Stereoselective synthesis of oxime containing Pd(II) compounds: highly effective, selective and stereo-regulated cytotoxicity against carcinogenic PC-3 cells
Stereoselective synthesis of oxime containing Pd(II) compounds: highly effective, selective and stereo-regulated cytotoxicity against carcinogenic PC-3 cells
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DOI：
10.1039/d2dt01403c
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发表时间：
2022-06-22
影响因子：
4
通讯作者：
Royo, Eva
中科院分区：
文献类型：
--
作者：
de la Cueva-Alique, Isabel;de la Torre-Rubio, Elena;Royo, Eva
新的钯化合物 [Pd{(1S,4R)-NOHNH(R)}Cl-2] (R = Ph 1a 或 Bn 1b)、[Pd{(1S,4R)-NOHNH(R)}{(1S,4R)-NONH(R)}][Cl] (R = Ph 2a 或 Bn 2b) 以及相应的合成了[Pd{(1R,4S)-NOHNH(R)}Cl-2]（R = Ph 1a'或Bn 1b'）和[Pd{(1R,4S)-NOHNH(R)}{(1R,4S)-NONH(R)}][Cl]（R = Ph 2a'或Bn 2b'）。新化合物 1a、1b 和 2b（以及 1a'、1b' 和 2b'）在溶液中作为非对映体混合物获得，其相对比例取决于溶剂和氨基取代基的性质。相反，衍生物2a和2a'的合成反应是立体定向的，并分别提供绝对构型的单一对映体(S-N,1S(C),4R(C))-(R-N,1S(C),4R(C))和(R-N,1R(C),4S(C))-(S-N,1R(C),4S(C))。所有化合物均已通过 NMR 和 IR 光谱、时间依赖性 UV 光谱、水中的 ESI-HR-MS 以及 CHN 元素分析进行了全面表征。 1a 和 1a' 的主要差向异构体（1b 的差向异构体和对映异构体 2a'）的绝对构型通过单晶 X 射线晶体学测定，并通过溶液中的 2D NOESY NMR 实验进行证实。此外，通过 H-1-NMR 光谱评估了 2b 在水中的 pH 依赖性稳定性。金属衍生物已针对三种人类癌症（前列腺 PC-3、宫颈 HeLa 和乳腺癌 MCF-7）细胞系进行了体外测试。钯化合物 2a' 在所有癌细胞中显示出最高的抗癌活性，其 IC50 值比顺铂低 80 倍。 2a 和 2a'' 的细胞毒性是立体依赖性的，在所有测试的细胞系中，每种对映体的 IC50 值显着不同。进一步评估了 2a 和 2a' 针对非致瘤性人前列腺 RWPE-1 细胞系的细胞毒活性，显示选择性指数 (SI) 约为 100%。导数 2a' 为 30。 DNA 相互作用已通过平衡透析、荧光共振能量转移 (FRET) DNA 熔解测定和粘度滴定进行研究，指向凹槽和/或外部结合。用2a或2a'处理后对PC-3细胞的细胞周期测定显示细胞周期停滞在S和G2/M期，特别是当用化合物2a'处理细胞时。
New palladium compounds [Pd{(1S,4R)-NOHNH(R)}Cl-2] (R = Ph 1a or Bn 1b), [Pd{(1S,4R)-NOHNH(R)}{(1S,4R)-NONH(R)}][Cl] (R = Ph 2a or Bn 2b) and corresponding [Pd{(1R,4S)-NOHNH(R)}Cl-2] (R = Ph 1a' or Bn 1b') and [Pd{(1R,4S)-NOHNH(R)}{(1R,4S)-NONH(R)}][Cl] (R = Ph 2a' or Bn 2b') have been synthesized. Novel compounds 1a, 1b, and 2b (and 1a', 1b', and 2b') were obtained in solution as a mixture of diastereomers whose relative ratios depend on the solvent and the nature of the amino substituent. In contrast, the synthetic reactions of derivatives 2a and 2a' were stereospecific, and afforded single enantiomers of absolute configuration (S-N,1S(C),4R(C))-(R-N,1S(C),4R(C)) and (R-N,1R(C),4S(C))-(S-N,1R(C),4S(C)), respectively. All compounds have been fully characterized by NMR and IR spectroscopy, time-dependent UV-spectroscopy, ESI-HR-MS in water, and CHN elemental analysis. Absolute configurations of the major epimers of 1a and 1a', both epimers of 1b and enantiomer 2a', were determined by single crystal X-ray crystallography, and confirmed by 2D NOESY NMR experiments in solution. Additionally, the pH-dependent stability of 2b in water was assessed by H-1-NMR spectroscopy. Metal derivatives have been tested in vitro against three human cancer (prostate PC-3, cervical HeLa, and breast MCF-7) cell lines. The highest anticancer activities were shown by palladium compound 2a' in all cancer cells, with IC50 values up to 80 times lower than those found for cisplatin. The cytotoxicity of 2a and 2a '' is stereo-dependent, with IC50 values that differ significantly for each enantiomer in all the cell lines tested. The cytotoxic activity of 2a and 2a' was further evaluated against the non-tumorigenic human prostate RWPE-1 cell line, revealing a selectivity index (SI) of ca. 30 for derivative 2a'. DNA interactions have been investigated by equilibrium dialysis, fluorescence resonance energy transfer (FRET) DNA melting assays, and viscometric titrations, pointing to groove and/or external binding. Cell cycle assay on PC-3 cells after treatment with 2a or 2a' shows cell cycle arrest in the S and G2/M phases, especially when the cells are treated with compound 2a'.