Name: amide coupling reaction for the synthesis of bispyridine-based ligands and their complexation to platinum as dinuclear anticancer agents
Uploaded: 2014-05-28T14:00:00.000+00:00
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Description: Watch this Scientific Journal Video about Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents at JoVE.com

1对N，N&#39;的合成1 - （烷-1，N-二基）diisonicotinamide <ol><li>干燥烘箱中（100℃，1小时）一个单颈或三颈圆底烧瓶中，以确保除去所有水分。 </li><li>添加固体异烟酸，或其衍生物，以连同磁力搅拌棒的烧瓶中。如果二氨基配体（S）的固体在室温下，然后0.5摩尔（以异烟酸的摩尔数）加入到烧瓶中，在这个阶段。 </li><li>帽用橡胶隔片烧瓶的颈部（次），要么通过连续的氮气流中或通过使用氮气填充的气球代替空气与氮气的烧瓶中。 </li><li>用皮下注射针和注射器添加无水二甲基甲酰胺或二甲亚砜（每500毫克异烟酸，2 - 甲基 - 异烟酸4毫升）以溶解固体。如果固体不容易溶解，然后轻轻加热溶液。 </li><li>新增7摩尔当量（以一安装三乙胺（弱碱）和二氨基烷烃0.5摩尔当量使用异烟酸）的。如果溶液是液体在室温下，再加入1.5摩尔当量。 </li><li>添加1 - 丙基膦酸酐（偶联剂）1摩尔当量在连续搅拌下，让反应完成超过5-12小时。 </li></ol>的配体的2。纯化<ol><li>对于双吡啶配体用二氨基配有10个以上亚甲基制成，等待产品从溶液中沉淀随着反应的进行。 </li><li>使用二氨基联吡啶配体的制造中，在约40毫升的水沉淀产物。 </li><li>使用五点五十八亚甲基基团的二氨基烷烃双吡啶制成，添加〜40毫升的水，并允许该化合物结晶过1-3天。 </li><li>通过真空过滤收集每个双吡啶配体及由约400-500毫升沸水重结晶，每200毫克配体。注:需要，因为它们大大减少水中的溶解度越长双吡啶配体更多的水。 </li><li>添加NaOH和KOH（pH为9）的溶液，以确保化合物是经重结晶游离碱。 </li></ol> 3，合成了双核铂配合物的纯化<ol><li>充分溶解反式 diamminodichloridoplatinum（II）中，transplatin，在热的（70-80℃）水（每200毫克transplatin 150毫升）中，以产生清晰的强黄色溶液。 </li><li>添加双吡啶配体的0.5摩尔当量和搅拌溶液在温度，直到配体溶解（透明溶液）。等待该溶液转接近无色，关火，并在室温下搅拌了几个额外小时。 </li><li>通过旋转蒸发除去溶剂，将得到黄色粉末。 </li><li>净化，铂络合物（ES）溶解在温水的最低金额（〜50＆＃186，C）。如果剩余的黄色或白色的固体都存在，然后过滤这些了。 </li><li>加丙酮至这似乎是金属配合物的聚合形式，并代表最多的反应产物的10％，直至白色沉淀物形成的溶液。继续加入丙酮（〜额外20-30毫升），直至没有更多的沉淀出现。注意:此白色沉淀物是杂质。 </li><li>通过尼龙滤纸（0.2微米孔径）和旋转剩余的溶液至干，将得到的纯品的蒸发过滤的内容中移除该沉淀物。注:如有必要，可直到复杂的是纯粹的进行再额外丙酮沉淀步骤。 </li></ol>

