CN105586373A - Sclerotiorin衍生物及其制备方法与作为海洋防污剂的应用 - Google Patents
Sclerotiorin衍生物及其制备方法与作为海洋防污剂的应用 Download PDFInfo
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Abstract
一种Sclerotiorin衍生物及其制备方法与作为海洋防污剂的应用,制备时先对真菌Penicillium?sp.(TA33-1)进行菌种培养,再对该真菌进行发酵培养,将所得菌丝体用氯仿-甲醇混合液(1∶1)浸提3次减压浓缩后,用乙酸乙酯萃取3次得粗浸膏;依次进行正相硅胶柱层析、Sephadex?LH-20凝胶柱层析、HPLC高效液相色谱,得黄色粉末,即为(+)-Sclerotiorin;在溶有(+)-Sclerotiorin的二氯甲烷溶液中,加入有机伯胺和碳酸钾,反应后得到式I化合物。本发明提供一种海洋生物防污剂,其特征在于以本发明的式I化合物或其药学上可接受的盐,用于防治海洋生物附着引起的海洋污损。
Description
技术领域
本发明涉及一种Sclerotiorin衍生物及其制备方法与应用,特别是涉及一种对海洋污损生物藤壶Balanusamphitrite幼虫具有极强的抑制活性的Sclerotiorin衍生物及其制备方法与应用。
背景技术
海洋生物污损是有机分子、微生物、动物、植物、以及它们的副产物在海洋潜没设施表面的危害性积聚。这种危害性积聚经常发生在没有保护的海洋潜没设施的表面,包括海运和旅游的船舶,海军军舰,热交换器,海洋传感器以及水产养殖基地等。生物污损引起了巨大的经济损失,仅以美国海军军舰为例,每年在这方面的经济损失在18到26亿美元之间,而美国海军军舰数量仅占全球船舶数量的0.5%,因此海洋生物污损是极其严重的自然危害。藤壶因其很强的黏附能力是目前所知的污损生物中非常普遍的代表性生物。自2008年全球取消了有毒防污剂有机锡的使用后,寻找安全高效的海洋防污剂成为国际上急需解决的课题。海洋天然产物被认为是新型海洋防污剂的重要来源。实际上,在过去的几十年里已经从海绵,珊瑚和海藻等海洋生物中发现了很多有强抗污损活性的化合物。然而,从上述大型生物中发现的活性化合物由于受到量的限制而大大影响了其潜在的应用。海洋微生物由于在实验室中可以大规模发酵,不易破坏自然环境,而成为活性海洋化合物的最重要来源。然而,近年来尚未见到从海洋微生物中获得有重要抗污损活性的Sclerotiorin衍生物作为防污剂的使用。(J.A.Callow,M.E.Callow,Nat.Commun.2011,2,244-253;C.M.Kirschner,A.B.Brennan,Annu.Rev.Mater.Res.2012,42,1-19;M.Schultz,J.Bendick,E.Holm,W.Hertel,Biofouling2011,27,87-98;N.Fusetani,Nat.Prod.Rep.2004,21,94-104;N.Fusetani,Nat.Prod.Rep.2011,28,400-410;P.-Y.Qian,Y.Xu,N.Fusetani,Biofouling2010,26,223-234。)
发明内容
本发明的目的在于提供一种来源于海洋真菌的Sclerotiorin衍生物的制备方法与作为海洋防污剂的应用,它能满足现有技术的上述需求。菌种保藏信息:保藏单位名称:中国微生物菌种保藏管理委员会普通微生物中心;保藏单位地址:北京市朝阳区北辰西路1号院3号中国科学院微生物研究所;保藏日期:2014年4月3日;保藏编号:CGMCCNo.8994;分类命名:Penicilliumsp.。
本发明提供式I化合物或其药学上可接受的盐:
或其药学上可接受的盐。式I中R为
本发明提供式I化合物的制备方法,其特征在于先在菌种培养基中对分离自柳珊瑚的内生真菌Penicilliumsp.(TA33-1)进行菌种培养,再在发酵培养基中对该真菌进行发酵培养,将所得菌丝体用氯仿-甲醇混合液(1∶1)浸提3次减压浓缩后,用乙酸乙酯萃取3次得粗浸膏;乙酸乙酯相粗浸膏分别进行正相硅胶柱层析、SephadexLH-20凝胶柱层析后,再经HPLC高效液相制备色谱,将所得洗脱液浓缩,得黄色粉末,即为(+)-Sclerotiorin;在溶有(+)-Sclerotiorin的二氯甲烷溶液中,加入有机伯胺和碳酸钾,反应后得到式I化合物。
上述制备方法中菌种培养基优选含有葡萄糖0.1%-5.0%(重量百分比,下同)、酵母膏0.01%-1%、蛋白胨0.01%-1%、琼脂0.1%-3.0%、氯化钠0.05%-5%,其余为水,培养温度优选为0-30℃,培养时间优选为3-15天;发酵培养基优选含有大米1.0%-80.0%(重量百分比,下同)、氯化钠0.05%-5%,其余为水,培养温度优选为0-30℃,培养时间优选为10-60天;所述的正相硅胶柱层析采用的固定相优选200-300目硅胶,流动相优选体积比为15%-60%的乙酸乙酯-石油醚混合溶剂;所述SephadexLH-20凝胶柱层析采用的流动相优选体积比为石油醚∶氯仿∶甲醇=2∶1∶1的混合溶剂;所述HPLC高效液相制备色谱中采用的色谱柱为本领域常规ODSC18柱,优选为Kromasil10×250mm,5μm,流速优选为1.0-5.0mL/min,流动相优选体积比为50%-80%的甲醇-水混合溶剂;所述的有机伯胺为
本发明的另一实施方案提供式I化合物的晶体,其Cu靶X-射线晶体衍射数据:空间群为P2(1)2(1)2(1),晶胞参数为 β=90(0)°,Z=4,Dc=1.233g/cm3,F(000)=920,μ=0.193mm-1。
本发明的另一实施方案提供上述式I化合物晶体的制备方法,其特征在于将式I化合物溶于甲醇、乙醇、水、四氢呋喃或丙酮中的任一种或几种,静置缓慢结晶即可得到式I化合物的晶体。
上述晶体的制备方法中静置缓慢结晶的条件优选在0-30℃下,静置1-30天。
本发明从海洋真菌中获得的Sclerotiorin衍生物对海洋污损生物藤壶Balanusamphitrite幼虫具有极强的抑制活性,可用于开发海洋防污剂,应用前景广阔。
