CN107652190B - 一种非对称寡聚苯乙炔的制备方法及其抗菌应用 - Google Patents
一种非对称寡聚苯乙炔的制备方法及其抗菌应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
Description
技术领域
本发明属于寡聚苯乙炔类化合物制备技术领域,具体涉及一种非对称寡聚苯乙炔的制备方法及其抗菌应用。
背景技术
寡聚苯乙炔类化合物(英文简称“OPE”)是一类具有苯环和乙炔三键交替的高共轭程度的寡聚化合物,通常具有三个或以上的苯环和乙炔共轭结构。由于其共轭程度较高,光学性能独特,引起包括生物传感器、导电分子、光动力抗菌等多领域学者的研究兴趣。美国新墨西哥大学Whitten教授课题组合成了一系列对称和非对称的OPE分子,并深入研究了OPE分子与生物大分子的相互作用,特别是带正电的OPE与羧甲基纤维素、羧甲基淀粉、DNA的相互作用。研究表明,带正电的OPE与上述分子均有较强的相互作用,能与上述分子形成超分子自组装复合物,其典型表现为吸收光谱发生明显的红移,荧光光谱发生显著增强,是典型的J-aggregate的光谱表现(Tang,Zhou,et al.J.Photochem.Photobiol.A:Chemistry,2009,207,4-6;Tang,Zhou,et al.Langmuir,2009,25(1),21-25;Tang,Zhou,etal.,Langmuir,2011,27,4945-4955)。
OPE与DNA也能发生超分子自组装行为,通过对OPE与不同序列的DNA自组装的研究,发现该自组装与DNA序列有明显的相关性,即使相差一个碱基的两个序列,自组装现象也各不相同。利用该现象,Whitten组发展了基于OPE的DNA错配检测方法。该方法对于基因检测、DNA突变等具有潜在应用价值(Tang,Achyuthan,et al.,Langmuir,2010,26(9),6832-6837)。
OPE光物理研究表明中间苯环被支链修饰的OPE(M-OPE)具有两个吸收峰,而末端支链修饰的OPE(EO-OPE)则只具有一个吸收峰,这种差异很可能源于M-OPE具有两个不同的LUMO分子轨道,而EO-OPE则只有一个LUMO分子轨道,而计算结果也很好地支持该推测。OPE的三线态研究表明,大多数OPE均具有较高的三线态产率,从而在有氧气存在的情况下,OPE较容易被激发产生单线态氧和其他氢氧自由基。由于单线态氧和其他活性氧自由基具有很强的氧化性,能够氧化细胞的不饱和脂、蛋白质和DNA,因此,对细胞产生致命的伤害(Zhou,Corbitt,et al.,J.Phy.Chem.Lett.,2010,1,3207-3212;Tang,Corbitt,et al.,Langmuir,2011,27(8),4956-4962)。
Whitten组和佛罗里达大学的Schanze组通过对OPE以及其高分子CPE研究表明,无论是高分子还是寡聚物,紫外光照条件下均能对革兰氏阳性菌和革兰氏阴性菌产生细胞毒性。相比之下,OPE毒性更大。研究也发现,EO-OPE比M-OPE水溶性虽然差一些,但是细胞毒性却更强。另外,所有OPE对革兰氏阳性菌毒性大至少一个数量级。进一步的暗毒性机理研究发现,EO-OPE分子对细胞的形态破坏很大,而M-OPE在相应浓度条件下则并未造成细胞的破损,相应细胞暗毒性较低。最近,周志军等人发现,中性OPE分子表现出远超正电OPE的细胞毒性,甚至可见光照条件下就能产生直接的细胞毒性。