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在此工作的双核铂络合物合成了作为潜在的抗癌药物。这样做是通过使用异烟酸和可变长度的二氨基烷烃酰胺偶联反应合成的双吡啶桥连配体。先前的双吡啶配体和其甲基类似物具有2至8个亚甲基基团和它们各自的铂配合物的合成已有报道。在本文中，合成和纯化方法已修订，使其更快，更便宜，已经证明了这一点通过合成双吡啶配体与8，10和12的亚甲基（最短与八亚甲基，彪，被做了比较新的纯化方法的旧方法）。双核铂配合物利用这些配体也。 的双吡啶配位体的合成是使用三乙胺作为弱碱的无水溶剂和惰性氮气氛下完成，并丙基膦酸酐作为偶联剂。无论是DMF或DMSO中，可以用作溶剂，虽然异烟酸溶解在DMSO中比它在DMF中。对于任一溶剂，在热水的运行流温和加热可用于帮助溶解。 这个老方法需要较长的反应时间（天数）和一个多步骤纯化工艺，包括液/液萃取对二乙醚及中和用NaHCO 3，这是目前消除。该配体的合成反应正在完成的在室温下几小时后，所有的反应物加到一起在一个步骤。的双吡啶配体从溶液中沉淀通过加入水（对于配体具有8个或更少个亚甲基），并从在形成溶液为10和12亚甲基基团的配位体中沉淀出来。所有的配体可从沸腾的水，在某些情况下，它们缓慢recrystall重结晶化可以产生适于X射线衍射的晶体。 的双核铂配合物是由transplatin的2摩尔反应的双吡啶配体的1摩尔制成。该chlorido配体的反式labializing效果确保了主要产物是通过对双吡啶配体（该环的氮原子）单活性中心配位的铂类药物。该双核铂配合物具有良好的溶解性为二价阳离子盐在水，DMF和DMSO。 净化是通过分级沉淀，用丙酮实现。本产品之前，身份不明的杂质沉淀和过滤，通过细孔滤纸被删除。重要的是要注意，丙酮沉淀作品更好地与产品的待纯化增加量。在低于200毫克量，该方法不工作，以及和丙酮反复降水可能被要求。对于约200毫克或金额以上我们已经发现，一般只需要单一的丙酮沉淀步骤。 虽然本文详述的特定的配体和铂配合物的合成，此处所使用的技术可以应用到合成更广范围的配位体和多核铂配合物。例如，用合适的保护基团等二氨基配体，如精胺和亚精胺，可用于制造双吡啶配体。非对称双吡啶配体也可以通过使用异烟酸在一端制成并在其另一端-2 - 甲基 - 异烟酸。这些非对称配位体可通过对二氨基烷烃链的一端使用FMOC / BOC-保护的产生。链的无保护的胺可与具有使用所述的酰胺偶联反应一异烟酸衍生物。该保护基，然后从二氨基烷烃链裂解和异烟酸的不同衍生物是使用一个附加的其它酰胺偶联反应。三核铂配合物也可能被使用的吡唑基配位体，以使通过三核的方法的适应使用任何这些配体的制造，BBR3464状，复合物22。

铂抗癌药物残留的药物在人类癌症的治疗1最广泛使用的家庭中的一个。尽管取得了成功，它们在各自的应用程序有严重的剂量限制性副作用2-4限制。有限的剂量可给予患者也意味着肿瘤可产生耐药性5。因此，新的药物不断被开发以改善的副作用特性和克服获得性抗性，如phenanthriplatin 6和phosphaplatin 7。 20世纪90年代后期，三核铂类药物的开发，BBR3464（ 方案1）8，比领先的铂类药物，顺铂在体外高达1000倍以上的细胞毒性。 BBR3464也能够克服获得抗性的人类肿瘤细胞株9的面板。不幸的是，BBR3464的活性增加匹配由50 - 100 - 倍的毒性，这限制了它的使用10-12。它也易于降解在体内，这意味着该药物很少到达肿瘤细胞核完好9。 吡铂是一种单核铂为基础的药物，其中包含2 -甲基-吡啶配体（ 方案1）13。这种药物的甲基保护它免受攻击生物亲核试剂;特别是半胱氨酸和含有肽/蛋白质14-16蛋氨酸。因此，该药物是相当稳定的，并具有高得多的浓度与两个BBR3464，顺铂17相比到达癌的细胞核。它的反应性降低也意味着吡具有较高的最大耐受剂量与BBR3464，顺铂10,18,19比较。 因此，该项目旨在结合BBR3464和吡铂的属性，以产生新的药物，是能够克服的获得性耐药的显示改进的生物稳定性和不太严重的副作用EFFE仙（ 例如 ， 图1）。在这样做时，制备了双吡啶桥联配体20的范围内的双核铂络合物。的配位体使用的酰胺偶联反应，用异烟酸，或如2 - 甲基 - 异烟酸，可变长度的二氨基烷烃及其衍生物制成。的配位体的1摩尔当量与transplatin的2摩尔当量反应得到所需的铂络合物（ 方案1）。

