嗜神经病毒衍生肽RVG29介导的靶向纳米载药胶束的合成及抗肿瘤活性

将羧基化的水溶性葡聚糖(Dex)与紫杉醇(PTX)化学偶联, 制得载药纳米胶束M(PTX), 再将M(PTX)与嗜神经性病毒衍生肽(RVG29)化学偶联, 得到RVG29靶向的载药纳米胶束M(RVG,PTX). 采用核磁共振氢谱(¹H NMR)测定了Dex-PTX及RVG-Dex-PTX键合物的分子量, 并对2种胶束进行了表征, 考察了2种胶束对肿瘤细胞的抑制效果及细胞凋亡情况, 观察了C₆细胞对荧光标记M(RVG,PTX)和M(PTX)的摄取情况. 结果表明, 羧基化葡聚糖-紫杉醇键合物的分子量约为16500, 紫杉醇的质量约为葡聚糖的20%, RVG29的质量约为葡聚糖的10%. 2种胶束的粒径在45~60 nm之间; M(RVG,PTX)胶束对C₆细胞的抑制作用具有浓度和时间依赖性, 细胞抑制率随着作用时间和药物浓度增加而增加, 且M(RVG,PTX)胶束对C₆细胞的抑制作用强于M(PTX)胶束. 细胞摄取实验结果表明, 与M(PTX)相比, C₆细胞摄取了更多的M(RVG,PTX)胶束. 如果先用游离的RVG29处理C₆细胞, 再进行细胞实验, 则M(RVG,PTX)胶束对C₆细胞生长的抑制作用及被C₆细胞摄取的比率显著降低, 与 M(PTX)相当. 表明靶向载药胶束M(RVG,PTX)中的RVG29保留了游离RVG29的活性, 对C₆细胞依然具有靶向效应, 从而介导了M(RVG,PTX)被C₆细胞的摄取, 增强了对C₆细胞的生长抑制作用. 由于M(RVG,PTX)胶束只使用水溶性葡聚糖作载体, 不涉及疏水高分子链段, 不需要分别制备载药高分子和靶向高分子然后再共组装, 因而制备过程比较简单, 同时具有载药和靶向功能.     

基于硝基苯类光扳机两亲性嵌段共聚物的合成及其光响应性质研究

以香草醛为原料,制备了连接十二烷基长链的硝基苯类光扳机S-(o-硝基-m-甲氧基-p-十二烷氧基苄醇)(VND),并通过酰胺化反应与PEG₁₀₀₀-NH₂生成具有光响应性的两亲性嵌段共聚物聚乙二醇-S-(o-硝基-m-甲氧基-p-十二烷氧基苄酯)(PEG-VND)。红外光谱(FT-IR)、核磁共振(¹HNMR)证明了合成的结构即为目标产物。PEG-VND可以在水中自组装成胶束,通过马尔文粒径仪和透射电镜(TEM)测定胶束的粒径。用紫外-可见光谱法(UV-Vis)研究胶束溶液随光照时间推移吸收光谱的变化。包载模型药物尼罗红后,检测PEG-VND对尼罗红的光控释放性质,结果表明:PEG-VND随光照时间的增加逐渐降解,尼罗红荧光发射强度逐渐减小,说明光照使得胶束解组装,释放模型药物。制备的快速光响应型控制释药聚合物胶束,具有潜在的生物医学应用的可能性。     

基于透明质酸的缺氧响应型胶束的制备及性能研究

以透明质酸（HA）及硝基咪唑（NI）衍生物为原料,通过酰胺反应合成了一种两亲性接枝聚合物（HA-NI）.该聚合物具有缺氧响应性和肿瘤靶向性.利用傅里叶红外光谱（FT-IR）和核磁共振（NMR）对接枝聚合物的结构进行了表征,同时基于¹H NMR计算出接枝聚合物中NI的取代度.HA-NI在水中自组装形成胶束,利用动态光散射仪（DLS）表征胶束大小并对胶束的稳定性进行了研究,利用原子力显微镜（AFM）和透射电镜（TEM）观察胶束形貌.载药胶束的载药率（DL）和包封率（EE）通过紫外-可见吸收光谱（UV）测试并计算得到.胶束的缺氧响应性利用DLS、AFM、TEM、UV等探究.实验证明,该聚合物胶束具有缺氧响应性并对药物表现出良好的控制释放能力,在常氧环境下,胶束稳定存在;而在缺氧环境下,胶束散开,药物快速且完全地释放.     

