CN106749170A - 沙蚕毒素类化合物在防止海洋生物污损中的应用 - Google Patents
沙蚕毒素类化合物在防止海洋生物污损中的应用 Download PDFInfo
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Classifications
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- C07D339/02—Five-membered rings
- C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
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Abstract
沙蚕毒素类化合物在防止海洋生物污损中的应用，涉及沙蚕毒素类化合物。所述沙蚕毒素类化合物能显著抑制海洋污损生物藤壶附着以及抑制贝类产生足丝，具高效防污活性，同时对非靶标生物丰年虫毒性较低。所述沙蚕毒素类化合物由天然存在的有机化合物仿生合成，易降解，对环境友好，安全性高；同时其合成工艺成熟，适合于大规模生产，对于将其规模化应用于海洋防污涂料具巨大潜力。
Description
技术领域
本发明涉及沙蚕毒素类化合物，尤其是涉及沙蚕毒素类化合物在防止海洋生物污损中的应用。
背景技术
海洋污损生物是指海洋环境中栖息或附着在船舶以及各种水下人工设施表面上微生物、植物和动物的总称。海洋污损生物给人类经济活动和环境生态带来了巨大的威胁，如引起船舶航行阻力增大和能耗增加，温室气体排放量增大，降低设施使用性能，加速金属腐蚀，造成外来生物入侵，破坏生态平衡甚至酿成生态灾难。在防止海洋污损生物附着、生长(防污)的技术发展过程中，使用化学防污涂料是最经济、有效和普遍采用的方法。化学防污涂料是以化学防污剂缓慢地释放到海洋设施表面的层流水层中，以杀死或驱避污损生物来达到防除的效果。传统防污剂如有机锡、氧化亚铜、氧化汞、铅等在达到防污目的的同时也严重污染了环境，危害海洋生态环境和威胁人类健康，其中有机锡防污涂料已被完全禁用。在寻找替代传统高毒、难降解防污剂的路线中，一系列杀虫剂、除藻剂等化合物，如百菌清(Chlorothalonil)、敌草隆(Diuron)、Irgarol 1051、Sea Nine-211等，逐渐被应用于防污领域，但随后发现这些化合物有降解速率慢、毒性高或易富集等缺点，对各类生物表现出了一系列生态毒性，这些化合物部分也已经被禁用或限用。因此迫切需要开发出环境友好型的海洋防污剂，其中从生物来源筛选出天然防污产物作为海洋防污剂，是研制新型高效无毒(或低毒)防污涂料的重要途径。天然防污产物具有毒性低、生物相容性好、易降解、不以杀灭污损生物为目的等优点，对于无毒(或低毒)防污涂料的发展具有重要意义，并且有望开发成新一代绿色环保型防污剂，对生态环境和人类健康威胁都较低。目前研究报道从海绵、珊瑚、海藻、微生物等已经分离得到很多天然防污产物，这些化合物结构类别多样，防污活性显著，且毒性一般较低。然而这些化合物大部分存在量少、成本高、提取或合成工艺复杂等不足，严重制约着开发和应用。
沙蚕毒素(nereistoxin)是由日本学者Nitta首次从海洋多毛类——异足索沙蚕Lumbricomerereis hateropoda体内分离出来的一种毒素。随后，日本武田药品工业株式会社成功开发了人类历史上第一个利用动物毒素进行仿生合成的沙蚕毒素类杀虫剂——巴丹(cartap)，其后掀起了对该类化合物研究的热潮，相继开发了一系列高效的沙蚕毒素类杀虫剂，如杀虫磺(bensultap)、易卫杀(thiocyclam)、杀虫双(bisultap)、杀虫单(monosultap)和多噻烷(polythiacycloalkane)。