Barve Vivek, Ahmed Fakhara, Adsule Shreelekha, Banerjee Sanjeev, Kulkarni Sudhir, Katiyar Prashant, Anson Christopher E, Powell Annie K, Padhye Subhash, Sarkar Fazlul H
Department of Chemistry, University of Pune, Pune 411007, India.
J Med Chem. 2006 Jun 29;49(13):3800-8. doi: 10.1021/jm051068y.
The synthesis and characterization of Schiff base derivatives of 3-formylchromone 3-6 (FPA-120 to FPA-123), the minimal biologically active structural motif of soy isoflavone, genistein, and their copper(II) complexes 7-10 (FPA-124 to FPA-127) are reported here. These copper complexes possess distorted square-planar geometries capable of stabilizing Cu2+/Cu+ redox forms. The molecular modeling study revealed that the key interaction of the metal complexes was with amino acids in the pleckstrin homology (PH) and the kinase domain of the PKB (Akt) protein. Copper complex 7 significantly forms stronger charge interactions in the kinase domain than genistein, leading to better stabilization in the active pocket. In vitro evaluation of copper complexes against hormone-independent and metastatic breast (BT20), prostate (PC-3), and K-ras mutant (COLO 357) and K-ras wild-type (BxPC-3) pancreatic cancer cells revealed that 7 was the most potent compound which exhibited PKB (Akt protein) inhibitory activities and caused NF-kappaB inactivation in a well-established orthotopic pancreatic tumor model using COLO 357 cells. An inverse relationship was observed between IC50 values of the anti-proliferative activities and the Cu2+/Cu+ redox couple for these compounds, which may provide a rapid screen for evaluating the efficacy of active metallodrugs affecting redox-sensitive transcription factors such as NF-kappaB and its upstream target, the PKB (Akt) pathway, in multiple cancers.
本文报道了3-甲酰基色酮3-6(FPA-120至FPA-123)的席夫碱衍生物的合成与表征,3-甲酰基色酮是大豆异黄酮染料木黄酮的最小生物活性结构基序,以及它们的铜(II)配合物7-10(FPA-124至FPA-127)。这些铜配合物具有扭曲的平面正方形几何结构,能够稳定Cu2+/Cu+氧化还原形式。分子建模研究表明,金属配合物的关键相互作用是与普列克底物蛋白同源性(PH)结构域和蛋白激酶B(Akt)蛋白的激酶结构域中的氨基酸相互作用。铜配合物7在激酶结构域中比染料木黄酮形成更强的电荷相互作用,从而在活性口袋中实现更好的稳定性。对铜配合物针对激素非依赖性和转移性乳腺癌(BT20)、前列腺癌(PC-3)、K-ras突变型(COLO 357)和K-ras野生型(BxPC-3)胰腺癌细胞的体外评估显示,7是最有效的化合物,它表现出蛋白激酶B(Akt蛋白)抑制活性,并在使用COLO 357细胞建立的原位胰腺肿瘤模型中导致核因子κB失活。观察到这些化合物的抗增殖活性的IC50值与Cu2+/Cu+氧化还原对之间呈反比关系,这可能为评估影响氧化还原敏感转录因子如核因子κB及其上游靶点蛋白激酶B(Akt)途径的活性金属药物在多种癌症中的疗效提供一种快速筛选方法。