pH敏感型聚合物PEG-b-PHEMA(His)的合成及胶束性能研究

通过点击化学(Click chemistry)与原子转移自由基聚合(ATRP)一锅法合成AB型嵌段聚合物聚乙二醇嵌段聚甲基丙烯酸羟乙酯(PEG-b-PHEMA), 之后对所得聚合物进行组氨酸(His)修饰得到pH敏感型聚合物PEG-b-PHEMA(His), 运用核磁共振(¹H NMR)及凝胶渗透色谱(GPC)表征了该嵌段聚合物及组氨酸修饰后的产物的结构和分子量分布(M_n= 8.2×10³～13.0×10³ g/mol, PDI=1.27～1.51), 说明聚合物被成功地合成且具有较小的多分散系数. 之后对嵌段聚合物PEG-b-PHEMA(His)进行了动态光散射(DLS)、透射电镜(TEM)和临界胶束浓度(CMC)的测试, 结果表明, 聚合物胶束呈球形且粒径分布均匀, 并且粒径随组氨酸接枝率增大而减小. 最后我们做不同接枝比的PEG-b-PHEMA(His)的酸碱滴定曲线, 结果表明, 组氨酸的接入使聚合物具备明显的pH响应能力, 进一步的释药试验也证明了这一结果.     

ARGET ATRP 与ROP 结合制备pH 响应两亲性聚合物分子刷及其自组装研究

结合电子转移活化剂再生-原子转移自由基聚合(ARGET ATRP)和开环聚合(ROP)法合成了一种具有无规疏水/ pH 响应结构的两亲性聚合物分子刷聚(甲基丙烯酸聚丙交酯酯-co-甲基丙烯酸)-b-聚甲基丙烯酸单甲氧基聚乙二醇酯 [P(PLAMA-co-MAA)-b-PPEGMA]. 通过核磁共振氢谱(¹H NMR)和凝胶渗透色谱(GPC)表征了聚合物的结构、分子量及分子量分布. 优化了反应条件并合成出分子量可控、分子量分布窄的聚合产物. 采用动态光散射法(DLS)、扫描电子显微镜(SEM)研究了聚合物分子刷在水溶液中自组装胶束的粒径、形貌及pH 响应行为. P(PLAMA-co-MAA)-b-PPEGMA 自组装形成粒径分布均匀的球形胶束. 且随着溶液pH 值从7 降低至3, 胶束中的PMAA 逐渐去离子化, 溶胀的胶束逐渐收缩, 粒径由200～300 nm 减小至150 nm 左右; 但当pH 值减小到2 以下, 胶束表面电荷量非常小, 胶束聚集, 使得粒径增大.     

一种还原响应性紫杉醇胶束的制备与性能

首先,以甲氧基聚乙二醇(mPEG)为大分子引发剂,以辛酸亚锡为催化剂使D,L-丙交酯开环聚合,得到共聚物甲氧基聚乙二醇-聚乳酸(mPEG-PLA);然后,在该共聚物的末尾端进行羟基树枝化并接枝硫辛酸(LA),制备了可交联聚合物mPEG-PLA-(LA)4。采用核磁共振氢谱(1 H-NMR)和凝胶渗透色谱(GPC)对聚合物的结构和分子量进行了表征。进一步采用薄膜水化法制备了包载紫杉醇的交联共聚物胶束,并利用动态光散射(DLS)和透射电镜(TEM)对胶束结构进行了表征,采用动物实验评价了载药胶束的抑瘤效果。结果表明:胶束的平均粒径为34.0nm,结构规整。相比于未交联胶束,交联胶束具有更好的稳定性与还原响应性,抑瘤效果提高显著。     