本发明的另一实施方案提供式I化合物或其药学上可接受的盐在制备海洋防污剂中的应用。
本发明中术语“药学上可接受的盐”是指非毒性的无机或有机酸和/或碱的加成盐。可参见“Saltselectionforbasicdrugs”,Int.J.Pharm.(1986),33,201-217。
附图说明
说明书附图为式I化合物的XRD图。
具体实施方式
为了便于对本发明的进一步理解,下面提供的实施例对其做了更详细的说明。但是这些实施例仅供更好的理解发明而并非用来限定本发明的范围或实施原则,本发明的实施方式不限于以下内容。
实施例1
(1)柳珊瑚内生真菌Penicilliumsp.(TA33-1)的菌种培养
菌种培养所用的培养基含有葡萄糖1.0%(重量百分比,下同)、酵母膏0.2%、蛋白胨0.2%、琼脂1.0%、氯化钠3.0%,其余为水,使用时制成试管斜面,真菌菌株在30℃下培养3天。
(2)柳珊瑚内生真菌Penicilliumsp.(TA33-1)的发酵
发酵培养所用的培养基含有大米40.0%(重量百分比,下同)、氯化钠3.0%,其余为水;真菌菌株于28℃培养30天。
(3)(+)-Sclerotiorin的提取分离
取60瓶步骤(2)得到的菌丝体,用氯仿-甲醇混合液(1∶1)浸提3次减压浓缩后,用乙酸乙酯萃取3次得粗浸膏;乙酸乙酯相粗浸膏分别进行正相硅胶柱层析(固定相为200-300目硅胶;流动相为30%乙酸乙酯/石油醚混合溶剂,体积比)、SephadexLH-20凝胶柱层析(石油醚∶氯仿∶甲醇=2∶1∶1的混合溶剂,体积比)后,再经HPLC高效液相制备色谱分离(色谱柱为Kromasil10×250mm,5μm,流速为2.0mL/min,流动相为65%的甲醇-水混合溶剂,体积比),将所得洗脱液浓缩,得黄色粉末,即为(+)-Sclerotiorin。
实施例2
(1)柳珊瑚内生真菌Penicilliumsp.(TA33-1)的菌种培养
菌种培养所用的培养基含有葡萄糖0.1%-5.0%(重量百分比,下同)、酵母膏0.01%-1%、蛋白胨0.01%-1%、琼脂0.1%-3.0%、氯化钠0.05%-5%,其余为水,使用时制成试管斜面,真菌菌株在0-30℃下培养3-15天。
(2)柳珊瑚内生真菌Penicilliumsp.(TA33-1)的发酵
发酵培养所用的培养基含有大米1.0%-80.0%(重量百分比,下同)、氯化钠0.05%-5%,其余为水,真菌菌株于0-30℃培养10-60天。
(3)(+)-Sclerotiorin化合物的提取分离
取10-300瓶步骤(2)所得的将所得菌丝体用氯仿-甲醇混合液(1∶1)浸提3次减压浓缩后,用乙酸乙酯萃取3次得粗浸膏;乙酸乙酯相粗浸膏浓缩后分别进行正相硅胶柱层析(固定相为本领域常规正相硅胶,流动相为15%-40%的乙酸乙酯-石油醚混合溶剂,体积比)、SephadexLH-20凝胶柱层析(流动相为石油醚∶氯仿∶甲醇=2∶1∶1的混合溶剂,体积比)后,再经HPLC高效液相制备色谱(色谱柱为本领域常规ODSC18柱,流速为1.0-5.0mL/min,流动相为50%-80%的甲醇-水混合溶剂,体积比),将所得洗脱液浓缩,得黄色粉末固体,即为(+)-Sclerotiorin化合物。
实施例1-2中未具体指明的其他菌种培养、发酵条件,以及正相硅胶柱色谱分离、SephadexLH-20凝胶柱层析分离、高效液相色谱分离等其他实验操作条件均为本领域常规的实验操作条件,本领域的技术人员可以根据实际需要,进行合理的选择。
实施例3
称取上述干燥后的(+)-Sclerotiorin(0.1mol)溶解在二氯甲烷中,常温条件下,在充分搅拌下将有机伯胺(0.12mol)逐滴滴加到反应溶液中,反应1小时后,向反应物中加入蒸馏水(200mL)来终止反应,用乙酸乙酯(500mL)进行萃取,将萃取液浓缩后,进行柱层析,用乙酸乙酯洗脱,洗脱液浓缩,重结晶后得到式I化合物。
实施例3中未具体指明的其他有机化学反应条件,以及正相硅胶柱色谱分离等其他实验操作条件均为本领域常规的实验操作条件,本领域的技术人员可以根据实际需要,进行合理的选择。
式I化合物的具体化合物结构实例:
式I化合物的结构确证数据:
1:1HNMR(600MHz,CDCl3)δH7.84(1H,s,H-1),7.16(1H,s,H-4),6.98(1H,d,J=15.6Hz,H-10),6.58(1H,t,J=2.4Hz),6.41(2H,d,J=1.8Hz),5.70(1H,d,J=15.6Hz,H-9),5.68(1H,d,J=9.6Hz,H-12),3.83(6H,s),2.42(1H,m,H-13),2.18(3H,s,H-20),1.59(3H,s,H-17),1.57(3H,s,H-18),1.42(1H,m,H-14),1.32(1H,m,H-14),1.00(3H,d,J=6.6Hz,H-16),0.85(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC193.9(C-6),184.7(C-8),170.3(COCH3),161.8,161.8,147.9(C-1),147.4,144.2,143.2,141.8,141.1,132.0(C-11),116.2(C-9),114.3(C-5),109.6,109.6,109.6,103.3(C-8a),101.8(C-4),84.9(C-7),56.0(-OCH3),55.9(-OCH3),35.1(C-13),30.1(C-14),23.3(C-18),20.4(C-16),20.3(COCH3),12.5(C-17),12.1(C-15).ESIMSm/z526.05/528.05[M+H]+/[M+H+2]+(3∶1),547.99/550.01[M+Na]+/[M+Na+2]+(3∶1),1072.84/1072.77[2M+Na]+/[2M+Na+2]+(3∶1).HRESIMSm/z526.1981[M+H]+(calcdforC29H33O6NCl,526.1991).