目前沙蚕毒素类化合物能通过化学合成，低成本快速大量获取，形成商业化应用。这类化合物作为杀虫剂，其作用机制已被广泛研究。它们属于烟碱乙酰胆碱受体抑制剂，作用于昆虫神经系统的突触体，阻遏神经正常传递而使害虫的神经对外来刺激不产生反应。沙蚕毒素类杀虫剂一般具有广谱、高效、低毒等特点，而且作用方式多样，包括胃毒、触杀、内吸和拒食作用。这类杀虫剂在结构上，与先导化合物具有一定的相似性，因此易于被微生物降解，减少了其在环境中的残留，避免了毒素通过生物富集和食物链累积而危害高等动物，破坏生态平衡，一般被认为是毒性低、对环境危害小的一类环境友好型杀虫剂。2009年世界卫生组织(World Health Organization，WHO)将巴丹、杀虫磺和易卫杀均列入毒副作用较低、使用相对安全的杀虫剂范围。此类杀虫剂已得到了世界各主要农业大国的大规模广泛应用。关于沙蚕毒素类化合物的开发和应用，国内外已有大量的专利和文献报道。美国专利US 6221896 B1公开了将沙蚕毒素类化合物复合溴虫腈、硫丹杀虫剂和丁醚脲制备成复合型杀虫剂和杀螨剂，表现出良好的杀虫效果。中国专利CN 103420880 A公开了一种农药沙蚕毒素的衍生物及其制备合成的方法，杀虫活性良好，甚至优于现有沙蚕毒素类农药杀虫单。中国专利CN 103250716 A公开了一种含螺虫乙酯和沙蚕毒素类的杀虫组合物，对多种害虫均具有明显的增效作用。但迄今为止，在海洋防污领域尚未发现沙蚕毒素类化合物的任何报道和应用。
发明内容
本发明的目的是提供一类具显著抗海洋污损生物附着活性的沙蚕毒素类化合物或其盐。
本发明的另一个目的是提供沙蚕毒素类化合物或其盐在制备海洋防污涂料中的应用。
所述沙蚕毒素类化合物的化学通式如式I所示：
其中，A部分为开链或环状结构部分，R1和R2均可各自独立地选自－R、－SR、－OR、－COR、－SO2R或－CSOR，或者R1和R2与各自连接的原子一起形成含至少2个S原子作为杂原子的5～8元杂环烷基，所述杂环烷基可以进一步被取代；n为选自0～3的整数，优选1；
B部分L不存在，L或者为环状连接基团或链状连接基团，所述环状连接基团可以为3～8元环烷基，所述链状连接基团可以为C1-C6烷基；
C部分R3可以选自－OR、－SR、－R或－NR1R2，R1和R2均可各自独立地选自R)；或者当L不存在时，R3可以与A部分连接的碳原子一起形成包含至少1个N原子的5～6元螺环；
其中R为H原子、羟基、C1-C6烷基、氨基、氰基、C6-C10芳香基或C6-C10杂芳香基，所述C6-C10芳香基或C6-C10杂芳香基可以进一步被卤素原子取代。
其中L优选为(CH2)m，其中m为0～6的整数，优选0或1。
本发明所述沙蚕毒素可选自表1和2中所列的化合物。
表1
注：表1中R1、R2、R3和R4均各自独立选自R，其中R可以为H原子、羟基、C1-C6烷基、氨基、氰基、C6-C10芳香基或C6-C10杂芳基，所述C6-C10芳香基或C6-C10杂芳基可以进一步被卤素原子取代。
表2
注：表2中R1、R2、R3和R4均各自独立选自R，其中R可以为H原子、羟基、C1-C6烷基、氨基、氰基、C6-C10芳香基或C6-C10杂芳基，所述C6-C10芳香基或C6-C10杂芳基可以进一步被卤素原子取代。
表1和2中的这些沙蚕毒素类化合物已经公开(参见科技文献：于观平,王刚,王素华,李正明.沙蚕毒素类杀虫剂研究进展[J].农药学学报,2011,13(2):103-109.)，它们都可以根据本领域已知的方法获得。
实验表明，本发明所述沙蚕毒素类化合物能显著抑制海洋污损生物(如藤壶)的附着和污损贝类产生足丝，具有高效的防污活性，同时对非靶标生物丰年虫呈现出较低的毒性，在环境友好型海洋防污剂和防污涂料方面具良好应用潜力。