机理研究认为,中性OPE具有更好的细胞内化能力,因此,单线态氧等活性氧自由基可以更为直接造成细胞毒性。而细胞的内化能力与OPE的电性关系密切,较多的静电荷虽然提高了其溶解性,却降低了细胞内化能力,因而,大大降低其细胞毒性能力(Wang,Zhou,et al.,Polymers,2011,3,1199-1214;Zhou,Corbitt,et al.,J.Phy.Chem.Lett.,2010,1,3207-3212;Tang,Corbitt,et al.,Langmuir,2011,27(8),4956-4962;Wang,Tang,et al.,Langmuir,2010,26(15),12509-12514;Dimitri,Ji,et al.,Langmuir,2012,28(31),11286-11290)。
发明内容
本发明所要解决的一个技术问题是提供一种非对称寡聚苯乙炔,本发明所要解决的另一个技术问题是提供一种非对称寡聚苯乙炔的制备方法,本发明要解决的再一个技术问题是提供一种非对称寡聚苯乙炔的抗菌应用。
本发明的非对称寡聚苯乙炔,其特点是:所述的非对称寡聚苯乙炔为具有苯环和乙炔交替构成π键共轭体系;非对称寡聚苯乙炔的分子两端的一端为叔胺或季铵,另一端为伯胺;非对称寡聚苯乙炔化学结构式如下:
本发明的非对称寡聚苯乙炔的制备方法,包括以下反应式:
还包括以下合成步骤:
a.化合物B的合成:称取化合物A加入到四氢呋喃中,冰水浴冷却,依次加入催化剂和有机碱,氩气鼓泡5分钟,氩气保护下加入三甲基硅基乙炔,自然升温反应,过夜,停止反应。过滤,用二氯甲烷淋洗固体,滤液真空旋蒸除去溶剂,将残余物过硅胶柱,得到B;
b.化合物C的合成:将B溶于二氯甲烷和甲醇的混合溶液中,加入碳酸钾,室温搅拌反应6小时,真空旋蒸除去溶剂,加入水溶解固体,二氯甲烷萃取三次,合并有机相,无水硫酸钠干燥,过滤除去无水硫酸钠,滤液真空旋蒸除去溶剂,将残余物过硅胶柱,得白色固体C;
c.化合物F的合成:分别称取化合物D,化合物C,催化剂,加入四氢呋喃,使用氩气鼓泡3分钟,然后在氩气保护下加入有机碱,室温搅拌反应12h,然后加入化合物E,接着反应12h。反应液浓缩,直接使用快速硅胶柱色谱分离,得到F;
d.化合物OPE-1的合成:称取化合物F,加入酸,室温搅拌过夜。真空旋蒸除去溶剂,加入二氯甲烷溶解,使用1摩尔/升的氢氧化钠溶液洗涤两次,饱和食盐水洗涤两次,分液,有机相二氯甲烷用无水硫酸钠干燥,过滤除去无水硫酸钠,旋干得到化合物OPE-1;
e.化合物OPE-2的合成:将OPE-1溶于二氯甲烷,加入碘甲烷,室温搅拌反应5分钟,真空旋蒸除去溶剂,过滤,二氯甲烷洗涤,得白色固体OPE-2。
所述的步骤a和步骤c中的有机碱为三乙胺、二乙胺、二异丙基胺、三甲胺或吡啶中的一种;所述的步骤a和步骤c中的催化剂为二(三苯基膦)二氯化钯/碘化亚铜或四-(三苯基膦)钯/碘化亚铜中的一种。
所述的步骤d中的酸为盐酸、三氟乙酸或甲酸中的一种。
本发明的非对称寡聚苯乙炔的抗菌应用,所述的抗菌应用包括以下步骤:将非对称寡聚苯乙炔中的任一种与细菌在溶液中混合,再施加2小时光照,非对称寡聚苯乙炔产生细菌毒性。
所述的微生物为金黄色葡萄球菌、大肠杆菌中的一种。