2:1HNMR(600MHz,CDCl3)δH7.85(1H,s,H-1),7.16(1H,s,H-4),6.98(1H,d,J=15.6Hz,H-10),6.98(1H,d,J=8.4Hz),6.88(1H,dd,J=8.4,2.4Hz),6.77(1H,d,J=2.4Hz),5.68(1H,d,J=9.6Hz,H-12),5.67(1H,d,J=15.6Hz,H-9),3.97(3H,s),3.90(3H,s),2.42(1H,m,H-13),2.18(3H,s,H-20),1.59(3H,s,H-17),1.55(3H,s,H-18),1.42(1H,m,H-14),1.32(1H,m,H-14),0.99(3H,d,J=6.6Hz,H-16),0.85(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC193.9(C-6),184.6(C-8),170.2(COCH3),150.2,149.9,147.9,147.9,144.3,143.2,141.5,133.1,131.9(C-11),119.0,116.2(C-9),114.2(C-5),111.4,109.7,109.6,103.0(C-8a),84.8(C-7),56.4(-OCH3),56.3(-OCH3),35.0(C-13),30.0(C-14),23.2(C-18),20.3(C-16),20.3(COCH3),12.4(C-17),12.0(C-15).ESIMSm/z526.01/528.06[M+H]+/[M+H+2]+(3∶1),548.03/550.01[M+Na]+/[M+Na+2]+(3∶1),1072.83[2M+Na]+;HRESIMSm/z526.1984[M+H]+(calcdforC29H33O6NCl,526.1991).
3:1HNMR(600MHz,CDCl3)δH7.85(1H,s,H-1),7.16(1H,s,H-4),6.99(1H,d,J=15.6Hz,H-10),6.50(2H,s),5.68(2H,overlapped,H-9andH-12),3.91(3H,s),3.87(6H,s),2.42(1H,m,H-13),2.19(3H,s,H-20),1.59(3H,s,H-17),1.57(3H,s,H-18),1.42(1H,m,H-14),1.32(1H,m,H-14),1.00(3H,d,J=6.6Hz,H-16),0.85(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC193.9(C-6),184.7(C-8),170.4(COCH3),154.1,148.0,148.0,147.6,144.1,143.3,141.2,141.2,139.2,135.8,131.9(C-11),116.2,114.3(C-5),109.6,104.2,103.4(C-8a),84.8(C-7),61.2(-OCH3),56.7(-OCH3),56.6(-OCH3),35.1(C-13),30.1(C-14),23.3(C-18),20.4(C-16),20.3(COCH3),12.5(C-17),12.0(C-15).ESIMSm/z556.07/558.06[M+H]+/[M+H+2]+(3∶1),578.05/580.04[M+Na]+/[M+Na+2]+(3∶1),1132.83[2M+Na]+;HRESIMSm/z556.2087[M+H]+(calcdforC30H35O7NCl,556.2097).
4:1HNMR(600MHz,CDCl3)δH9.20(1H,s),8.29(1H,d,J=8.4Hz),7.97(1H,d,J=2.4Hz),7.88(1H,s,H-1),7.45(1H,dd,J=8.4,2.4Hz),7.18(1H,s,H-4),7.00(1H,d,J=15.6Hz,H-10),5.69(1H,d,J=9.6Hz,H-12),5.58(1H,d,J=15.6Hz,H-9),2.39(1H,m,H-13),2.19(3H,s,H-20),1.60(3H,s,H-17),1.46(3H,s,H-18),1.42(1H,m,H-14),1.32(1H,m,H-14),0.98(3H,d,J=6.6Hz,H-16),0.84(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC193.8(C-6),184.9(C-8),170.4(COCH3),157.1,153.8,148.4,147.5,143.9,143.6,141.3,137.9,135.4,131.9,125.1,120.5,116.1,114.6(C-5),110.0,104.0100.0,84.9(C-7),35.1(C-13),30.1(C-14),23.3(C-18),20.4(C-16),20.3(COCH3),12.4(C-17),12.1(C-15).ESIMSm/z523.00/525.01[M+H]+/[M+H+2]+(3∶1),544.98/546.98[M+Na]+/[M+Na+2]+(3∶1),1066.77[2M+Na]+;HRESIMSm/z523.1451[M+H]+(calcdforC28H28O4N2ClS,523.1453).
