Effect of lipophilicity of amylamine and amylglycine ligands on biological activity of new anticancer cisplatin analog

Abstract

Investigation of side effects and solubility of anticancer drugs is a major challenge in chemotherapy science. Thus, design and synthesis of cisplatin analogs with higher lipophilicity as novel water-soluble anticancer drugs is valuable. In this work, two new Pt(II) complexes were synthesized with formula cis-[Pt(NH3)2(amylgly)]NO3 and cis-[Pt(amylamine)2(amylgly)]NO3, where gly is penthyl glycine as an amino acid. The new compounds were synthesized and extensively characterized using analytical techniques; spectroscopic methods, and conductivity measurement. The anticancer activity of synthesized complexes was investigated against colon cancer cell line HCT116 using MTT assay and results showed excellent anticancer activity with Cc50 values of 36 and 270 M after 24-h incubation time for cis-[Pt(NH3)2(amylgly)]NO3 and cis-[Pt(NH2-amyl)2(amylgly)]NO3, respectively; which is lower than that for cisplatin. These complexes were also interacted with highly polymerized calf thymus DNA and the binding mode of the complexes to CT-DNA was evaluated by fluorescence, circular dichroism, and UV spectroscopy. The calculation of binding and thermodynamic of Pt(II) complexes with CT-DNA can provide deeper insight into mechanism of the action of these types of complexes with nucleic acids. So, thermodynamic parameters were also determined according to isothermal titration. In comparison with cis-[Pt(NH3)2(amylgly)]NO3 in DNA interaction, the result show that cis-[Pt(NH2-amyl)2(amylgly)]NO3 has higher affinity with binding constant Kf = 8.72 mM to CT-DNA. The results indicate that cis-[Pt(amylamine)2(amylgly)]NO3 with large and bulky aliphatic group bind to CT-DNA by different modes and covalent and groove bindings were preferred mode of interaction with DNA.