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
Summary
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。
Abstract
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.
Introduction
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）。
Protocol
Representative Results
Discussion
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…
Declarações
The authors have nothing to disclose.
Materials
| D2O | Aldrich | 151882 | 99.9% D |
| DMSO-d6 | Aldrich | 156914 | 99.96% D |
| 1,8-diaminooctane | Aldrich | D22401 | 98% |
| 1,10-diaminodecane | Aldrich | D14204 | 98% |
| 1,12-diaminododecane | Aldrich | D1,640-1 | 98% |
| Isonicotinic acid | Aldrich | I17508 | 99% |
| 1-Propylphosphonic anhydride solution | Aldrich | 431303 | 50 wt% in ethyl acetate |
| Trans-diaminodichloridoplatinum(II) | Aldrich | P1525 | |
| Dimethylsulfoxide | Sigma-Aldrich | Z76855 | >99.9%, anhydrous |
| N,N’-dimethylformamide | Sigma-Aldrich | 227056 | 99.8%, anhydrous |
| Triethylamine | Sigma-Aldrich | T0886 | >99% |
| Nylon filter membranes | Whatman | 7402-004 | Pore size, 0.2 µm |
| Equipment | |||
| Magnetic stirring hotplate | |||
| Magnetic stirring bar | |||
| Round bottom or three neck flask | |||
| Rubber septums of sufficient size for chosen round bottom or three neck flask | |||
| 5 mL hypodermic syringes | |||
| Hypodermic needles | |||
| Rubber party ballons | |||
| Rubber bands | |||
| A source of N2 gas | |||
| Rotary evaporator | |||
| Drying oven | |||
| NMR tubes | |||
| NMR spectrometer | |||
| 500 mL beakers | |||
| Glass or plastic pipettes |
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