5:1HNMR(600MHz,CDCl3)δH8.84(1H,d,J=2.4Hz),8.24(1H,d,J=8.4Hz),8.20(1H,d,J=2.4Hz),7.94(1H,d,J=7.8Hz),7.91(1H,ddd,J=8.4,6.6,1.2Hz),7.88(1H,s,H-1),7.74(1H,ddd,J=7.8,7.2,1.2Hz),7.19(1H,s,H-4),7.04(1H,d,J=15.6Hz,H-10),5.70(1H,d,J=9.6Hz,H-12),5.58(1H,d,J=15.6Hz,H-9),2.38(1H,m,H-13),2.19(3H,s,H-20),1.61(3H,s,H-17),1.46(3H,s,H-18),1.42(1H,m,H-14),1.32(1H,m,H-14),0.98(3H,d,J=6.6Hz,H-16),0.84(3H,t,J=7.2Hz,H-15);13CNMR(150MHz,CDCl3)δC193.6(C-6),185.1(C-8),170.4(COCH3),148.7,147.9,147.6,147.4,144.3,143.5,141.1,134.1,133.1,131.9,131.7,129.9,128.9,128.2,127.3,115.7,115.1(C-5),110.4,104.6,84.8(C-7),35.1(C-13),30.1(C-14),23.2(C-18),20.4(C-16),20.3(COCH3),12.5(C-17),12.1(C-15).ESIMSm/z517.05/519.10[M+H]+/[M+H+2]+(3∶1),539.01/541.01[M+Na]+/[M+Na+2]+(3∶1),1054.85[2M+Na]+.HRESIMSm/z517.1885[M+H]+(calcdforC30H30O4N2Cl,517.1889).
6:1HNMR(600MHz,CDCl3)δH7.89(1H,s,H-1),7.85(1H,m),7.59(2H,m,),7.27(1H,m),7.19(1H,s,H-4),6.94(1H,d,J=15.6Hz,H-10),6.78(1H,brs,-NH),5.62(1H,d,J=9.6Hz,H-12),5.48(1H,d,J=15.6Hz,H-9),2.38(1H,m,H-13),1.82(3H,s,H-20),1.55(3H,s,H-17),1.45(3H,s,H-18),1.38(1H,m,H-14),1.28(1H,m,H-14),0.97(3H,d,J=6.6Hz,H-16),0.81(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC193.2(C-6),184.2(C-8),170.9(COCH3),168.8,149.4,147.7,144.8,143.5,141.1,138.7,132.4,132.0,131.5,130.4,130.3,128.7,116.8,114.3(C-5),109.7,102.6,85.6(C-7),35.0(C-13),30.1(C-14),23.3(C-18),20.4(C-16),20.3(COCH3),12.3(C-17),12.0(C-15).ESIMSm/z509.08/511.05[M+H]+/[M+H+2]+(3∶1),531.06/533.01[M+Na]+/[M+Na+2]+(3∶1),1038.98[2M+Na]+.HRESIMSm/z509.1844[M+H]+(calcdforC28H30O5N2Cl,509.1838).
7:1HNMR(600MHz,CDCl3)δH8.12(1H,dt,J=8.4,1.2Hz),7.91(1H,t,J=1.8Hz),7.81(1H,s,H-1),7.69(1H,t,J=7.8Hz),7.51(1H,ddd,J=7.8,2.4,1.2Hz),7.16(1H,s,H-4),6.99(1H,d,J=15.6Hz,H-10),5.69(1H,d,J=9.6Hz,H-12),5.53(1H,d,J=15.6Hz,H-9),2.67(3H,s),2.40(1H,m,H-13),2.19(3H,s,H-20),1.60(3H,s,H-17),1.49(3H,s,H-18),1.42(1H,m,H-14),1.32(1H,m,H-14),0.99(3H,d,J=6.6Hz,H-16),0.85(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC196.1,193.7(C-6),184.9(C-8),170.3(COCH3),148.4,147.2,143.8,143.7,141.0,140.9,139.1,131.8,131.1,130.7,129.8,126.2,115.9,114.7(C-5),110.1,104.0,84.8(C-7),35.1(C-13),30.1(C-14),26.9,23.2(C-18),20.4(C-16),20.3(COCH3),12.4(C-17),12.0(C-15).ESIMSm/z508.05/510.10[M+H]+/[M+H+2]+(3∶1),530.04/532.01[M+Na]+/[M+Na+2]+(3∶1),1036.83[2M+Na]+.HRESIMSm/z508.1886[M+H]+(calcdforC29H31O5NCl,508.1885).
8:1HNMR(600MHz,CDCl3)δH8.10(1H,d,7.8Hz),7.88(1H,s),7.87(1H,s,H-1),7.64(1H,t,J=7.8Hz),7.43(1H,d,J=7.8Hz),7.13(1H,s,H-4),6.97(1H,d,J=15.6Hz,H-10),6.09(1H,brs,-NH),5.68(1H,d,J=9.6Hz,H-12),5.60(1H,d,J=15.6Hz,H-9),2.41(1H,m,H-13),2.11(3H,s,H-20),1.57(3H,s,H-17),1.51(3H,s,H-18),1.42(1H,m,H-14),1.32(1H,m,H-14),0.99(3H,d,J=6.6Hz,H-16),0.85(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC193.3(C-6),184.9(C-8),170.3(COCH3),167.3,148.4,147.8,144.6,143.9,143.8,141.5,140.6,135.9,132.0,130.4,129.9,126.0,116.2,116.2,114.6(C-5),109.9,85.1(C-7),35.1(C-13),30.1(C-14),23.4(C-18),20.4(C-16),20.3(COCH3),12.4(C-17),12.1(C-15).ESIMSm/z509.05/511.06[M+H]+/[M+H+2]+(3∶1),531.07/533.03[M+Na]+/[M+Na+2]+(3∶1),1038.93[2M+Na]+.HRESIMSm/z509.1839[M+H]+(calcdforC28H30O5N2Cl,509.1838).
