Abstract
6‐mercaptopurine (6‐MP) is used for treating various cancers and autoimmune disorders. A few examples of transition metal complexes of 6‐MP have been shown to enhance its anticancer activity, but many remain untested. We isolated five highly stable and colored metal complexes of 6‐MP and confirmed their structures by elemental analysis, spectral, and thermal techniques. Infrared (IR) spectra revealed that 6‐MP is a bidentate ligand that interacts through sulfur and pyrimidine nitrogen in a 1:2 (M:L) molar ratio. The magnetic susceptibility and electron paramagnetic resonance (EPR) spectra for the Cu(II) complex revealed an octahedral arrangement around the metal ion with strong covalent bonding. The fully optimized geometries of the metal structures obtained using density function theory (DFT)/B3LYP calculations were used to verify the structural and biological features. DNA titration revealed that the octahedral Cu(II) complex has a critical binding constant value of Kb = 8 × 105. Docking studies using three different cancer protein receptors were used to predict the biological applications of the synthesized drug‐metal complexes. Finally, cytotoxicity assays against a myeloma cancer cell line (MM) and a colon cancer cell line (Caco‐2) revealed favorable anticancer activity for the copper complex, exceeding that of the gold‐standard chemotherapeutic cisplatin.
Highlights
Cancer chemotherapy is an aggressive treatment that uses chemical drugs to halt or stagger uncontrolled cell growth in the body
There are various chemotherapeutic drugs, such as cisplatin,[2] docetaxel,[3] and oxaliplatin,[4] which are most often used for lung cancer, breast cancer, and colon cancer, respectively.[1] 6-Mercaptopurine (6-MP) is one of the antineoplastic agents most widely used for children's leukemia.[5]
Reacting divalent transition metal with 6-MP ligand has been described in the literature with the formula [MII(6-MP)2X2] or [MII(6-MP)n]X2,[12c] which they coordinated via S and N(7) donor atoms.[6,12b] Most transition metal complexes of 6-MP have been obtained and characterized, but some of their biological activities have not yet been discussed
Summary
Cancer chemotherapy is an aggressive treatment that uses chemical drugs to halt or stagger uncontrolled cell growth in the body. The crystal structures of Bruton's tyrosine kinase (a leukemia protein receptor; PDB code = 3PIY),[22] human topoisomerase II alpha (a colon cancer receptor; PDB code = 4FM9),[23] and aromatase cytochrome P450 (a breast cancer receptor protein; PDB code = 3EQM)[24] were retrieved from the protein databank (PDB) Those receptor proteins were chosen based on research demonstrating their key roles in leukemia,[21,22] colon cancer,[25] and breast cancer treatments.[24,26] The molecular docking protocol has been reported previously using Molecular Operating Environment (MOE) software.[23,27] The water molecules and ions were removed from the target receptors with the energy minimized by the three-dimensional (3-D) protonation process. The higher negative values of protein-ligand docking scores were saved along with two-dimensional (2-D) and 3-D structures
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