两亲性树状接枝己内酯共聚物的合成与表征

通过树状接枝聚己内酯的侧羟基及端羟基与氯甲酰化的聚乙二醇进行接枝反应,得到带有亲水性聚乙二醇链段的新型两亲性树状接枝共聚物.1H-NMR分析显示,接枝率为50%左右.GPC分析结果表明,共聚物分子量呈较窄的单峰分布,分子量与接枝前相比明显增高.两亲性共聚物能直接分散在水中形成胶束溶液.以芘为荧光探针的测试结果表明其临界胶束浓度有降低.动态光散射测得胶束平均粒径在16至31 nm之间,粒径分散指数适中,PDI在0.25至0.39之间.TEM显示胶束粒子为不规整球形,由更小的粒径为几个纳米的微粒聚集而成,这些微粒的大小刚好与单个大分子的尺寸相匹配.因此,两亲性树状接枝聚己内酯在水相中存在单分子胶束与多分子组装胶束的平衡.得益于支化聚合物结构中的纳米空腔,两亲性树状接枝聚合物胶束对紫杉醇具有优良的包载能力.     

非甾体类药物含糖乙烯醇酯共聚物制备及药物释放研究

分别利用化学法和酶促法合成了三种药物(萘普生、酮洛芬、布洛芬)乙烯酯和葡萄糖丁二酸乙烯酯(6-O-乙烯丁二酰-D-葡萄糖)两种聚合单体, 通过两种单体的自由基聚合反应制备了具有较高分子量的含糖聚合物前药. 通过IR、NMR对聚合物的结构进行了表征, 用GPC测定共聚物分子量. 含糖聚合物前药的体外释放研究表明, 将小分子原药制备成含糖聚合物前药后, 药物的释放时间大大延长, 达到了缓释的目的. 三种含糖聚合物的药物释放研究表明, 酮洛芬含糖高分子前药的药物释放速率较快, 萘普生含糖高分子前药的药物释放速率较慢. 不同的pH条件下的含糖聚合物的药物释放研究表明, 碱性环境下的药物释放较快, 酸性环境下的药物释放较慢.     

酸敏感型嵌段共聚物mPEG-acetal-PIB的合成、表征及用于构筑水凝胶敷料

利用点击化学(“Click”)反应, 成功制备了一种通过酸敏感缩醛基团键合的两亲性嵌段共聚物, 聚乙二醇单甲醚-acetal-聚异丁烯(简写为mPEG-acetal-PIB). 通过核磁共振氢谱(¹H NMR)、红外光谱(FT-IR)和凝胶渗透色谱(GPC)对聚合物的结构、分子量及分子量分布进行表征. 利用芘荧光探针法、动态激光光散射(DLS)和透射电子显微镜(TEM), 研究共聚物在水溶液中组装的临界聚集浓度(CAC), 胶束的粒径大小、分布以及形貌. 利用DLS跟踪测试聚合物胶束在酸性条件下的粒径变化, 验证mPEG-acetal-PIB的酸敏感性质. 随后, 在体系中引入α-环糊精(α-CD), 诱导形成超分子水凝胶. 利用X射线衍射(XRD)分析PEG与α-CD的包结络合作用, 流变仪测试水凝胶的凝胶化时间和黏弹性. 通过体外细胞毒性试验(MTT法)证明嵌段共聚物mPEG-acetal-PIB及水凝胶均具有良好的生物相容性. 这种水凝胶能够保持创面湿润, 具有温和的冷却作用, 并且由于其带有酸敏感基团, 能够在偏酸性环境降解, 减少炎症发生率, 在水凝胶创伤敷料中具有潜在的应用.     