9:1HNMR(600MHz,CDCl3)δH8.05(2H,d,J=8.4Hz),7.81(1H,s,H-1),7.41(2H,d,J=8.4Hz),7.15(1H,s,H-4),6.99(1H,d,J=15.6Hz,H-10),6.63(1H,s,-NH),5.94(1H,s,-NH),5.69(1H,d,J=9.6Hz,H-12),5.57(1H,d,J=15.6Hz,H-9),2.41(1H,m,H-13),2.18(3H,s,H-20),1.60(3H,s,H-17),1.52(3H,s,H-18),1.42(1H,m,H-14),1.32(1H,m,H-14),0.99(3H,d,J=6.6Hz,H-16),0.85(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC193.6(C-6),185.0(C-8),170.4(COCH3),167.5,148.5,147.3,143.9,143.8,143.2,140.8,135.0,131.9,129.7,129.7,126.9,126.9,116.0,114.8(C-5),110.2,103.9,85.0(C-7),35.1(C-13),30.1(C-14),23.3(C-18),20.4(C-16),20.3(COCH3),12.5(C-17),12.1(C-15).ESIMSm/z509.07/511.07[M+H]+/[M+H+2]+(3∶1),531.03/533.03[M+Na]+/[M+Na+2]+(3∶1),1038.75[2M+Na]+.HRESIMSm/z509.1848[M+H]+(calcdforC28H30O5N2Cl,509.1838).
10:1HNMR(600MHz,CDCl3)δH7.85(1H,dt,J=7.8,1.2Hz),7.74(1H,s,H-1),7.73(1H,t,J=7.8Hz),7.66(1H,t,J=1.8Hz),7.60(1H,ddd,J=7.8,1.8,0.6Hz),7.13(1H,s,H-4),6.99(1H,d,J=15.6Hz,H-10),5.71(1H,d,J=9.6Hz,H-12),5.46(1H,d,J=15.6Hz,H-9),2.42(1H,m,H-13),2.18(3H,s,H-20),1.58(3H,s,H-17),1.53(3H,s,H-18),1.42(1H,m,H-14),1.32(1H,m,H-14),1.00(3H,d,J=6.6Hz,H-16),0.86(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC193.4(C-6),185.1(C-8),170.3(COCH3),148.9,146.7,144.1,143.2,141.3,140.4,133.6,131.7,131.5,131.4,130.3,116.8,115.5,114.9,114.8(C-5),110.3,104.8,84.8(C-7),35.2(C-13),30.1(C-14),23.1(C-18),20.4(C-16),20.3(COCH3),12.4(C-17),12.1(C-15).ESIMSm/z491.06/493.06[M+H]+/[M+H+2]+(3∶1),513.01/515.05[M+Na]+/[M+Na+2]+(3∶1),1002.83[2M+Na]+.HRESIMSm/z491.1730[M+H]+(calcdforC28H28O4N2Cl,491.1732).
11:1HNMR(600MHz,Acetone)δH8.94(1H,s,-NH),7.79(2H,d,J=7.8Hz),7.78(1H,s,H-1),7.16(2H,d,J=7.8Hz),7.16(1H,s,H-4),6.98(1H,d,J=15.6Hz,H-10),5.68(1H,d,J=9.6Hz,H-12),5.64(1H,d,J=15.6Hz,H-9),2.41(1H,m,H-13),2.20(3H,s),2.16(3H,s,H-20),1.61(3H,s,H-17),1.53(3H,s,H-18),1.42(1H,m,H-14),1.32(1H,m,H-14),0.99(3H,d,J=6.6Hz,H-16),0.85(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC193.7(C-6),184.7(C-8),170.5(COCH3),169.6,148.4,144.9,143.8,141.6,140.5,135.1,132.0,126.9,122.6,120.6,116.2,116.2,115.4,114.6(C-5),109.9,102.7,85.1(C-7),35.1(C-13),30.1(C-14),29.4,23.5(C-18),20.5(C-16),20.3(COCH3),12.5(C-17),12.1(C-15).ESIMSm/z523.05/525.07[M+H]+/[M+H+2]+(3∶1),545.03/547.02[M+Na]+/[M+Na+2]+(3∶1),1066.91[2M+Na]+.HRESIMSm/z523.1989[M+H]+(calcdforC29H32O5N2Cl,523.1994).
12:1HNMR(600MHz,acetone)δH9.91(1H,s,-NH),7.70(1H,s,H-1),7.20(H,d,J=8.4Hz),7.09(1H,d,1.8Hz),7.04(1H,d,J=15.6Hz,H-10),6.93(1H,d,J=2.4Hz),6.89(1H,s,H-4),6.71(H,dd,J=8.4,2.4Hz),6.26(1H,d,J=15.6Hz,H-9),5.72(1H,d,J=9.6Hz,H-12),4.52(1H,m),4.29(1H,m),3.23(2H,m),2.50(1H,m,H-13),2.02(3H,s,H-20),1.72(3H,s,H-17),1.43(1H,m,H-14),1.35(3H,s,H-18),1.32(1H,m,H-14),1.00(3H,d,J=6.6Hz,H-16),0.86(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,acetone-d6)δC193.9(C-6),183.8(C-8),169.9(COCH3),152.1,149.9,147.1,145.4,144.8,142.7,133.6,132.5,129.1,125.3,125.2,117.3,115.3(C-5),112.9,112.8,111.0,110.0103.0,86.2(C-7),55.4,35.6(C-13),30.9(C-14),26.9,23.7(C-18),20.7(C-16),20.4(COCH3),12.6(C-17),12.4(C-15).ESIMSm/z549.13/551.12[M+H]+/[M+H+2]+(3∶1),571.16/573.12[M+Na]+/[M+Na+2]+(3∶1),1118.99[2M+Na]+.HRESIMSm/z549.2144[M+H]+(calcdforC31H34O5N2Cl,549.2151).