本发明提供的防污剂中含有至少一种所述沙蚕毒素类化合物。本发明防污剂不仅可单独作为防污剂用于制备海洋防污涂料，也可与其它防污物质复配使用。
本发明可作为海洋防污剂以常规方法制备海洋防污涂料，涂料中含有至少一种本发明所述沙蚕毒素类化合物，可通过浸渍、喷涂或涂布等常规方式施用所述防污涂料至海洋人工设施表面，这些海洋人工设施包括但不限于：船只、海上油气平台、浮标、码头、桥墩、船坞、海水管道、海洋探测器、木桩及海水养殖网箱。
本发明具有以下有益效果：
1.本发明中的沙蚕毒素类化合物以天然存在的有机化合物仿生合成获得，毒性较低，不含有毒重金属，在海洋环境中易降解，对环境友好，安全性高。
2.本发明中的沙蚕毒素类化合物对多种海洋污损生物均表现出显著的抑制附着活性，可为海洋防污涂料或其它抗污损产品的开发提供有价值的先导化合物，有着很好的应用前景。
3.本发明中的沙蚕毒素类化合物，目前已有多种作为商业杀虫剂被广泛应用，其人工合成工艺成熟，获取途径简便，成本低，适合于大规模生产，不受限于生物体内的含量，具有可靠稳定的来源，推广应用潜力大。
附图说明
图1为沙蚕毒素对白脊藤壶金星幼体附着的影响。
图2为沙蚕毒素对白脊藤壶金星幼体存活的影响。
图3为杀虫单对白脊藤壶金星幼体附着的影响。
图4为杀虫单对白脊藤壶金星幼体存活的影响。
图5为沙蚕毒素对沙筛贝足丝分泌的影响。
图6为杀虫单对沙筛贝足丝分泌的影响。
图7为沙蚕毒素对丰年虫无节幼体存活的影响。
图8为杀虫单对丰年虫无节幼体存活的影响。
图1～8中，ck1表示空白对照，ck2表示溶剂对照。
具体实施方式
下面结合附图和实施例对本发明作进一步说明，但不以任何方式限制本发明。
实施例1沙蚕毒素类化合物对白脊藤壶金星幼体的防污活性检测
藤壶隶属于节肢动物门甲壳纲蔓足亚纲，是世界范围内污损危害最大的一类生物，主要通过其金星幼体附着变态形成稚体藤壶，进而形成污损。目前以藤壶金星幼体为生物模型已成为应用最久、最广泛、最主要的防污检测活性模型。本实施方式选择白脊藤壶Balanus albicostatus金星幼体作为防污活性检测模型，通过化合物作用下对金星幼体的附着率影响来作为评估防污活性的指标。成体于厦门市五通海域的礁石和牡蛎养殖架上采集获得，其金星幼体在实验室培养获得。
以甲醇为溶剂，将沙蚕毒素和杀虫单分别配制成一系列浓度梯度溶液，分别取1mL各溶液加入到培养皿中，另取1mL甲醇加到干净培养皿中，设为相应的溶剂对照组，待溶剂完全蒸发、化合物均匀分布在培养皿底面及侧面后，加入10mL膜滤海水(经孔径为0.22μm的滤膜过滤，下同)到每个培养皿中。空白对照组中不加化合物溶液或甲醇，直接加入10mL膜滤海水。各实验组和对照组均设3个平行组，每组加入白脊藤壶金星幼体数30只左右。26℃下置于黑暗环境中，待溶剂对照组幼体附着率达80％以上时，用体视显微镜观察金星幼体的附着情况，并求出各化合物对白脊藤壶金星幼体的半抑制附着浓度EC50值(指抑制50％所检测生物附着的有效浓度，此值越低，表明防污活性越高，下同)。
防污活性检测结果见附图1和3，沙蚕毒素和杀虫单对金星幼体的EC50分别为0.17和0.27μg mL-1，表现出高效的防污活性，表明沙蚕毒素和杀虫单均能强烈地抑制藤壶金星幼体的附着。对藤壶幼体的毒性检测结果如附图2和4所示，沙蚕毒素和杀虫单对金星幼体的LC50/EC50值分别能达到6.47和8.70，表明这两个化合物对藤壶金星幼体的抑制附着主要是通过非急性毒性作用。
实施例2沙蚕毒素类化合物对沙筛贝的防污活性检测
沙筛贝Mytilopsis sallei是一种典型的外来入侵污损贝类，原产于中美洲热带水域，隶属于双壳纲帘蛤目饰贝科，常分布水流较缓的内湾海域，以其足丝进行附着生活，在海洋设施形成较厚的污损层，对水产养殖以及内湾航运造成巨大的经济损失。本实施方式是通过化合物作用下对沙筛贝足丝的分泌条数影响来作为评估其防污活性的依据。