<table><tbody><tr><td>D&lt;sub&gt;2&lt;/sub&gt;O</td><td>Aldrich</td><td>151882</td><td>99.9% D</td></tr><tr><td>DMSO-d&lt;sub&gt;6&lt;/sub&gt;</td><td>Aldrich</td><td>156914</td><td>99.96% D</td></tr><tr><td>1,8-diaminooctane</td><td>Aldrich</td><td>D22401</td><td>98%</td></tr><tr><td>1,10-diaminodecane</td><td>Aldrich</td><td>D14204</td><td>98%</td></tr><tr><td>1,12-diaminododecane</td><td>Aldrich</td><td>D1,640-1</td><td>98%</td></tr><tr><td>Isonicotinic acid</td><td>Aldrich</td><td>I17508</td><td>99%</td></tr><tr><td>1-Propylphosphonic anhydride solution</td><td>Aldrich</td><td>431303</td><td>50 wt% in ethyl acetate</td></tr><tr><td>Trans-diaminodichloridoplatinum(II)</td><td>Aldrich</td><td>P1525</td><td></td></tr><tr><td>Dimethylsulfoxide</td><td>Sigma-Aldrich</td><td>Z76855</td><td>&gt;99.9%, anhydrous</td></tr><tr><td>&lt;em&gt;N,N&amp;rsquo;&lt;/em&gt;-dimethylformamide</td><td>Sigma-Aldrich</td><td>227056</td><td>99.8%, anhydrous</td></tr><tr><td>Triethylamine</td><td>Sigma-Aldrich</td><td>T0886</td><td>&gt;99%</td></tr><tr><td>Nylon filter membranes</td><td>Whatman</td><td>7402-004</td><td>Pore size, 0.2 &amp;micro;m</td></tr><tr><td>Magnetic stirring hotplate</td><td></td><td></td><td></td></tr><tr><td>Magnetic stirring bar&amp;nbsp;</td><td></td><td></td><td></td></tr><tr><td>Round bottom or three neck flask</td><td></td><td></td><td></td></tr><tr><td>Rubber septums of sufficient size for chosen round bottom or three neck flask</td><td></td><td></td><td></td></tr><tr><td>5 ml hypodermic syringes</td><td></td><td></td><td></td></tr><tr><td>Hypodermic needles</td><td></td><td></td><td></td></tr><tr><td>Rubber party ballons</td><td></td><td></td><td></td></tr><tr><td>Rubber bands</td><td></td><td></td><td></td></tr><tr><td>A source of N&lt;sub&gt;2&lt;/sub&gt; gas</td><td></td><td></td><td></td></tr><tr><td>Rotary evaporator</td><td></td><td></td><td></td></tr><tr><td>Drying oven</td><td></td><td></td><td></td></tr><tr><td>NMR tubes</td><td></td><td></td><td></td></tr><tr><td>NMR spectrometer</td><td></td><td></td><td></td></tr><tr><td>500 ml beakers</td><td></td><td></td><td></td></tr><tr><td>Glass or plastic pipettes</td><td></td><td></td><td></td></tr></tbody></table>

amide coupling reaction for the synthesis of bispyridine-based ligands and their complexation to platinum as dinuclear anticancer agents

Amide coupling reactions can be used to synthesize bispyridine-based ligands for use as bridging linkers in multinuclear platinum anticancer drugs. Isonicotinic acid, or its derivatives, are coupled to variable length diaminoalkane chains under an inert atmosphere in anhydrous DMF or DMSO with the use of a weak base, triethylamine, and a coupling agent, 1-propylphosphonic anhydride. The products precipitate from solution upon formation or can be precipitated by the addition of water. If desired, the ligands can be further purified by recrystallization from hot water. Dinuclear platinum complex synthesis using the bispyridine ligands is done in hot water using transplatin. The most informative of the chemical characterization techniques to determine the structure and gross purity of both the bispyridine ligands and the final platinum complexes is 1H NMR with particular analysis of the aromatic region of the spectra (7-9 ppm). The platinum complexes have potential application as anticancer agents and the synthesis method can be modified to produce trinuclear and other multinuclear complexes with different hydrogen bonding functionality in the bridging ligand.