PCL-g-PEI聚合物载药胶束的制备及其性能研究

以苯甲醇(Bn OH)为引发剂,异辛酸亚锡[Sn(Oct)2]为催化剂,开环聚合制得不同臂长的聚己内酯(PCL)聚合物,并接枝不同分子量聚乙烯亚胺(PEI)得到一系列两亲性聚合物PCL-g-PEI,对该聚合物结构进行核磁、红外表征。采用染料增溶法检测该聚合物形成胶束的临界胶束浓度(CMC),并以该胶束作为药物载体用于共包载葫芦素B(Cuc B)和阿霉素(Dox)两种药物,考察其载药效果及体外释药性能。结果表明,该系列聚合物具有较小的CMC值,且该CMC值随着疏水端PCL的增长而减小;载药胶束对Cuc B、Dox具有较高的包封率和载药量,体外释放行为表明,PCL-g-PEI载药胶束具有良好的缓释性能,有望成为抗癌中药(Cuc B)与化疗药物(Dox)联合用药的新型药物载体。     

二氧化碳和丙烯直接合成甲基丙烯酸的NiPMo/TiO2催化剂的研究

用溶胶-凝胶法以磷钼酸(MPA)的镍盐溶液水解钛酸四丁酯制备了NiPMo/TiO2催化剂.使用ICP、 XRD、 TG-DTA、 IR、 TPD-MS和微反应技术研究了催化剂的化学组成、热稳定性、化学吸附性质和催化反应性能.杂多钼酸盐与TiO2通过O2-在TiO2表面发生了键合.在623 K下,杂多阴离子仍保持原有的Keggin结构.CO2在Lewis酸位Ni(Ⅱ)和Lewis碱位Ni-O-Mo的桥氧协同作用下生成CO2卧式吸附态Ni(Ⅱ)←O-(CO)←(O--Ni).丙烯有多种吸附态在催化剂上吸附.在563 K、 1 MPa和空速1500 h-1的反应条件下,丙烯的摩尔转化率为3.2%,产物MAA选择性为95%.     

CoFe2O4自形成磁性液体场致结构化对磁化的影响

The Langevin paramagnetic theory can’t describe the relation between magnetization of ferrofluids and applied magnetic field. The structuralization of ferrofluids, which is considered the main influence factor of the magnetization, is regarded. The part of magnetization works is deposited when the structure is forming. This action influences the magnetization of ferrofluids directly or indirectly. On the base of the “compressing” model, the Langevin function that usually describes the magnetization of ferrofluid is modified, and a well-fitted curve is obtained. An equation of the relation between the equivalent volume fraction after being “compressed” and the intensity of magnetic field is discovered, which approximately describes the process of magnetization. The relation between the approximate initial susceptibility and the volume fraction can be obtained from modified formula.     

Highly regioselective Buchwald–Hartwig amination at C-2 of 2,4-dichloropyridine enabling a novel approach to 2,4-bisanilinopyridine (BAPyd) libraries

The highly regioselective Buchwald–Hartwig amination at C-2 of the cheap and readily accessible reagent, 2,4-dichloropyridine with a range of anilines and heterocyclic amines is described. This new methodology is robust and provides a facile access to 4-chloro-N-phenylpyridin-2-amines on 0.25 mol scale. These intermediates undergo a further Buchwald–Hartwig amination at higher temperature to enable rapid exploration of the chemical space at C-4 and to provide a library of 2,4-bisaminopyridines.     

Sulfur-directed metal-free and regiospecific methyl C(sp3)–H imidation of thioanisoles

Regiospecific and direct imidation of the methyl C(sp³)–H bond of thioanisoles is realized under mild and metal-free conditions with N-fluorobis(benzenesulfonyl)imide as an oxidant and nitrogen source. Proposed mechanism suggests that thionium ion intermediates and a Pummerer-type reaction are involved. The imidation has advantages such as high step-economy, excellent functionality tolerance, and regiospecificity, giving structurally diverse imidation products.     