13:1HNMR(600MHz,CDCl3)δH7.88(2H,d,J=8.4Hz),7.76(1H,s,H-1),7.49(2H,d,J=8.4Hz),7.13(1H,s,H-4),6.98(1H,d,J=15.6Hz,H-10),5.71(1H,d,J=9.6Hz,H-12),5.49(1H,d,J=15.6Hz,H-9),2.42(1H,m,H-13),2.18(3H,s,H-20),1.58(3H,s,H-17),1.54(3H,s,H-18),1.42(1H,m,H-14),1.32(1H,m,H-14),1.00(3H,d,J=6.6Hz,H-16),0.86(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC193.4(C-6),185.1(C-8),170.3(COCH3),148.7,146.6,144.0,143.9,143.1,140.2,134.2,134.2,131.7,127.7,127.7,117.2,115.8,114.9,114.1,110.5,104.9,84.8(C-7),35.1(C-13),30.1(C-14),23.1(C-18),20.3(C-16),20.3(COCH3),12.4(C-17),12.1(C-15).ESIMSm/z491.04/493.07[M+H]+/[M+H+2]+(3∶1),513.04/514.99[M+Na]+/[M+Na+2]+(3∶1),1118.99[2M+Na]+.HRESIMSm/z491.1728[M+H]+(calcdforC28H28O4N2Cl,491.1732).
14:1HNMR(600MHz,CDCl3)δH7.89(1H,s,H-1),7.00(1H,s,H-4),6.96(1H,d,J=15.6Hz,H-10),6.31(1H,d,J=15.6Hz,H-9),5.72(1H,d,J=9.6Hz,H-12),4.60(2H,s,H-21),2.63(1H,t,2.4Hz,H-23),2.50(1H,m,H-13),2.17(3H,s,H-20),1.88(3H,s,H-17),1.55(3H,s,H-18),1.45(1H,m,H-14),1.35(1H,m,H-14),1.03(3H,d,J=6.6Hz,H-16),0.89(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC193.5(C-6),184.7(C-8),170.2(COCH3),148.4,147.7,145.4,144.2,140.8,132.0,114.9,114.6,111.4,103.0,85.0(C-7),77.5,75.3,43.8,35.2(C-13),30.1(C-14),23.3(C-18),20.4(C-16),20.3(COCH3),12.7(C-17),12.1(C-15).ESIMSm/z428.03/430.09[M+H]+/[M+H+2]+(3∶1),450.01/452.02[M+Na]+/[M+Na+2]+(3∶1),876.80/878.80[2M+Na]+/[2M+Na+2]+.HRESIMSm/z428.1621[M+H]+(calcdforC24H27O4NCl,428.1623).
15:1HNMR(600MHz,CDCl3)δH7.89(2H,m),7.73(1H,td,J=7.8,1.2Hz),7.71(1H,s,H-1),7.52(1H,d,J=7.8Hz),7.15(1H,s,H-4),7.00(1H,d,J=15.6Hz,H-10),5.68(1H,d,J=9.6Hz,H-12),5.37(1H,d,J=15.6Hz,H-9),2.39(1H,m,H-13),2.18(3H,s,H-20),1.62(3H,s,H-17),1.48(3H,s,H-18),1.41(1H,m,H-14),1.31(1H,m,H-14),0.99(3H,d,J=6.6Hz,H-16),0.84(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC193.4(C-6),185.2(C-8),170.4(COCH3),148.8,146.9,144.6,143.3,142.4,140.1,135.0,134.4,131.6,131.0,129.1,115.0,114.8,114.6,114.5,112.3,110.1,105.2,85.0(C-7),35.1(C-13),30.1(C-14),23.1(C-18),20.4(C-16),20.2(COCH3),12.3(C-17),12.1(C-15).ESIMSm/z491.07/493.11[M+H]+/[M+H+2]+(3∶1),513.03/515.07[M+Na]+/[M+Na+2]+(3∶1),1002.76[2M+Na]+.HRESIMSm/z491.1741[M+H]+(calcdforC28H28O4N2Cl,491.1732).
16:1HNMR(600MHz,CDCl3)δH8.15(2H,d,J=8.4Hz),7.81(1H,s,H-1),7.44(2H,d,J=8.4Hz),7.16(1H,s,H-4),6.99(1H,d,J=15.6Hz,H-10),5.70(1H,d,J=9.6Hz,H-12),5.56(1H,d,J=15.6Hz,H-9),2.69(3H,s),2.41(1H,m,H-13),2.18(3H,s,H-20),1.60(3H,s,H-17),1.52(3H,s,H-18),1.42(1H,m,H-14),1.32(1H,m,H-14),0.99(3H,d,J=6.6Hz,H-16),0.85(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC196.4(C-6),193.6(C-8),185.0,170.3(COCH3),148.4,147.0,144.1,143.6,143.6,140.6,138.0,131.8,130.3,127.0,127.0,116.1,116.1,114.7,110.3,104.2,84.8(C-7),35.1(C-13),30.1(C-14),26.9,23.2(C-18),20.4(C-16),20.3(COCH3),12.4(C-17),12.1(C-15).ESIMSm/z508.09/510.09[M+H]+/[M+H+2]+(3∶1),530.03/532.05[M+Na]+/[M+Na+2]+(3∶1),1036.81[2M+Na]+.HRESIMSm/z508.1878[M+H]+(calcdforC29H31O5NCl,508.1885).
17:1HNMR(600MHz,CDCl3)δH7.78(1H,s,H-1),7.31(2H,m),7.25(2H,m),7.13(1H,s,H-4),6.96(1H,d,J=15.6Hz,H-10),5.68(1H,d,J=9.6Hz,H-12),5.55(1H,d,J=15.6Hz,H-9),2.41(1H,m,H-13),2.17(3H,s,H-20),1.58(3H,s,H-17),1.53(3H,s,H-18),1.41(1H,m,H-14),1.32(1H,m,H-14),0.99(3H,d,J=6.6Hz,H-16),0.85(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC193.7(C-6),184.9(C-8),170.3(COCH3),148.3,147.5,143.9,143.6,143.5,141.1,136.5,131.9,128.8,128.8,117.5,117.4,116.0,114.6,110.0,103.8,84.9(C-7),35.1(C-13),30.1(C-14),23.2(C-18),20.4(C-16),20.3(COCH3),12.3(C-17),12.0(C-15).ESIMSm/z484.02/486.06[M+H]+/[M+H+2]+(3∶1),506.00/508.03[M+Na]+/[M+Na+2]+(3∶1),988.72/990.71[2M+Na]+/[2M+Na+2]+.HRESIMSm/z484.1679[M+H]+(calcdforC27H28O4NClF,484.1685).