的双吡啶配体和它们各自的双核铂络合物的特征在于，用1 H，13 C和195的Pt NMR（ 表1和2），和电喷雾电离质谱法。准确的熔点可以使用差示扫描量热法和纯度最好是通过元素分析的C，H和N的百分含量测定来确定。最普遍使用的是1 H-NMR，因为它是快速和易于使用的，给人以共鸣，能够明确证明成功酰胺耦合和铂协调（ 表1和表2）最终产品的隔离分钟内的结果。 异烟酸有三个共振;在芳族区域的两个二重峰（7-9 ppm）的一个非常广泛的谐振约13 ppm的羧酸质子。的二氨基烷烃质子共振均位于脂肪族区域1和4 ppm的之间。为t他的二氨基烷烃链增长多亚甲基共振的长度成为相等的，因此，更少的峰中观察到的脂肪族区域比预期;虽然它们是显著更强烈，并且可以通过整合（ 表1和表2）松散地分配。例如参见图1和图2的化学结构和N，N&#39;的1 H NMR谱- （辛烷-1,8 -二基）双（异烟酰胺），标，配体。由于对称性的分子在5脂族共振通常会被预期为标;但四个内最亚甲基峰是所有磁等价的，并显示为一个大的共振〜1.2 ppm的。 非耦合二氨基烷烃链的胺的质子共振位于脂肪族区域，并且是​​最重要的共振，因为它移动显著前冲，进芳香区域，​​在耦合吨Ø羧酸。随后的酰胺质子共振被看见周围8.7 ppm的所有这些配体，作为一个比较宽三重共振（ 图2）。 铂族的双吡啶配体的协调是通过配体的芳族共振（0.15 ppm的低磁场的哈共振转移和0.07 ppm的高场血红蛋白共振转移），并在二重共振遵守铂耦合的用于选择性地转移观察哈质子（ 图3）。铂基团的双吡啶配体的协调也可以用195的Pt NMR容易观察到。铂共振的化学位移直接相关的协调21原子的类型。 Chlorido配体转移195铂共振前冲（朝0 PPM）和AM（M）鲍配体转移的共振高场（朝-2,500 ppm的）。这里合成的双核铂配合物表现出单R<html> esonance周围-2,300 ppm的由于3×上午（米）鲍和1×chlorido协调的状态（ 图4）22。未反应transplatin杂质会显示为一个共振周围-2,100 ppm的，而如果两个配体与单一transplatin分子（4×分（M）伊诺环境）反应，那么这种杂质会是-2,400 ppm的22高场。 <img alt="Sheme 1" width="400" src="/files/ftp_upload/51740/51740scheme1highres.jpg" /> 方案1的铂类药物吡铂和BBR3464和用于双吡啶配体和它们各自的双核铂络合物的合成的一般合成方案的化学结构; R = H或CH 3; N = 1-6反离子的铂配合物已经被省略;通过使用这里描述的方法，它们是二氯化盐。 tp_upload/51740/51740fig1highres.jpg"/&gt; 图1中的N，N&#39;的化学结构- （辛烷-1,8 -二基）双（异烟酰胺）配体，标，并用于在1 H-NMR的共振分配质子编号方案 ，请注意等价四亚甲基质子（赫）在该分子的中心。 <img alt="图2" src="/files/ftp_upload/51740/51740fig2highres.jpg" /> 图2中的1 H-NMR（DMSO-D 6，400兆赫）的N，N&#39;谱- （辛烷-1,8 -二基）双（异烟酰胺），标注三重酰胺共振的位置在大约8.7。 ppm时，从1-2 ppm的耦合前二氨基胺共鸣。 图3:1 H-NMR（D 2 O，400兆赫）反式频谱[{铂（NH 3）2氯} 2μ标] 2 +。注意铂耦合的芳香哈共振8.82 ppm的。 <img alt="图4" src="/files/ftp_upload/51740/51740fig4highres.jpg" /> 图4，195铂核磁共振（D 2 O，400兆赫）的频谱反式- [{铂（NH 3）2氯}2μ标] 2 +注单宽共振周围-2,300 ppm的附带PTN 3氯环境相一致; N =时（m）我的。 <img alt="表1" fo:content-width="6in" src="/files/ftp_upload/51740/51740table1.jpg" width="600" /> 表1在400兆赫峰d =双峰的双吡啶配体在DMSO-D 6中的1 H NMR的特征数据; t =三重峰; q =四重; m =多重峰。 <img alt="表2" fo:content-width="6in" src="/files/ftp_upload/51740/51740table2.jpg" width="600" /> 表2的双核铂络合物在D 2的1 H NMR的特征数据&lt;/ STRONG&gt; 0，在400 MHz的 D =双峰; t =三重峰; q =四重; m =多重峰。

Watch this Scientific Journal Video about Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents at JoVE.com

Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents

这个协议描述了使用异烟酸和二氨基​​烷烃的酰胺偶联反应，以形成适合于在多核铂配合物，其中结合的抗癌药物BBR3464和吡铂方面的合成中使用的桥接配体。

酰胺偶联反应为双吡啶基配体及其络合合成，以白金为双核抗癌药物

Amide coupling reactions can be used to synthesize bispyridine-based ligands for use as bridging linkers in multinuclear platinum anticancer drugs. ...

amide-coupling-reaction-for-synthesis-bispyridine-based-ligands-their

Nanyang Technological University

Research

JoVE Journal

Chemistry

13.9K 次观看.  The University of Sydney. 这个协议描述了使用异烟酸和二氨基​​烷烃的酰胺偶联反应，以形成适合于在多核铂配合物，其中结合的抗癌药物BBR3464和吡铂方面的合成中使用的桥接配体。 

视频: Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents

Anticancer Metal Complexes: Synthesis and Cytotoxicity Evaluation by the MTT Assay

Titanium (IV) and vanadium (V) complexes are highly potent anticancer agents. A challenge in their synthesis refers to their hydrolytic instability; therefore their preparation should be conducted under an inert atmosphere. Evaluation of the anticancer activity of these complexes can be achieved by the MTT assay.
The MTT assay is a colorimetric viability assay based on enzymatic reduction of the MTT molecule to formazan when it is exposed to viable cells. The outcome of the reduction is a color change of the MTT molecule. Absorbance measurements relative to a control determine the percentage of remaining viable cancer cells following their treatment with varying concentrations of a tested compound, which is translated to the compound anticancer activity and its IC50 values. The MTT assay is widely common in cytotoxicity studies due to its accuracy, rapidity, and relative simplicity.
Herein we present a detailed protocol for the synthesis of air sensitive metal based drugs and cell viability measurements, including preparation of the cell plates, incubation of the compounds with the cells, viability measurements using the MTT assay, and determination of IC50 values.