Selective syntheses of 2H-1,3-oxazines and 1H-pyrrol-3(2H)-ones via temperature-dependent Rh(II)-carbenoid-mediated 2H-azirine-ring expansion

The Rh(II)-catalyzed reaction of 2-carbonyl-substituted 2H-azirines with ethyl 2-cyano-2-diazoacetate or 2-diazo-3,3,3-trifluoropropionate provides an easy access to 2H-1,3-oxazines and 1H-pyrrol-3(2H)-ones. These compounds can be selectively prepared from the same starting material using temperature as the only varied parameter. The 2-azabuta-1,3-diene intermediate, a common precursor for both heterocyclic products, isomerizes into 2H-1,3-oxazine under kinetic control, while 1H-pyrrol-3(2H)-one is the sole product of the reaction at elevated temperatures. According to DFT-calculations a one-atom oxazine ring contraction involving ring-opening to a 2-azabuta-1,3-diene intermediate, followed by a 1,5- and 1,2-prototropic shift leads to the consecutive formation of imidoylketene and azomethine ylide, which then further undergo cyclization to the pyrrole derivative.     

Copper catalyzed/mediated synthetic methodology for ebselen and related isoselenazolones

Scope of the copper catalyzed/mediated selenium-nitrogen coupling reaction has been studied for the synthesis of isoselenazolones. It is noticed that the 2-chloro, 2-bromo-, and 2-iodo-aryl amides substrates can be exploited in the selenium-nitrogen coupling reaction by employing 25-100 mol % of CuI/1,10-phenanthroline (L) and potassium carbonate as a base in DMF. Furthermore, electron rich 2-chloro-arylamides also underwent selenium-nitrogen coupling reaction to give biologically important selenium-nitrogen heterocycles. Also, copper-catalyzed selenium-nitrogen coupling reaction has been meticulously applied for the synthesis of diaryl diselenides having methoxy, amine, and amide functionality from respective aryl iodides in the presence of stoichiometric amount of succinimide as an external Se-N coupling partner.     

Knoevenagel condensation catalyzed by novel Nmm-based ionic liquids in water

A series of novel N-methyl morpholine (Nmm) based ionic liquids with 1,2-propanediol group were synthesized and used as catalysts for Knoevenagel condensation at room temperature in water. Under the effect of the catalyst, various aldehydes or aliphatic ketones could react with a wide range of activated methylene compounds well, including malononitrile, alkyl cyanoacetate, cyanoacetamide, β-diketone, barbituric acid, 2-arylacetonitrile and thiazolidinedione. Furthermore, most of the products could be separated just by filtrating and washing with water. Additionally, the catalyst is recyclable and applicable for the large-scale synthesis.     

Construction of polyheterocyclic spirotetrahydrothiophene derivatives via sulfa-Michael/aldol cascade reaction

A series of polyheterocyclic spirotetrahydrothiophene derivatives were obtained in moderate to excellent yields via a catalyst-free sulfa-Michael/aldol cascade reaction of chalcones 1 and commercially available 1,4-dithiane-2,5-diol 2 under mild conditions. We also present the first asymmetric sulfa-Michael/aldol cascade reaction of chalcones 1 and commercially available 1,4-dithiane-2,5-diol 2 with moderate to good enantioselectivities catalyzed by readily available chiral phase-transfer catalysts (PTCs).     

Suzuki-Miyaura reactions of the soluble guanylate cyclase inhibitor NS2028: a non-product specific route to C-8 substituted analogues

Both soluble guanylate cyclase (sGC) inhibitors ODQ 1 and NS2028 2 are synthesized via improved protocols. In the former case treating 3,4-dihydroquinoxalin-2(1H)-one oxime 8, which can be prepared in two steps from 1,2-benzenediamine, with 1,1′-carbonyldiimidazole (CDI) gives the dihydro-ODQ 10 that in the presence of KMnO₄ oxidises to give ODQ 1 in an overall yield of 46% starting from 1,2-benzenediamine. In the latter case, the synthesis affords NS2028 2 from 2-amino-4-bromophenol 3 in three steps with an overall yield of 85% and avoids the need for chromatography. Furthermore, Suzuki-Miyaura reaction conditions are described that enable the preparation of 8-aryl and 8-heteroaryl derivatives of NS2028 directly from NS2028 2. Finally, demethylation of the 8-(methoxyphenyl) substituted analogues afforded the 8-(hydroxyphenyl) derivatives 40-42. All new products are fully characterised.