18:1HNMR(600MHz,CDCl3)δH8.43(2H,d,J=9.0Hz),7.78(1H,s,H-1),7.55(2H,d,J=9.0Hz),7.13(1H,s,H-4),6.99(1H,d,J=15.6Hz,H-10),5.71(1H,d,J=9.6Hz,H-12),5.51(1H,d,J=15.6Hz,H-9),2.42(1H,m,H-13),2.17(3H,s,H-20),1.59(3H,s,H-17),1.54(3H,s,H-18),1.42(1H,m,H-14),1.33(1H,m,H-14),1.00(3H,d,J=6.6Hz,H-16),0.86(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC193.3(C-6),185.2(C-8),170.4(COCH3),148.8,148.1,146.6,145.5,144.0,143.0,140.1,131.7,127.9,127.9,125.7,125.7,115.8,115.0,110.6,105.1,84.8(C-7),35.2(C-13),30.1(C-14),23.1(C-18),20.3(C-16),20.2(COCH3),12.5(C-17),12.1(C-15).ESIMSm/z511.05/513.06[M+H]+/[M+H+2]+(3∶1),533.06/535.02[M+Na]+/[M+Na+2]+(3∶1).HRESIMSm/z511.1625[M+H]+(calcdforC27H28O6N2Cl,511.1630).
19:1HNMR(600MHz,CDCl3)δH7.91(1H,s,H-1),6.97(1H,s,H-4),6.89(1H,d,J=15.6Hz,H-10),6.16(1H,d,J=15.6Hz,H-9),5.69(1H,d,J=9.6Hz,H-12),3.98(1H,m,H-21),2.49(1H,m,H-13),2.17(3H,s,H-20),1.97-2.04(4H,m),1.87(3H,s,H-17),1.66(2H,m),1.55(3H,s,H-18),1.32-1.48(4H,m),1.26(2H,m),1.03(3H,d,J=6.6Hz,H-16),0.90(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC194.1(C-6),184.5(C-8),170.2(COCH3),148.6,147.6,145.0,144.5,136.9,131.6,115.1,112.8,112.8,102.2,84.9(C-7),61.2,35.1(C-13),33.3,33.1,30.1(C-14),25.8,25.0,23.4(C-18),20.4(C-16),20.3(COCH3),12.7,12.7(C-17),12.1(C-15).ESIMSm/z472.14/474.18[M+H]+/[M+H+2]+(3∶1),494.10/496.10[M+Na]+/[M+Na+2]+(3∶1),964.96/966.94[2M+Na]+/[2M+Na+2]+.HRESIMSm/z472.2250[M+H]+(calcdforC27H35O4NCl,472.2249).
20:1HNMR(600MHz,CDCl3)δH7.75(1H,s,H-1),7.02(1H,s,H-4),6.96(1H,d,J=15.6Hz,H-10),6.15(1H,d,J=15.6Hz,H-9),5.71(1H,d,J=9.6Hz,H-12),3.84(2H,m,H-21),2.49(1H,m,H-13),2.17(3H,s,H-20),1.86(3H,s,H-17),1.76(2H,m),1.55(3H,s,H-18),1.26-1.48(8H,overlapped),1.03(3H,d,J=6.6Hz,H-16),0.88-0.91(6H,overlapped).13CNMR(150MHz,CDCl3)δC194.0(C-6),184.4(C-8),170.2(COCH3),148.1,147.9,145.0,144.7,141.1,131.7,114.8,114.7,111.7,102.2,84.9(C-7),54.4,35.1(C-13),31.2,30.3,30.1(C-14),26.0,23.3(C-18),22.5,20.4(C-16),20.3(COCH3),14.0,12.7(C-17),12.1(C-15).ESIMSm/z474.15/476.15[M+H]+/[M+H+2]+(3∶1),496.09/498.06[M+Na]+/[M+Na+2]+(3∶1),968.91[2M+Na]+.HRESIMSm/z474.2397[M+H]+(calcdforC27H37O4NCl,474.2406).
21:1HNMR(500MHz,CDCl3)δH7.75(1H,s,H-1),7.03(1H,s,H-4),6.97(1H,d,J=15.6Hz,H-10),6.12(1H,d,J=15.6Hz,H-9),5.71(1H,d,J=9.6Hz,H-12),3.81(2H,m,H-21),2.49(1H,m,H-13),2.17(3H,s,H-20),1.85(3H,s,H-17),1.80(2H,m,H-22),1.55(3H,s,H-18),1.45(1H,m,H-14),1.35(1H,m,H-14),1.03(6H,overlapped),0.89(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC194.0,184.4,170.2,148.1,147.9,145.0,144.7,141.2,131.7,114.7,114.7,111.7,102.2,84.9,55.9,35.1,30.1,23.7,23.3,20.4,20.3,12.7,12.1,10.9.ESIMSm/z432.10/434.06[M+H]+/[M+H+2]+(3∶1),454.07/456.06[M+Na]+/[M+Na+2]+(3∶1),884.82/886.81[2M+Na]+/[2M+Na+2]+.HRESIMSm/z432.1934[M+H]+(calcdforC24H31O4NCl,432.1936).