A method for synthesis of air-sensitive titanium and vanadium anticancer agents is described, along with the evaluation of their cytotoxic activity towards human cancer cell line by the MTT Assay.

抗癌金属配合物的合成与细胞毒性评价MTT法

Titanium (IV) and vanadium (V) complexes are highly potent anticancer agents. A challenge in their synthesis refers to their hydrolytic instability; ...

科研

化学

Mizoroki-Heck Cross-coupling Reactions Catalyzed by Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium Under Mild Reaction Conditions

Dichloro-bis(aminophosphine) complexes of palladium with the general formula of [(P{(NC5H10)3-n(C6H11)n})2Pd(Cl)2] (where n = 0-2), belong to a new family of easy accessible, very cheap, and air stable, but highly active and universally applicable C-C cross-coupling catalysts with an excellent functional group tolerance. Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium [(P(NC5H10)3)2Pd(Cl)2] (1), the least stable complex within this series towards protons; e.g. in the form of water, allows an eased nanoparticle formation and hence, proved to be the most active Heck catalyst within this series at 100 &#176;C and is a very rare example of an effective and versatile catalyst system that efficiently operates under mild reaction conditions. Rapid and complete catalyst degradation under work-up conditions into phosphonates, piperidinium salts and other, palladium-containing decomposition products assure an easy separation of the coupling products from catalyst and ligands. The facile, cheap, and rapid synthesis of 1,1',1"-(phosphinetriyl)tripiperidine and 1 respectively, the simple and convenient use as well as its excellent catalytic performance in the Heck reaction at 100 &#176;C make 1 to one of the most attractive and greenest Heck catalysts available.
We provide here the visualized protocols for the ligand and catalyst syntheses as well as the reaction protocol for Heck reactions performed at 10 mmol scale at 100 &#176;C and show that this catalyst is suitable for its use in organic syntheses.

Mizoroki-Heck Cross-coupling Reactions Catalyzed by Dichloro{bis[1,1',1''-phosphinetriyltripiperidine]}palladium Under Mild Reaction Conditions

Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium [(P(NC5H10)3)2Pd(Cl)2] (1) is an easy accessible, cheap, and air stable, but highly active Heck catalyst with an excellent functional group tolerance that efficiently operates under mild reaction conditions to give the coupling products in very high yields.

Mizoroki-哎呀交叉偶联反应由二氯{双[1,1&#39;，1&#39;&#39;  - （phosphinetriyl）tripiperidine]}钯催化在温和的反应条件

Dichloro-bis(aminophosphine) complexes of palladium with the general formula of [(P{(NC5H10)3-n(C6H11)n})2Pd(Cl)2] (where n = 0-2), belong to a new family ...

The Synthesis, Characterization and Reactivity of a Series of Ruthenium N-triphosPh Complexes

Herein we report the synthesis of a tridentate phosphine ligand N(CH2PPh2)3 (N-triphosPh) (1) via a phosphorus based Mannich reaction of the hydroxylmethylene phosphine precursor with ammonia in methanol under a nitrogen atmosphere. The N-triphosPh ligand precipitates from the solution after approximately 1 hr of reflux and can be isolated analytically pure via simple cannula filtration procedure under nitrogen. Reaction of the N-triphosPh ligand with [Ru3(CO)12] under reflux affords a deep red solution that show evolution of CO gas on ligand complexation. Orange crystals of the complex [Ru(CO)2{N(CH2PPh2)3}-&#954;3P] (2) were isolated on cooling to RT. The 31P{1H} NMR spectrum showed a characteristic single peak at lower frequency compared to the free ligand. Reaction of a toluene solution of complex 2 with oxygen resulted in the instantaneous precipitation of the carbonate complex [Ru(CO3)(CO){N(CH2PPh2)3}-&#954;3P] (3) as an air stable orange solid. Subsequent hydrogenation of 3 under 15 bar of hydrogen in a high-pressure reactor gave the dihydride complex [RuH2(CO){N(CH2PPh2)3}-&#954;3P] (4), which was fully characterized by X-ray crystallography and NMR spectroscopy. Complexes 3 and 4 are potentially useful catalyst precursors for a range of hydrogenation reactions, including biomass-derived products such as levulinic acid (LA). Complex 4 was found to cleanly react with LA in the presence of the proton source additive NH4PF6 to give [Ru(CO){N(CH2PPh2)3}-&#954;3P{CH3CO(CH2)2CO2H}-&#954;2O](PF6) (6).