本发明的非对称寡聚苯乙炔OPE-1具有中性的电荷特性,具有良好的疏水性,容易插入到细胞膜内,从而光照时产生细菌毒性或作为药物传递载体靶向细胞内部成分。该分子具有非对称结构,末端氨基容易与其他功能基团链接,易于通过修饰末端形成靶向药物,纳米药物,新药传递体系,新型生物传感器,荧光显像剂等,而叔胺部分则可通过甲基化形成水溶性更好季铵盐类抗菌剂,因而可拓展性好;该中性化合物相比目前普遍使用的季铵抗菌药物抗菌效果更好。该光动力杀菌过程采用可见光源,其应用范围更广。
本发明的非对称寡聚苯乙炔OPE-2则具有正电荷的结构,具有良好的亲水性,而末端非对称氨基结构赋予OPE-2具有很好的结构延展性,与羧基链接后可形成靶向药物,纳米药物,新药传递体系,新型生物传感器,荧光显像剂等。
本发明的非对称寡聚苯乙炔的制备方法原材料易得,采用“一锅煮”方法合成非对称寡聚苯乙炔,缩短了实验步骤,提高了合成效率。
具体实施方式
下面通过结合实施例详细说明本发明。
值得指出的是实施例仅为对本发明进一步进行说明,不能简单地理解为对本发明的保护范围的限制,该领域的技术熟练人员可根据本发明内容作出非本质改进和调整。
实施例1
本实施例的具体工作步骤如下:
1.制备非对称寡聚苯乙炔OPE-1和OPE-2
a.化合物B的制备
依次称取化合物A(0.34克,0.94毫摩尔),二氯二(三苯基膦)钯(0.0772克,0.11毫摩尔),碘化亚铜(0.0418克,0.22毫摩尔),加入28毫升四氢呋喃,冰水浴冷却下滴加二异丙胺(1.29克,12.8毫摩尔),氩气鼓泡5分钟,氩气保护下加入三甲基硅基乙炔(0.5402克,5.50毫摩尔),自然升温反应,过夜,停止反应。过滤,用二氯甲烷淋洗固体,滤液真空旋蒸除去溶剂,将残余物过硅胶柱,得到B,收率96%。
b.化合物C的制备
将化合物B(333毫克,1毫摩尔)溶于15毫升二氯甲烷和15毫升甲醇的混合溶液中,加入碳酸钾(207毫克,1.5毫摩尔),室温搅拌反应6小时,真空旋蒸除去溶剂,加入水溶解固体,二氯甲烷萃取三次,合并有机相,无水硫酸钠干燥,静置,过夜,过滤,滤液真空旋蒸除去溶剂,得白色固体C,收率97%。
c.化合物F的制备
分别称取化合物D(0.1913g,0.58mmol),化合物C(0.2273g,0.87mmol),二(三苯基膦)二氯化钯(0.0204g,0.029mmol),碘化亚铜(0.0110g,0.058mmol),加入6mL四氢呋喃,使用氩气鼓泡3分钟,然后在氩气保护下加入二异丙胺(0.2929g,2.9mmol),室温搅拌反应12h,然后加入化合物E(0.1158g,0.58mmol),接着反应12h。反应液浓缩,直接使用快速硅胶柱色谱分离,得到化合物F,收率43%。
d.化合物OPE-1的制备
称取化合物F(0.0784g,0.146mmol),加入1毫升甲酸,室温搅拌过夜。真空旋蒸除去溶剂,加入二氯甲烷溶解,使用1摩尔/升的氢氧化钠溶液洗涤两次,饱和食盐水洗涤两次,分液,有机相二氯甲烷用无水硫酸钠干燥,过滤除去无水硫酸钠,旋干得到化合物OPE-1,收率79%。1H NMR(400MHz,DMSO)δ1.77(m,2H),2.21(s,6H),2.28(t,2H);3.28(t,2H),3.89(t,2H),4.01(m,2H),6.82-6.95(m,4H),7.38-7.45(m,4H),7.49-7.52(m,4H);13C NMR(101MHz,DMSO)δ28.2,40.8,48.2,57.3,70.9,74.2,88.7,116.1,122.8,134.5,159.7。
e.化合物OPE-2的制备
