A Tetrazolato-Bridged Dinuclear Platinum(II) Complex Exhibits Markedly High in vivo Antitumor Activity against Pancreatic Cancer
A Tetrazolato-Bridged Dinuclear Platinum(II) Complex Exhibits Markedly High in vivo Antitumor Activity against Pancreatic Cancer
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DOI：
10.1002/cmdc.201100141
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发表时间：
2011-06-06
期刊：
影响因子：
3.4
通讯作者：
Chikuma, Masahiko
中科院分区：
文献类型：
--
作者：
Komeda, Seiji;Lin, Yuh-Ling;Chikuma, Masahiko
一些铂（II）配位络合物是有效的抗癌剂。顺式二氨氯铂（II）（顺铂）是一种单核铂（II）络合物，是最常用的抗癌药物之一。[1]虽然铂类化疗可能导致严重的副作用，但其疗效促使设计和合成下一代抗癌铂（II）药物，这些药物可有效对抗通常对化疗耐药的癌症，如肺癌，胰腺癌和铂难治性癌症。[2，3]肺癌是全球癌症死亡的主要原因，非小细胞肺癌（NSCLC）占肺癌的80%。胰腺癌仍然是美国癌症相关死亡的第四大原因。[4]临床铂类药物通过形成Pt-DNA加合物显示抗肿瘤功效。[5-8]我们和其他人已经报道了偶氮桥连的双核PtII配合物，例如[{cis-Pt-（NH3）2} 2（μ-OH）（μ-吡唑基）]（NO3）2（1）和[{cis-Pt（NH3）2} 2（μ-OH）（μ-1，2，3-triazolato-N1，N2）]（NO3）2（2），通过与顺铂不同机制与DNA相互作用，并表现出比顺铂高得多的体外细胞毒性。1和2的化学结构见图1。为了进一步扩大药物发现，我们设计了两种新的四唑桥联配合物，[{cis-Pt（NH3）2} 2（μ-OH）（μ-tetrazolato-N1，N2）]（ClO 4）2（3）和[{cis-Pt（NH3）2} 2（μ-OH）（μ-tetrazolato-N2，N3）]（ClO 4）2（4），它们是结构异构体（图1）。在此，我们报告了它们的合成，表征，体外细胞毒性，和初步的体内抗肿瘤疗效。如前所述（方案1），通过使用唑根桥联络合物的改进方案合成络合物3和4。[12]将略微过量的四唑加入到起始材料[cis-Pt（NH3）2（μ-OH）] 2（NO3）2的水溶液中，然后在40 ℃下在黑暗中孵育，得到摩尔比为6.5：3.5的3和4（参见支持信息）。该制备比率可能是由于与结合至两个氮原子的N2或N3相比，结合至一个碳原子和一个氮原子的N1或N4的亲核性更高。通过反相液相色谱法分离和纯化两种结构异构体，并通过1H，13 C和195 Pt NMR光谱和ESI质谱进行表征。对于3，两个195 Pt NMR化学位移出现在2127和2177 ppm，反映了两个略有不同的Pt [N3 O]环境，因为四唑桥以不对称的方式排列;存在Pt原子的N1，N2配位。[12]与此相反，4的195 PtNMR化学位移出现在约2180 ppm处，证实了Pt [N3 O]环境和四唑桥上的络合物的对称结构;存在Pt原子的N2，N3配位。我们在H460人NSCLC细胞系上测试了我们的唑根桥联双核Pt II复合物的细胞毒性，沿着顺铂进行比较; IC 50值列于表1中。复合物1在一定浓度下没有活性，
Some platinum (II) coordination complexes are effective anticancer agents. cis-Diamminedichloridoplatinum (II)(cisplatin), a mononuclear platinum (II) complex, is one of the most commonly used anticancer drugs.[1] Although platinum-based chemotherapy can cause serious side effects, its efficacy has prompted the design and synthesis of next-generation anticancer platinum (II) drugs which are effective against cancers that are typically resistant to chemotherapy, such as lung cancer, pancreatic cancer, and platinum-refractory cancer.[2, 3] Lung cancer is the leading cause of cancer deaths worldwide, and non-small-cell lung cancer (NSCLC) accounts for 80% of lung cancers. Pancreatic cancer remains the fourth leading cause of cancer-related deaths in the United States.[4] Clinical platinum-based drugs show antitumor efficacy by forming Pt–DNA adducts.[5–8] We and others have reported that azolato-bridged dinuclear PtII complexes such as [{cis-Pt-(NH3) 2} 2 (μ-OH)(μ-pyrazolato)](NO3) 2 (1) and [{cis-Pt (NH3) 2} 2 (μ-OH)(μ-1, 2, 3-triazolato-N1, N2)](NO3) 2 (2), interact with DNA through a mechanism different from that of cisplatin and exhibit much higher in vitro cytotoxicity than cisplatin.[9–11] The chemical structures of 1 and 2 are shown in Figure 1. To further expand drug discovery, we designed two new tetrazolatobridged complexes,[{cis-Pt (NH3) 2} 2 (μ-OH)(μ-tetrazolato-N1, N2)](ClO4) 2 (3) and[{cis-Pt (NH3) 2} 2 (μ-OH)(μ-tetrazolato-N2, N3)](ClO4) 2 (4), which are structural isomers (Figure1). Herein we report their synthesis, characterization, in vitro cytotoxicity, and preliminary in vivo antitumor efficacy. Complexes 3 and 4 were synthesized by using a modified protocol for azolato-bridged complexes, as previously described (Scheme 1).[12] A slight excess of tetrazole was added to an aqueous solution of the starting material,[cis-Pt (NH3) 2 (μ-OH)] 2 (NO3) 2, which was then incubated at 408C in the dark to yield 3 and 4 at a molar ratio of 6.5: 3.5 (see Supporting Information). This preparation ratio likely resulted from the higher nucleophilicity of N1 or N4 bound to one carbon and one nitrogen atom, compared with N2 or N3 bound to two nitrogen atoms. The two structural isomers were separated and purified by reversed-phase liquid chromatography and characterized by 1H, 13C, and 195Pt NMR spectroscopy and ESI mass spectrometry. For 3, two 195Pt NMR chemical shifts appeared at À2127 and À2177 ppm, reflecting two slightly different Pt [N3O] environments, because the tetrazolato bridge is arranged in an asymmetric fashion; there is N1, N2 coordination of Pt atoms.[12] In contrast, for 4, a single 195PtNMR chemical shift appears at about À2180 ppm, confirming the Pt [N3O] environment and the symmetric structure of the complexes on the tetrazolato bridge; there is N2, N3 coordination of Pt atoms. We tested the cytotoxicity of our azolato-bridged dinuclear PtII complexes, along with cisplatin for comparison, on the H460 human NSCLC cell line; the IC50 values are listed in Table 1. Complex 1 showed no activity at concentrations