The Synthesis, Characterization and Reactivity of a Series of Ruthenium N-triphosPh Complexes

Ruthenium phosphine complexes are widely used for homogeneous catalytic reactions such as hydrogenations. The synthesis of a series of novel tridentate ruthenium complexes bearing the N-triphos ligand N(CH2PPh2)3 is reported. Additionally, the stoichiometric reaction of a dihydride Ru&#8211;N-triphos complex with levulinic acid is described.

一系列钌的合成，表征和反应<em&gt;Ñ</em&gt; -triphos<sup&gt;博士</sup&gt;配合

Herein we report the synthesis of a tridentate phosphine ligand N(CH2PPh2)3 (N-triphosPh) (1) via a phosphorus based Mannich reaction of the ...

Palladium N-Heterocyclic Carbene Complexes: Synthesis from Benzimidazolium Salts and Catalytic Activity in Carbon-carbon Bond-forming Reactions

Detailed and generalized protocols are presented for the synthesis and subsequent purification of four palladium N-heterocyclic carbene complexes from benzimidazolium salts. Detailed and generalized protocols are also presented for testing the catalytic activity of such complexes in arylation and Suzuki-Miyaura cross-coupling reactions. Representative results are shown for the catalytic activity of the four complexes in arylation and Suzuki-Miyaura type reactions. For each of the reactions investigated, at least one of the four complexes successfully catalyzed the reaction, qualifying them as promising candidates for catalysis of many carbon-carbon bond-forming reactions. The protocols presented are general enough to be adapted for the synthesis, purification and catalytic activity testing of new palladium N-heterocyclic carbene complexes.

Palladium N-Heterocyclic Carbene Complexes: Synthesis from Benzimidazolium Salts and Catalytic Activity in Carbon-carbon Bond-forming Reactions

Detailed and generalized protocols are presented for the synthesis and subsequent purification of four palladium N-heterocyclic carbene complexes from benzimidazolium salts. The complexes were tested for catalytic activity in arylation and Suzuki-Miyaura reactions. For each reaction investigated, at least one of the four complexes successfully catalyzed the reaction.

钯<em&gt;ñ</em&gt; - 杂环碳烯配合物:苯并咪唑盐的合成和碳 - 碳键合反应中的催化活性

Detailed and generalized protocols are presented for the synthesis and subsequent purification of four palladium N-heterocyclic carbene complexes from ...

Preparation of Silver-Palladium Alloyed Nanoparticles for Plasmonic Catalysis under Visible-Light Illumination

Localized surface plasmon resonance (LSPR) in plasmonic nanoparticles (NPs) can accelerate and control the selectivity of a variety of molecular transformations. This opens possibilities for the use of visible or near-IR light as a sustainable input to drive and control reactions when plasmonic nanoparticles supporting LSPR excitation in these ranges are employed as catalysts. Unfortunately, this is not the case for several catalytic metals such as palladium (Pd). One strategy to overcome this limitation is to employ bimetallic NPs containing plasmonic and catalytic metals. In this case, the LSPR excitation in the plasmonic metal can contribute to accelerate and control transformations driven by the catalytic component. The method reported herein focuses on the synthesis of bimetallic silver-palladium (Ag-Pd) NPs supported on ZrO2 (Ag-Pd/ZrO2) that acts as a plasmonic-catalytic system. The NPs were prepared by co-impregnation of corresponding metal precursors on the ZrO2 support followed by simultaneous reduction leading to the formation of bimetallic NPs directly on the ZrO2 support. The Ag-Pd/ZrO2 NPs were then used as plasmonic catalysts for the reduction of nitrobenzene under 425 nm illumination by LED lamps. Using gas chromatography (GC), the conversion and selectivity of the reduction reaction under the dark and light irradiation conditions can be monitored, demonstrating the enhanced catalytic performance and control over selectivity under LSPR excitation after alloying non-plasmonic Pd with plasmonic metal Ag. This technique can be adapted to a wide range of molecular transformations and NPs compositions, making it useful for the characterization of the plasmonic catalytic activity of different types of catalysis in terms of conversion and selectivity.

Presented here is a protocol for the synthesis of silver-palladium (Ag-Pd) alloy nanoparticles (NPs) supported on ZrO2 (Ag-Pd/ZrO2). This system allows for harvesting energy from visible light irradiation to accelerate and control molecular transformations. This is illustrated by nitrobenzene reduction under light irradiation catalyzed by Ag-Pd/ZrO2 NPs.