将OPE-1(0.0251g,0.0572mmol)溶于二氯甲烷,加入碘甲烷(0.0406g,0.286mmol),室温搅拌反应5分钟,真空旋蒸除去溶剂,过滤,二氯甲烷洗涤,得白色固体OPE-2,收率89%。1H NMR(400MHz,DMSO)δ2.22(m,2H),3.28(t,2H),3.34(s,9H);4.05(t,2H),4.33(t,2H),6.78-6.96(m,4H),7.35-7.48(m,4H),7.51-7.58(m,4H);13C NMR(101MHz,DMSO)δ25.4,40.9,52.3,57.3,66.2,69.7,91.1,117.1,122.5,134.3,161.3。
实施例2
1.制备非对称寡聚苯乙炔OPE-1
a.化合物B的制备
依次称取化合物A(0.27克,0.75毫摩尔),二氯二(三苯基膦)钯(0.0618克,0.088毫摩尔),碘化亚铜(0.0334克,0.18毫摩尔),加入20毫升四氢呋喃,冰水浴冷却下滴加三乙胺(1.03克,10.2毫摩尔),氩气鼓泡5分钟,氩气保护下加入三甲基硅基乙炔(0.43克,4.4毫摩尔),自然升温反应,过夜,停止反应。过滤,用二氯甲烷淋洗固体,滤液真空旋蒸除去溶剂,将残余物过硅胶柱,得到B,收率71%。
b.化合物C的制备
将化合物B(333毫克,1毫摩尔)溶于10毫升四氢呋喃中,加入四丁基氟化铵(523毫克,2毫摩尔),室温搅拌反应1小时,真空旋蒸除去溶剂,加入水溶解固体,二氯甲烷萃取三次,合并有机相,无水硫酸钠干燥,静置,过夜,过滤,滤液真空旋蒸除去溶剂,用快速硅胶柱色谱分离,得白色固体C,收率82%。
c.化合物F的制备
分别称取化合物D(0.1913g,0.58mmol),化合物C(0.2273g,0.87mmol),二(三苯基膦)二氯化钯(0.0204g,0.029mmol),碘化亚铜(0.0110g,0.058mmol),加入6mL四氢呋喃,使用氩气鼓泡3分钟,然后在氩气保护下加入三乙胺(0.2929g,2.9mmol),室温搅拌反应12h,然后加入化合物E(0.1158g,0.58mmol),接着反应12h。反应液浓缩,直接使用快速硅胶柱色谱分离,得到化合物F,收率31%。
d.化合物OPE-1的制备
称取化合物F(0.0784g,0.146mmol),加入1毫升三氟乙酸,室温搅拌过夜。真空旋蒸除去溶剂,加入二氯甲烷溶解,使用1摩尔/升的氢氧化钠溶液洗涤两次,饱和食盐水洗涤两次,分液,有机相二氯甲烷用无水硫酸钠干燥,过滤除去无水硫酸钠,旋干得到化合物OPE-1,收率54%。
实施例3
非对称寡聚苯乙炔的抗菌应用
测试非对称寡聚苯乙炔OPE-1和OPE-2对大肠杆菌、金黄色葡萄球菌在光照和非光照条件下的毒性,考察化合物OPE-1和OPE-2的浓度,光照时间等因素对上述细菌毒性的影响。
(1)OPE-1对大肠杆菌的抗菌性
大肠杆菌(ATCC BAA-2452)在通用培养液里37度下培养18个小时,离心机离心菌液,并倒掉上清液,加入适量的0.9%消毒过的食盐水后,在振荡器中混合均匀,再次离心,倒掉上清液,同样的水洗过程进行三遍后,将细菌均匀悬浮在1毫升的0.9%消毒过的食盐水中,并将其OD600调至1.0备用,将1毫克非对称寡聚苯乙炔OPE-1溶解在1毫升DMSO中,取100微升稀释用0.9%食盐水稀释至1毫升备用,准备8个1.5毫升容量的灭菌后的离心管,编号为1,2,3,4,5,6,7,8,分别在上述离心管1,2中加入400微升0.9%食盐水(OPE-1终浓度为0),3,4中加入395微