22:1HNMR(600MHz,CDCl3)δH7.76(1H,s,H-1),7.02(1H,s,H-4),6.94(1H,d,J=15.6Hz,H-10),6.13(1H,d,J=15.6Hz,H-9),5.93(1H,m,H-22),5.70(1H,d,J=9.6Hz,H-12),5.42(1H,d,J=10.8Hz,H-23),5.25(1H,d,J=17.4Hz,H-23),4.48(2H,d,J=4.8Hz,H-21),2.48(1H,m,H-13),2.17(3H,s,H-20),1.82(3H,s,H-17),1.55(3H,s,H-18),1.45(1H,m,H-14),1.34(1H,m,H-14),1.02(3H,d,J=6.6Hz,H-16),0.89(3H,t,J=7.2Hz,H-15).13CNMR(150MHz,CDCl3)δC193.9(C-6),184.5(C-8),170.2(COCH3),148.3,148.1,145.1,144.5,141.3,131.8,131.0,120.0(C-22),114.9,114.9,111.4,102.6,84.9(C-7),56.2(C-21),35.1(C-13),30.1(C-14),23.3(C-18),20.4(C-16),20.3(COCH3),12.6(C-17),12.1(C-15).ESIMSm/z430.08/432.04[M+H]+/[M+H+2]+(3∶1),452.05/454.02[M+Na]+/[M+Na+2]+(3∶1),880.78/882.83[2M+Na]+/[2M+Na+2]+.HRESIMSm/z430.1774[M+H]+(calcdforC24H29O4NCl,430.1780).
实施例4
取式I化合物2mg溶解在装有1000μL甲醇、乙醇、四氢呋喃或丙酮中任一种或几种的小瓶中,于30℃下静置7天后,缓慢结晶即得式I化合物的晶体。上述晶体的Cu靶X-射线晶体衍射数据:空间群为P2(1)2(1)2(1),晶胞参数为 β=90(0)℃,Z=4,Dc=1.233g/cm3,F(000)=920,μ=0.193mm-1。
实施例5
本发明的式I化合物对藤壶Balanusamphitrite幼虫附着活性试验按照如下文献方法测试:Thiyagarajan,V.;Harder,T.;Qiu,J.W.;Qian,P.Y.Mar.Biol.(Berlin)2003,143,543-554。
本发明的式I化合物及其晶体藤壶B.amphitrite幼虫附着具有极强的抑制活性,结果见上表。上述活性远远强于美国海军规定的潜在的防污损化合物EC50值25μg/mL的标准。这表明式I化合物或其药学上可接受的盐可用于制备高效低毒的海洋防污剂,并且海洋来源真菌Penicilliumsp.(TA33-1)可进行大规模发酵生产,保证了式I化合物的来源,具有广阔的应用前景。
Claims (12)
1.一种Sclerotiorin衍生物,其特征在于具有式I的结构:
或其药学上可接受的盐,其中R为
2.权利要求1所述的式I化合物的制备方法,其特征在于先在菌种培养基中对真菌Penicilliumsp.(TA33-1)进行菌种培养,再在发酵培养基中对该真菌进行发酵培养,将所得菌丝体用氯仿-甲醇混合液(1∶1)浸提3次减压浓缩后,用乙酸乙酯萃取3次得粗浸膏;乙酸乙酯相粗浸膏分别进行正相硅胶柱层析、SephadexLH-20凝胶柱层析后,再经HPLC高效液相制备色谱,将所得洗脱液浓缩,得黄色粉末,即为(+)-Sclerotiorin;在溶有(+)-Sclerotiorin的二氯甲烷溶液中,加入有机伯胺和碳酸钾,反应后得到式I氯代聚酮化合物;其中所述菌种培养基中含有葡萄糖、酵母膏、蛋白胨、琼脂、粗海盐、水;所述的发酵培养基中含有大米、粗海盐、水;所述的色谱分离为正相硅胶柱色谱分离、凝胶柱层析分离和高效液相色谱分离;所述的有机伯胺为
3.如权利要求2所述的制备方法,其特征在于所述菌种培养基优选含有葡萄糖0.1%-5.0%、酵母膏0.01%-1%、蛋白胨0.01%-1%、琼脂0.1%-3.0%、氯化钠0.05%-5%,其余为水,上述百分含量均为重量百分比,培养温度优选为0-30℃,培养时间优选为3-15天。
4.如权利要求2-3所述的制备方法,其特征在于所述发酵培养基优选含有大米1.0%-80.0%、氯化钠0.05%-5%,其余为水,上述百分含量均为重量百分比,培养温度优选为0-30℃,培养时间优选为10-60天。
5.如权利要求2-4任一项所述的制备方法,其特征在于所述的正相硅胶柱层析采用的固定相为200-300目硅胶,流动相为体积比为15%-60%的乙酸乙酯-石油醚混合溶剂;所述SephadexLH-20凝胶柱层析采用的流动相为体积比为石油醚∶氯仿∶甲醇=2∶1∶1的混合溶剂;所述HPLC高效液相制备色谱中采用的色谱柱为Kromasil10×250mm,5μm,流速为1.0-5.0mL/min,流动相为体积比50%-80%的甲醇-水混合溶剂。
6.权利要求1所述的式I化合物为晶体,其特征在于该晶体的空间群为P2(1)2(1)2(1),晶胞参数为β=90(0)°,Z=4,Dc=1.233g/cm3,F(000)=920,μ=0.193mm-1。
7.权利要求6所述晶体的制备方法,其特征在于将式I化合物溶于甲醇、乙醇、水、四氢呋喃或丙酮中的任一种或几种,静置缓慢结晶即可得到式I化合物的晶体。
8.如权利要求7所述的制备方法,其特征在于静置缓慢结晶的条件为在0-30℃下,静置1-30天。
9.一种海洋生物防污剂,其特征在于其含有权利要求1所述的式I化合物或其药学上可接受的盐作为有效成分。
10.一种海洋生物防污剂,其特征在于其含有权利要求6所述的晶体作为有效成分。
11.权利要求1所述的式I化合物或其药学上可接受的盐在制备海洋防污剂中的应用。
12.权利要求6所述的晶体在制备海洋防污剂中的应用。
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