在可见光照射下为质子催化准备银-铂合金纳米粒子

Localized surface plasmon resonance (LSPR) in plasmonic nanoparticles (NPs) can accelerate and control the selectivity of a variety of molecular ...

Dose Uptake of Platinum- and Ruthenium-based Compound Exposure in Zebrafish by Inductively Coupled Plasma Mass Spectrometry with Broader Applications

Metals and metal-based compounds comprise multifarious pharmaco-active and toxicological xenobiotics. From heavy metal toxicity to chemotherapeutics, the toxicokinetics of these compounds have both historical and modern-day relevance. Zebrafish have become an attractive model organism in elucidating pharmaco- and toxicokinetics in environmental exposure and clinical translation studies. Although zebrafish studies have the benefit of being higher-throughput than rodent models, there are several significant constraints to the model.
One such limitation is inherent in the waterborne dosing regimen. Water concentrations from these studies cannot be extrapolated to provide reliable internal dosages. Direct measurements of the metal-based compounds allow for a better correlation with compound-related molecular and biological responses. To overcome this limitation for metals and metal-based compounds, a technique was developed to digest zebrafish larval tissue after exposure and quantify metal concentrations within tissue samples by inductively coupled plasma mass spectrometry (ICPMS).
ICPMS methods were used to determine the metal concentrations of platinum (Pt) from cisplatin and ruthenium (Ru) from several novel Ru-based chemotherapeutics in zebrafish tissue. Additionally, this protocol distinguished concentrations of Pt that were sequestered in the chorion of the larval compared with the zebrafish tissue. These results indicate that this method can be applied to quantitate the metal dose present in larval tissues. Further, this method may be adjusted to identify specific metals or metal-based compounds in a broad range of exposure and dosing studies.

The increased rate of pharmaco- and toxicokinetic analyses of metals and metal-based compounds in zebrafish can be advantageous for environmental and clinical translation studies. The limitation of unknown waterborne exposure uptake was overcome by conducting trace metal analysis on digested zebrafish tissue using inductively coupled plasma mass spectrometry.

通过电感耦合等离子体质谱法对斑马鱼中铂基和钌基化合物暴露的剂量吸收，具有更广泛的应用

Metals and metal-based compounds comprise multifarious pharmaco-active and toxicological xenobiotics. From heavy metal toxicity to chemotherapeutics, the ...

Catalytic Reactions at Amine-Stabilized and Ligand-Free Platinum Nanoparticles Supported on Titania During Hydrogenation of Alkenes and Aldehydes

Ligands like amines are used in the colloidal synthesis approach to protect platinum nanoparticles (Pt NP&#39;s) from agglomeration. Normally, ligands like amines are removed by diverse pre-treatment procedures before use in heterogeneous catalysis as amines are considered as a catalyst poison. However, a possible beneficial influence of these surface modifiers on hydrogenation reactions, which is known from spectator species on metal surfaces, is often neglected.
Therefore, amine-stabilized Pt nanoparticles supported by titania (P25) were used without any pre-treatment in order to elucidate a possible influence of the ligand in liquid phase hydrogenation reactions. The catalytic activity of amine-stabilized Pt nanoparticles of two different sizes was investigated in a double-walled stirring tank reactor at 69 &#176;C to 130 &#176;C and 1 atm hydrogen pressure. The conversion of cyclohexene to cyclohexane was determined by gas chromatography (GC) and was compared to ligand-free Pt particles. All catalysts were checked before and after reaction by transmission electron spectroscopy (TEM) and X-ray photoelectron spectroscopy (XPS) for possible changes in size, shape, and ligand shell. The hydrogenation of cyclohexene in liquid phase revealed a higher conversion for amine-stabilized Pt nanoparticles on titania than the ligand-free particles. The hydrogenation of 5-methylfurfural (5-MF) was chosen for a further test reaction, since the hydrogenation of &#945;, &#946;-unsaturated aldehydes is more complex and exhibits various reaction paths. However, XPS and infrared spectroscopy (IR) proved that 5-MF acts as catalyst poison at the given reaction conditions.

This protocol shows a convenient method for comparing the catalytic properties of supported platinum catalysts, synthesized by deposition of nanosized colloids or by impregnation. The hydrogenation of cyclohexene serves as a model reaction to determine the catalytic activity of the catalysts.

烯烃和醛加氢过程中负载在二氧化钛上的胺稳定和无配体铂纳米颗粒的催化反应

Ligands like amines are used in the colloidal synthesis approach to protect platinum nanoparticles (Pt NP&#39;s) from agglomeration. Normally, ligands ...

