Syntheses, Characterizations, and Hirshfeld Analysis of Ag(I) and Cu(II) Complexes: A Novel Potent Ag(I)-Based Oxadiazole Anticancer Agent

Abstract

The Ag(I) and Cu(II) complexes of the ligand, 2,2 '-(1,2,4-oxadiazole-3,5-diyl) dianiline, (L; 4) were synthesized and characterized using different spectroscopic techniques. Their anticancer activities against three types of cancer cell lines were explored. The [AgL (NO3)](n) complex (5) has 1D polymeric structure whereas the [CuL (NO3)(2)] (6) and [CuLCl2] (7) are monomeric complexes. The Ag(I) in 5 is tetra-coordinated and has AgN2O2 coordination sphere where both L and NO3 over bar are bridging the Ag(I) sites along the polymer array. In 6 and 7, the coordination environments are CuN3O3 and CuN3Cl2, respectively. In both cases, the oxadiazole ligand is a tridentate chelate via two N-atoms from both amino groups and one N-atom from the oxadiazole moiety. Hirshfeld analysis revealed the importance of O horizontal ellipsis H (23.5%), H horizontal ellipsis H (24.8%), and C horizontal ellipsis C (6.6%) non-covalent interactions in the molecular packing of 5. In 6, the O horizontal ellipsis H (40.7%), N horizontal ellipsis H (4.9%), O horizontal ellipsis O (5.9%), N horizontal ellipsis O (3.2%), and C horizontal ellipsis N (2.2%) contacts are the most important. Regarding safety on normal human fibroblasts Wi-38, MTT assay for all metal complexes especially the Ag(I) complex 5 exhibited higher safety profiles than the free oxadiazole ligand as well as the standard chemotherapeutic drug 5-fluroruracil (5-FU). The cytotoxic activities of complexes 5-7 surpassed 5-FU against A549, Caco-2, and MDA-MB231 cell lines. 5 has the best anticancer activity (IC50 = 0.074, 0.085, and 0.533 mu M, respectively) and exhibiting pronounced selectivity index up to 44.3. Quantitative PCR analysis of BAX and BCL-2 revealed their apoptotic induction mechanism and showed that the metal complexes can repress the main oncogene BCL-2 and enhance the expression of proapoptotic gene BAX. Again, 5 is the most potent with 14.28 folds BCL-2 downregulation and 4.86 folds BAX upregulation.