升0.9%食盐水及5微升稀释OPE-1溶液(OPE-1终浓度为1微克/毫升),5,6中加入385微升0.9%食盐水及15微升稀释OPE-1溶液(OPE-1终浓度为3微克/毫升),7,8中加入355微升0.9%食盐水及45微升稀释OPE-1溶液(OPE-1终浓度为9微克/毫升),震荡1分钟,得到均匀溶解的OPE-1溶液,再分别向上述离心管加入100微升OD600为1.0的菌液,并在振荡器上震荡1分钟,取离心管1,3,5,7保存至暗室中并同时计时,取离心管2,4,6,8置于可见光源(400-800纳米)下进行辐照,并同时计时,1小时后,取出1-8号样品,用0.9%食盐水稀释18万倍后,取100微升滴于固体培养基上,并用涂布器涂抹均匀后置于37度的保温箱中培养10-15小时,计算细菌斑数,通过与1,2号管的数量对比计算细菌的存活率。
测试结果:(a)非光照条件:通过与非光照条件的参照对比发现,在浓度1微克/毫升,3微克/毫升,9微克/毫升,无论1小时还是2小时的保存,均没有观察到细胞毒性,细菌存活率和相应参照保持一致;(b)可见光光照条件:OPE-1展现出与非光照条件截然不同的细菌毒性。光照1小时条件下,1微克/毫升和3微克/毫升的OPE-1没有观察到明显的细胞毒性,而9微克/毫升的OPE-1则能看到约56%的细菌存活率;当光照时间延长到2小时,1微克/毫升的OPE-1观察到细菌存活率为76%,而3微克/毫升的OPE-1则能看到21%的细菌存活率,而9微克/毫升的OPE-1细菌的存活率则为1%。
(2)OPE-1对金黄色葡萄球菌的抗菌性
金黄色葡萄球菌(ATCC BAA-2452)在通用培养液里37度下培养18个小时,离心机离心菌液,并倒掉上清液,加入适量的0.9%灭菌过的食盐水后,在振荡器中混合均匀,再次离心,倒掉上清液,同样的水洗过程进行三遍后,将细菌均匀悬浮在1毫升的0.9%灭菌过的食盐水中,并将其OD600调至1.0备用,将1毫克化合物OPE-1溶解在1毫升DMSO中,取10微升用0.9%食盐水稀释至1毫升备用,准备8个1.5毫升容量的灭菌后的离心管,编号为1,2,3,4,5,6,7,8。分别在上述离心管1,2中加入400微升0.9%食盐水(OPE-1终浓度为0),3,4中加入395微升0.9%食盐水及5微升稀释OPE-1溶液(OPE-1终浓度为0.1微克/毫升),5,6中加入385微升0.9%食盐水及15微升稀释OPE-1溶液(OPE-1终浓度为0.3微克/毫升),7,8中加入355微升0.9%食盐水及45微升稀释OPE-1溶液(OPE-1终浓度为0.9微克/毫升),震荡1分钟,得到均匀溶解的OPE-1溶液,再分别向上述离心管加入100微升OD600为1.0的菌液,并在振荡器上震荡1分钟,取离心管1,3,5,7保存至暗室中并同时计时,取离心管2,4,6,8置于可见光源(400-800纳米)下进行辐照,并同时计时。1小时后,取出1-8号样品,用0.9%食盐水稀释18万倍后,取100微升滴于固体培养基上,并用涂布器涂抹均匀后置于37度的保温箱中培养10-15小时,计算细菌斑数,通过与1,2号管的数量对比计算细菌的存活率。
