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¯ 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 … H (23.5%), H … H (24.8%), and C … C (6.6%) non‐covalent interactions in the molecular packing of 5. In 6, the O … H (40.7%), N … H (4.9%), O … O (5.9%), N … O (3.2%), and C … 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 μM, 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.