107CFU/ml,取1ml菌液转入流式管中。加入10μl CCCP(试剂盒中)至去极化样本中,混匀,避光作用15min。除blank组外,每组均加入DiOC2(3)10μl,混匀。避光室温孵育30min。
流式细胞仪检测:选择FITC和Texas-Red两个通道,blank样本画门,定位细胞群;再应用去极化组,调节电压使此样品的红色与绿色荧光接近相等,设置补偿应用之所有样本;再用此电压条件测试余下样品。
3)实验结果
按照实验方法检测了α-MG及其衍生物对细菌的细胞壁通透性的影响,结果如图10所示。
4)实验结论
从实验结果可以看出,金黄色葡萄球菌经过α-MG及其衍生物8a、衍生物9a孵育后,与对照组相比,细胞膜电位均产生了影响,使细菌细胞膜去极化,但三个化合物作用的效果稍有差异。α-MG和8a浓度越高,去极化效果反而下降,这可能与药物作用的浓度有关,结合透射电镜结果分析,低浓度化合物可能主要影响细菌的膜电位,而高浓度则直接影响通透性导致细胞组分外溢。
实施例8、α-MG衍生物在动物病理模型体内的治疗效果试验
1)实验原理
建立金黄葡萄球菌多重耐药株小鼠皮肤脓肿感染模型,观察脓肿形成动态变化及化合物对脓肿愈合的影响。
2)实验方法
6-8周龄、体重20-25g的BALB/c小鼠手术前24小时,将所有实验动物背部剔除毛发,并记录体重。次日用戊巴比妥(30mg/kg)麻醉BALB/c小鼠(每组6只),随后将前一晚复苏的1×108CFU/mL的金黄色葡萄球菌临床分离多重耐药株(ATCC33591)菌悬液分别皮下接种100μL于每只老鼠,其中接种生理盐水组作为阴性对照。在感染一小时后,模型组分别给药化合物8a(50mg/kg、75mg/kg、100mg/kg)以及恩诺沙星(15mg/kg),其中恩诺沙星组作为阳性对照。随后在感染后第一天和第三天分别测定小鼠体重以及脓肿伤口大小,并各取每组三只小鼠,进行眼球取血,随后取伤口脓肿组织,最后再进行解剖。随后将组织称重并在无菌生理盐水中匀浆,悬液均匀涂布于MHA平板上,在37℃培养箱中培育18-24小时后进行菌落计数。
3)实验结果
按照实验方法检测了α-MG及其衍生物8a对金黄葡萄球菌多重耐药株小鼠皮肤脓肿感染模型的治疗效果,结果如图11和图12所示。
4)实验结论
生理盐水处理的阴性对照组小鼠皮肤无脓肿形成,阳性组、模型组和给药组可见到典型的脓肿,临床症状的时相性过程明显,在给药第一天以及第三天,给药组皮肤脓肿体积相较模型组明显减少,背部皮肤细菌数量相较模型组明显减少。化合物8a给药组与先导化合物α-MG给药组相比,皮肤脓肿体积和背部皮肤细菌数量均明显减少。
以上对本发明的具体实施例进行了描述。需要理解的是,本发明并不局限于上述特定实施方式,本领域技术人员可以在权利要求的范围内做出各种变形或修改,这并不影响本发明的实质内容。
Claims (10)
2.根据权利要求1所述的氧杂蒽酮α-MG衍生物,其特征在于,所述简单糖选自甘露糖、半乳糖、葡萄糖、古洛糖、鼠李糖、岩藻糖、红霉胺糖、博来霉素二糖。
3.根据权利要求1所述的氧杂蒽酮α-MG衍生物,其特征在于,所述不同位置糖胺取代物包括简单糖的一个或多个位置氨基取代物。
5.一种根据权利要求1-4中任一项所述的氧杂蒽酮α-MG衍生物的合成方法,其特征在于,以α-MG为起始原料,经不同化学反应组合得结构式I所述氧杂蒽酮α-MG衍生物。
6.根据权利要求5所述的氧杂蒽酮α-MG衍生物的合成方法,其特征在于,所述方法包括如下步骤:
或,S2、在氮气保护下,在0-5℃下,将α-MG溶于无水溶剂中,加入2-10倍有机碱与催化量的N,N-二甲基吡啶DMAP,然后再加入2-8倍酸酐或酰氯,在20-35℃下搅拌数小时得3,6-二酰基倒捻子素类似物
S5、在氮气保护下,将化合物D或E溶于无水有机溶剂,加入适量有机碱,0-5℃反应10分钟后,相同温度下滴加1.0-3倍当量的酰氯,常温下反应数小时得3,6-二烯丙基-1-单酰化倒捻子素衍生物F与6-烯丙基-1,3-二酰化倒捻子素衍生物G
或,S7、在氮气保护下,将α-MG溶于丙酮中,加入5倍当量无机碱,在40-70℃下,通过严格控制不同长度卤代醇的反应量,反应数小时选择性地得到3,6-二取代醚倒捻子素衍生物J或6-取代醚倒捻子衍生物K
S8、在氮气保护下,在0-5℃下,将化合物J或K溶于无水溶剂中,加入4A分子筛粉末,滴加1.1-5倍当量的三氯乙酰亚胺活化的全酰化简单糖,同时加入催化量三氟化硼乙醚复合物,低温反应数小时得3,6-二全乙酰化糖倒捻子素衍生物L与6-全乙酰化糖倒捻子衍生物M
7.根据权利要求6所述的氧杂蒽酮α-MG衍生物的合成方法,其特征在于,步骤S1中,所述无水溶剂选自四氢呋喃、乙醚;步骤S2中,所述无水溶剂选自四氢呋喃、乙醚、二氯甲烷;步骤S3中,所述有机碱选自吡啶、三乙胺、钠氢、N,N-二异丙基乙胺;所述碱选自碳酸钾、三乙胺、吡啶。
8.根据权利要求6所述的氧杂蒽酮α-MG衍生物的合成方法,其特征在于,步骤S4中,所述卤代烯丙基量控制与α-MG比例1.5-2.0:1;步骤S7中,所述不同长度卤代醇反应量与α-MG比例1.5-2.0:1。
9.一种根据权利要求1-4中任一项所述的氧杂蒽酮α-MG衍生物的用途,其特征在于,所述氧杂蒽酮α-MG衍生物用于抗革兰氏阳性菌或作为临床耐药菌株的致敏剂。所述氧杂蒽酮α-MG衍生物对青霉素、阿莫西林等具有协同增效作用。
10.一种根据权利要求1-4中任一项所述的氧杂蒽酮α-MG衍生物的用途,其特征在于,所述氧杂蒽酮α-MG衍生物用于动物养殖业中减少抗生素甚至代替抗生素;或氧杂蒽酮α-MG衍生物作为用于揭示氧杂蒽醌类的化合物抗菌作用机制的分子探针。
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