测试结果:(a)非光照条件:化合物OPE-1在非光照条件下,通过与非光照条件的参照对比发现,在浓度0.1微克/毫升,0.3微克/毫升,0.9微克/毫升,无论1小时还是2小时的保存,均没有观察到细菌毒性,细菌存活率和相应参照保持一致;(b)可见光光照条件:在可见光光照条件下,OPE-1展现出与非光照条件截然不同的细菌毒性,光照1小时条件下,0.1微克/毫升、0.3微克/毫升和的OPE-1没有观察到明显的细胞毒性,而0.9微克/毫升的OPE-1则能看到约65%的细菌存活率;当光照时间延长到2小时时,0.1微克/毫升的OPE-1观察到细菌存活率为91%,而0.3微克/毫升的OPE-1则能看到35%的细菌存活率,而0.9微克/毫升的OPE-1细菌的存活率则为0%。
(3)OPE-2对大肠杆菌的抗菌性
大肠杆菌(ATCC BAA-2452)在通用培养液里37度下培养18个小时,离心机离心菌液,并倒掉上清液,加入适量的0.9%消毒过的食盐水后,在振荡器中混合均匀,再次离心,倒掉上清液,同样的水洗过程进行三遍后,将细菌均匀悬浮在1毫升的0.9%消毒过的食盐水中,并将其OD600调至1.0备用,将1毫克化合物OPE-2溶解在1毫升DMSO中,取100微升稀释用0.9%食盐水稀释至1毫升备用,准备8个1.5毫升容量的灭菌后的离心管,编号为1,2,3,4,5,6,7,8。分别在上述离心管1,2中加入400微升0.9%食盐水(OPE-2终浓度为0),3,4中加入395微升0.9%食盐水及5微升稀释OPE-2溶液(OPE-2终浓度为1微克/毫升),5,6中加入385微升0.9%食盐水及15微升稀释OPE-2溶液(OPE-2终浓度为3微克/毫升),7,8中加入355微升0.9%食盐水及45微升稀释OPE-2溶液(OPE-2终浓度为9微克/毫升),震荡1分钟,得到均匀溶解的OPE-2溶液,再分别向上述离心管加入100微升OD600为1.0的菌液,并在振荡器上震荡1分钟,取离心管1,3,5,7保存至暗室中并同时计时;取离心管2,4,6,8置于可见光源(400-800纳米)下进行辐照,并同时计时,1小时后,取出1-8号样品,用0.9%食盐水稀释18万倍后,取100微升滴于固体培养基上,并用涂布器涂抹均匀后置于37度的保温箱中培养10-15小时,计算细菌斑数,通过与1,2号管的数量对比计算细菌的存活率。
测试结果:(a)非光照条件:通过与非光照条件的参照对比发现,在浓度1微克/毫升,3微克/毫升,9微克/毫升,无论1小时还是2小时的保存,均没有观察到细胞毒性,细菌存活率和相应参照保持一致;(b)可见光光照条件:OPE-2展现出与非光照条件截然不同的细菌毒性,光照1小时条件下,1微克/毫升和3微克/毫升的OPE-2没有观察到明显的细胞毒性,而9微克/毫升的OPE-2则能看到约95%的细菌存活率;当光照时间延长到2小时,1微克/毫升的OPE-2观察到细菌存活率为91%,而3微克/毫升的OPE-2则能看到81%的细菌存活率,而9微克/毫升的OPE-2细菌的存活率则为68%。
(4)OPE-2对金黄色葡萄球菌的抗菌性
金黄色葡萄球菌(ATCC BAA-2452)在通用培养液里37度下培养18个小时,离心机离心菌液,并倒掉上清液,加入适量的0.9%灭菌过的食盐水后,在振荡器中混合均匀,再次离心,倒掉上清液,同样的水洗过程进行三遍后,将细菌均匀悬浮在1毫升的0.9%灭菌过的食盐水中,并将其OD600调至1.0备用,将1毫克化合物OPE-2溶解在1毫升DMSO中,取10微升用0.9%食盐水稀释至1毫升备用,准备8个1.5毫升容量的灭菌后的离心管,编号为1,2,3,4,5,6,7,8,分别在上述离心管1,2中加入400微升0.9%食盐水(OPE-2终浓度为0),3,4中加入395微升0.9%食盐水及5微升稀释OPE-2溶液(OPE-2终浓度为0.1微克/毫升),5,6中加入385微升0.9%食盐水及15微升稀释OPE-2溶液(OPE-2终浓度为0.3微克/毫升),7,8中加入355微升0.9%食盐水及45微升稀释OPE-2溶液(OPE-2终浓度为0.9微克/毫升),震荡1分钟,得到均匀溶解的OPE-2溶液。