Scaled-Up Preparation of an Intermediate of Upatinib, ACT051-3

Upatinib, a Janus kinase inhibitor drug, was developed by a biotech company to treat immune diseases. The compound tert-butyl (5-toluenesulfonyl-5h-pyrrole [2,3-b] pyrazine-2-yl) carbamate (ACT051-3) is an important intermediate of Upatinib. To date, the steady industrial production of this intermediate compound (ACT051-3) has not been reported. In this study, we described the specific synthesis method and process of the compound ACT051-3 in terms of laboratory synthesis, pilot scale-up, and industrial production. During the exploration of the process route for ACT051-3, many appropriate adjustments and improvements were made to the reaction conditions, finally leading to the successful development of the optimal industrial production process for ACT051-3. The reaction time was nearly doubled by changing the state of the potassium carbonate involved in the reaction, which greatly improved the reaction efficiency. Additionally, by introducing N,N-diisopropylethylamine (DIPEA) to the reaction, the amount of the expensive catalyst Pd(OAc)2 was reduced 2.5-fold, significantly lowering production costs, confirming the feasibility of this process route and the industrial production of ACT051-3, and satisfying market demand for this important intermediate.

Here, we present a protocol for the scaled-up synthesis of the intermediate tert-butyl (5-toluenesulfonyl-5h-pyrrole [2,3-b] pyrazine-2-yl) carbamate (ACT051-3) of Upatinib.

乌帕替尼中间体ACT051-3的放大制备

Upatinib, a Janus kinase inhibitor drug, was developed by a biotech company to treat immune diseases. The compound tert-butyl ...

A Tripeptide-Stabilized Nanoemulsion of Oleic Acid

We describe a method to produce a nanoemulsion composed of an oleic acids-Pt(II) core and a lysine-tyrosine-phenylalanine (KYF) coating (KYF-Pt-NE). The KYF-Pt-NE encapsulates Pt(II) at 10 wt. %, has a diameter of 107 &#177; 27 nm and a negative surface charge. The KYF-Pt-NE is stable in water and in serum, and is biologically active. The conjugation of a fluorophore to KYF allows the synthesis of a fluorescent nanoemulsion that is suitable for biological imaging. The synthesis of the nanoemulsion is performed in an aqueous environment, and the KYF-Pt-NE forms via self-assembly of a short KYF peptide and an oleic acids-platinum(II) conjugate. The self-assembly process depends on the temperature of the solution, the molar ratio of the substrates, and the flow rate of the substrate addition. Crucial steps include maintaining the optimal stirring rate during the synthesis, permitting sufficient time for self-assembly, and pre-concentrating the nanoemulsion gradually in a centrifugal concentrator.

This protocol describes an efficient method to synthesize a nanoemulsion of an oleic acids-platinum(II) conjugate stabilized with a lysine-tyrosine-phenylalanine (KYF) tripeptide. The nanoemulsion forms under mild synthetic conditions via self-assembly of the KYF and the conjugate.

一种三肽稳定的油酸纳米乳液

We describe a method to produce a nanoemulsion composed of an oleic acids-Pt(II) core and a lysine-tyrosine-phenylalanine (KYF) coating (KYF-Pt-NE). The ...

生物工程

Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay

Spirocyclic heterocycles have recently been reported in literature to be potential drugs for cancer therapy. The synthesis of these novel orthogonal ring systems is challenging. An efficient methodology to synthesize these compounds was recently published that described the solid phase synthesis in four steps rather than the previously reported five steps. The advantage of this shorter synthesis is the elimination of the use of toxic reagents. Low-loading Regenerating Michael (REM) linker-based resin was found to be crucial in the synthesis as high-loading versions prevented the addition of reagents containing bulky phenyl and aromatic side chains. The colorimetric 3-(4&#8242;,5&#8242;-dimethylthiazol-2&#8242;-yl)-2,5- diphenyltetrazolium bromide (MTT) assay was used to examine the cytotoxicity of micromolar concentrations of these novel spirocyclic molecules in vitro. MTT is readily available commercially and produces relatively fast, reliable results, making this assay ideal for these spirocyclic heterocycles. Orthogonal ring structures as well as furfurylamine (a precursor in the synthesis method containing a similar 5-member ring motif) were tested.

Here, we describe a bioassay using 3-(4&#8242;,5&#8242;-dimethylthiazol-2&#8242;-yl)-2,5- diphenyltetrazolium bromide (MTT) to test previously synthesized spirocyclic oximes.

功能化螺环杂环合成和细胞毒性测定

Spirocyclic heterocycles have recently been reported in literature to be potential drugs for cancer therapy. The synthesis of these novel orthogonal ring ...

酰胺偶联反应为双吡啶基配体及其络合合成，以白金为双核抗癌药物

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