Dutra Jocely L, Honorato João, Graminha Angélica, Moraes Carlos André F, de Oliveira Kleber T, Cominetti Marcia R, Castellano Eduardo E, Batista Alzir A
Departamento de Química, Universidade Federal de São Carlos - UFSCar, CP 676, CEP 13561-901, São Carlos, SP, Brazil.
Departamento de Química, Universidade Federal do Amazonas - UFAM, CEP 69077-000, Itacoatiara, AM, Brazil.
Dalton Trans. 2024 Dec 3;53(47):18902-18916. doi: 10.1039/d4dt01045k.
Palladium(II) complexes have stimulated research interest mainly due to their cytotoxicity against various cancer cell lines and their low cytotoxicity in healthy cells. Thus, in this work, we combined Pd(II)/phosphine systems with the natural product curcumin as a ligand, obtaining a series of complexes, [Pd(cur)(PPh)]PF (A1), [Pd(cur)(dppe)]PF (A2), [Pd(cur)(dppp)]PF (A3), [Pd(cur)(dppb)]PF (A4) and [Pd(cur)(dppf)]PF (A5), where dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, dppb = 1,4-bis(diphenylphosphino)butane, and dppf = 1,1'-bis(diphenylphosphino)ferrocene (P-P), which were characterized by elemental analysis, molar conductivity analysis, and mass, NMR (H, C, P{H}), UV-vis, and IR spectroscopies, and four of them (A1, A2, A4, and A5) by X-ray crystallography. The cell viability of the complexes A1-A5, cisplatin, and the free ligand curcumin against MDA-MB-231 (human triple-negative breast tumor cells), SK-BR-3 (human breast tumor cells), A549 (human lung tumor cells), MRC-5 (non-tumor human lung cells), A2780 (human ovarian carcinoma cells), and A2780cis (cisplatin-resistant human ovarian carcinoma cells), was evaluated by the MTT colorimetric assay. For the tumor cell lines tested, the complexes showed good anticancer activities. The results showed that in general the complexes had lower IC values than free curcumin and the precursors [PdCl(P-P)]. IC results obtained for the A1-A5 complexes, in the MCF-7 cell line, are similar to those that had already been observed for some Pd/bipy/curcumin complexes. In the MDA-MB-231 cell line, complexes A1 and A5 stood out, with their lowest IC values, around 5 μmol L, and the complexes appeared to be more active (lower IC values) against the ovarian cell lines. Complex A1 was 23 and 22-fold more cytotoxic than cisplatin, against the A2780 and A2780cis cells, respectively. The complex A1 was studied on A2780cis cells and it was found that this complex inhibits colony formation and induces cell cycle arrest in the sub-G1 phase in a concentration-dependent manner and leads to cell death by apoptosis. The DCFDA assay revealed a potent ROS induction for complex A1.
钯（II）配合物主要因其对各种癌细胞系的细胞毒性以及在健康细胞中的低细胞毒性而激发了研究兴趣。因此，在本工作中，我们将钯（II）/膦体系与天然产物姜黄素作为配体相结合，得到了一系列配合物，[Pd(cur)(PPh)]PF（A1）、[Pd(cur)(dppe)]PF（A2）、[Pd(cur)(dppp)]PF（A3）、[Pd(cur)(dppb)]PF（A4）和[Pd(cur)(dppf)]PF（A5），其中dppe = 1,2 - 双（二苯基膦基）乙烷，dppp = 1,3 - 双（二苯基膦基）丙烷，dppb = 1,4 - 双（二苯基膦基）丁烷，dppf = 1,1'-双（二苯基膦基）二茂铁（P - P），通过元素分析、摩尔电导率分析、质谱、核磁共振（H、C、P{H}）、紫外 - 可见光谱和红外光谱对其进行了表征，其中四个（A1、A2、A4和A5）通过X射线晶体学进行了表征。通过MTT比色法评估了配合物A1 - A5、顺铂和游离配体姜黄素对MDA - MB - 231（人三阴性乳腺癌细胞）、SK - BR - 3（人乳腺癌细胞）、A549（人肺癌细胞）、MRC - 5（非肿瘤人肺细胞）、A2780（人卵巢癌细胞）和A2780cis（顺铂耐药人卵巢癌细胞）的细胞活力。对于所测试的肿瘤细胞系，这些配合物表现出良好的抗癌活性。结果表明，一般而言，这些配合物的IC值低于游离姜黄素和前体[PdCl(P - P)]。在MCF - 7细胞系中获得的A1 - A5配合物的IC结果与一些钯/联吡啶/姜黄素配合物已观察到的结果相似。在MDA - MB - 231细胞系中，配合物A1和A5表现突出，其IC值最低，约为5 μmol/L，并且这些配合物似乎对卵巢细胞系更具活性（IC值更低）。配合物A1对A2780和A2780cis细胞的细胞毒性分别比顺铂高23倍和22倍。对A2780cis细胞研究了配合物A1，发现该配合物以浓度依赖的方式抑制集落形成并诱导细胞周期停滞在亚G1期，并导致细胞凋亡死亡。DCFDA分析显示配合物A1有强烈的活性氧诱导作用。