再分别向上述离心管加入100微升OD600为1.0的菌液,并在振荡器上震荡1分钟。取离心管1,3,5,7保存至暗室中并同时计时;取离心管2,4,6,8置于可见光源(400-800纳米)下进行辐照,并同时计时。1小时后,取出1-8号样品,用0.9%食盐水稀释18万倍后,取100微升滴于固体培养基上,并用涂布器涂抹均匀后置于37度的保温箱中培养10-15小时,计算细菌斑数,通过与1,2号管的数量对比计算细菌的存活率。
测试结果:(a)非光照条件:化合物OPE-2在非光照条件下,通过与非光照条件的参照对比发现,在浓度0.1微克/毫升,0.3微克/毫升,0.9微克/毫升,无论1小时还是2小时的保存,均没有观察到细菌毒性,细菌存活率和相应参照保持一致;(b)可见光光照条件:OPE-2展现出与非光照条件截然不同的细菌毒性。光照1小时条件下,0.1微克/毫升、0.3微克/毫升和的OPE-2没有观察到明显的细胞毒性,而0.9微克/毫升的OPE-2则能看到约91%的细菌存活率;当光照时间延长到2小时时,0.1微克/毫升的OPE-2观察到细菌存活率为96%,而0.3微克/毫升的OPE-2则能看到87%的细菌存活率,而0.9微克/毫升的OPE-2细菌的存活率则为64%。
Claims (2)
1.一种非对称寡聚苯乙炔的制备方法,其特征在于,所述的非对称寡聚苯乙炔的化学结构式为:
所述的制备方法中的反应式为:
所述的制备方法中的合成步骤如下:
a.化合物B的合成:称取化合物A加入到四氢呋喃中,冰水浴冷却,再依次加入催化剂和有机碱,通氩气5分钟,氩气保护下加入三甲基硅基乙炔,反应12小时,过滤,用二氯甲烷淋洗固体,滤液真空旋蒸除去溶剂,将残余物过硅胶柱,得到化合物B;
b.化合物C的合成:将B溶于二氯甲烷和甲醇的混合溶液中,加入碳酸钾,室温搅拌反应6小时,真空旋蒸除去溶剂,加入水溶解固体,二氯甲烷萃取三次,合并有机相,无水硫酸钠干燥,过滤除去无水硫酸钠,滤液真空旋蒸除去溶剂,将残余物过硅胶柱,得白色固体C;
c.化合物F的合成:分别称取化合物D,化合物C,催化剂,加入四氢呋喃,通氩气3分钟,然后在氩气保护下加入有机碱,室温搅拌反应12h,然后加入化合物E,接着反应12h;反应液浓缩,直接使用快速硅胶柱色谱分离,得到F;
d.化合物OPE-1的合成:称取化合物F,加入酸,室温搅拌过夜;真空旋蒸除去溶剂,加入二氯甲烷溶解,使用1摩尔/升的氢氧化钠溶液洗涤两次,饱和食盐水洗涤两次,分液,有机相二氯甲烷用无水硫酸钠干燥,过滤除去无水硫酸钠,旋干得到化合物OPE-1;
e.化合物OPE-2的合成:将OPE-1溶于二氯甲烷,加入碘甲烷,室温搅拌反应5分钟,真空旋蒸除去溶剂,过滤,二氯甲烷洗涤,得白色固体OPE-2;
其中,步骤a和步骤c中的有机碱均为三乙胺、二乙胺、二异丙基胺、三甲胺或吡啶中的一种;步骤a和步骤c中的催化剂均为二(三苯基膦)二氯化钯/碘化亚铜或四-(三苯基膦)钯/碘化亚铜中的一种。
2.根据权利要求1所述的制备方法,其特征在于:步骤d中的酸为盐酸、三氟乙酸或甲酸中的一种。
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