实验所用沙筛贝稚体，壳长约10mm，通过海水洗净其表面，剪去原有足丝。称取沙蚕毒素和杀虫单，以二甲亚砜(DMSO)为溶剂，分别配制成一系列浓度梯度溶液。取干净的24孔板，在每个孔中先加入1990μL膜滤海水，再加入10μL所配溶液，设置空白对照(溶液和溶剂均不添加)和溶剂对照(仅添加溶剂)，每个梯度下设置10个平行组。将沙筛贝放入孔中，每孔一个。黑暗环境静置24h。24h后观察每个孔中沙筛贝足丝分泌数量。
防污活性检测结果如附图5～6，沙蚕毒素表现出强烈抑制沙筛贝足丝分泌的活性，EC50为1.70μg mL-1，同时杀虫单对沙筛贝也表现出防污活性，EC50为14.02μg mL-1。
实施例3沙蚕毒素类化合物对非靶标生物丰年虫的毒性检测
丰年虫Artemia salina是海洋浮游动物的重要类群之一，也是海仔鱼和幼虾的理想饵料，常被作为毒性测试的检测生物。本实施方式是通过检测沙蚕毒素类化合物对丰年虫幼体的24h急性毒性作用，以幼体的死亡率作为评估毒性高低的依据。将丰年虫卵加至膜滤海水中，曝气，在25℃下3000～4000Lux光照条件下进行孵化24h。24h后收集I期无节幼体，将幼体加入新鲜的膜滤海水中，曝气，在25℃黑暗环境下培养24h。24h后收集II～III期幼体作为实验材料。
以DMSO为溶剂，配制一系列浓度梯度沙蚕毒素和杀虫单溶液。以24孔板为实验容器，设置空白对照(溶液和溶剂均不添加)、溶剂对照(仅添加溶剂)以及实验组，每个浓度设6个平行组，每个孔2mL体系(10μL溶液/海水+1990μL膜滤海水)，每个孔幼体数量控制在10～20只。在25℃黑暗环境培养，24h后进行观察幼体的状态，统计幼体的健康数、死亡数并记录。
检测结果如附图7和8，沙蚕毒素和杀虫单对丰年虫II～III期无节幼体作用24h后的LC50(指杀死50％所检测生物的有效浓度，此值越高，表明毒性越低)分别为5.71和20.31μg mL-1。根据Panagoula报道(参考科技文献：Panagoula B,Panayiota M,Iliopoulou-Georgudaki J.Acute toxicity of TBT and Irgarol in Artemia salina[J].International journal of toxicology,2002,21(3):231-233.)，三丁基锡和IRGAROL对丰年虫II～III期无节幼体的24h-LC50分别为4.14×10-5和1.62μg mL-1。根据Koutsaftis报道(参考科技文献：Koutsaftis A,Aoyama I.Toxicity of four antifouling biocidesand their mixtures on the brine shrimp Artemia salina[J].Science of the TotalEnvironment,2007,387(1):166-174.)，吡硫锌(ZPT)、吡啶硫酮铜(CPT)和百菌清对丰年虫II～III期无节幼体的24h-LC50分别为3.17，0.83和1.00μg mL-1。通过比较，显然沙蚕毒素和杀虫单对丰年虫无节幼体的毒性要远低于上述商业防污剂，显示出沙蚕毒素和杀虫单可作为环境友好型海洋防污剂的良好潜力。
Claims (9)
1.沙蚕毒素类化合物在防止海洋生物污损中的应用，其特征在于所述沙蚕毒素类化合物的化学通式如式I所示：
其中，A部分为开链或环状结构部分，R1和R2均可各自独立地选自－R、－SR、－OR、－COR、－SO2R或－CSOR，或者R1和R2与各自连接的原子一起形成含至少2个S原子作为杂原子的5～8元杂环烷基，所述杂环烷基可以进一步被取代；n为选自0～3的整数；
B部分L不存在，L或者为环状连接基团或链状连接基团，所述环状连接基团可以为3～8元环烷基，所述链状连接基团可以为C1‐C6烷基；
C部分R3可以选自－OR、－SR、－R或－NR1R2，R1和R2均可各自独立地选自R；或者当L不存在时，R3可以与A部分连接的C原子一起形成包含至少1个N原子的5～6元螺环；
其中R为H原子、羟基、C1‐C6烷基、氨基、氰基、C6‐C10芳香基或C6‐C10杂芳香基。
2.如权利要求1所述应用，其特征在于所述C6‐C10杂芳香基被卤素原子取代。
3.如权利要求1所述应用，其特征在于所述n为1。
4.如权利要求1所述应用，其特征在于所述L为(CH2)m，其中m为0～6的整数。
5.如权利要求1所述应用，其特征在于所述R1、R2和R3各自独立地选自H原子、羟基、C1‐C6烷基、氨基、氰基、C6‐C10芳香基或C6‐C10杂芳香基。
6.如权利要求5所述应用，其特征在于所述C6‐C10杂芳香基被卤素原子取代。
7.如权利要求1所述应用，其特征在于所述沙蚕毒素类化合物的盐在防止海洋生物污损中的应用。
8.如权利要求1或7所述应用，其特征在于所述沙蚕毒素类化合物或沙蚕毒素类化合物的盐选自下列的化合物：
其中R1、R2、R3和R4均各自独立选自H原子、羟基、C1‐C6烷基、氨基、氰基、C6‐C10芳香基或卤代C6‐C10芳香基。
9.如权利要求1或7所述应用，其特征在于所述沙蚕毒素类化合物或沙蚕毒素类化合物的盐选自下列的化合物：
其中R1、R2、R3和R4均各自独立选自H原子、羟基、C1‐C6烷基、氨基、氰基、C6‐C10芳香基或卤代C6‐C10芳香基。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5032231A (zh) * | 1973-07-21 | 1975-03-28 | ||
| JPS52125532A (en) * | 1976-04-14 | 1977-10-21 | Hokko Chem Ind Co Ltd | Antifouling underwater coating |
| JPS52152429A (en) * | 1976-06-14 | 1977-12-17 | Kitahara Haruo | Soilproof and insect control coating agent in water |
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- 2016-11-30 CN CN201611081252.7A patent/CN106749170B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5032231A (zh) * | 1973-07-21 | 1975-03-28 | ||
| JPS52125532A (en) * | 1976-04-14 | 1977-10-21 | Hokko Chem Ind Co Ltd | Antifouling underwater coating |
| JPS52152429A (en) * | 1976-06-14 | 1977-12-17 | Kitahara Haruo | Soilproof and insect control coating agent in water |
Non-Patent Citations (1)
| Title |
|---|
| 于观平 等: "沙蚕毒素类杀虫剂研究进展", 《农药学学报》 * |
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