Two new platinum(II) complexes, [Pt(bpy)(IPG)]NO₃ and [Pt(bpy)(TPG)]NO₃, were successfully synthesized using iso-pentylglycine (IPG) and tert-pentylglycine (TPG), two structural isomers of pentylglycine. These complexes were characterized through a combination of spectroscopic techniques including FT-IR, UV-Vis, ¹H NMR, and CHN elemental analysis. The results confirmed the formation of the desired coordination compounds with high purity and yield. The molecular structures revealed that both ligands coordinate to the Pt(II) center via the nitrogen atoms of the bipyridine moiety and the amino group of glycine, forming square-planar geometries typical of Pt(II) complexes.
To investigate their potential as anticancer agents, the complexes were evaluated for DNA interaction using fluorescence spectroscopy, circular dichroism (CD), and UV-Vis absorption titration. Fluorescence quenching experiments with ethidium bromide (EB)-DNA indicated a static quenching mechanism for both complexes, suggesting the formation of non-covalent adducts. The binding constants (Kb) were determined to be 3.43 × 10⁴ M⁻¹ and 4.94 × 10⁵ M⁻¹ for [Pt(bpy)(IPG)]NO₃ and [Pt(bpy)(TPG)]NO₃, respectively, indicating significantly higher affinity for DNA by the tert-isomer. The Stern-Volmer analysis further supported this, showing a larger Ksv value for the TPG derivative. CD spectra revealed conformational changes in DNA from B-form to A-form upon complex binding, consistent with electrostatic interactions involving the positively charged metal centers.
Thermodynamic studies based on DNA denaturation profiles showed endothermic processes for both complexes, with positive ΔH° and ΔS° values, indicating that hydrophobic forces dominate the interaction. Notably, the [Pt(bpy)(TPG)]NO₃ complex exhibited greater destabilization of DNA helix stability compared to its IPG counterpart, likely due to enhanced steric effects and increased disorder caused by the branched tert-butyl group. This was reflected in higher entropy changes (ΔS° ≈ 9.4 times larger), suggesting greater disruption of water structure around the DNA complex.
Molecular docking simulations using AutoDock tools predicted favorable binding energies of −9.50 kcal/mol and −9.12 kcal/mol for [Pt(bpy)(IPG)]NO₃ and [Pt(bpy)(TPG)]NO₃, respectively. The best poses indicated groove binding as the primary mode, accompanied by partial intercalation and electrostatic interactions. Hydrogen bonding was observed between the Pt complex and DNA bases—specifically, a 2.13 Å bond with T20 O3 in the IPG complex and a 1.89 Å bond with C9 O3 in the TPG complex—highlighting the importance of desolvation energy and hydrogen bond formation in stabilizing the drug-DNA interface.
Density functional theory (DFT) calculations at the UB3LYP/6-311G(d,p)/LANL2DZ level provided insights into electronic properties.Cytokeratin 15 Antibody custom synthesis Both complexes displayed low HOMO-LUMO energy gaps (≈3.95 eV), indicating high reactivity and potential for electron transfer processes. The calculated dipole moments were moderate (13.89–15.93 D), supporting solubility and membrane permeability. Electrophilicity indices were higher than that of cisplatin, suggesting enhanced biological activity. Additionally, the presence of positive charge density on the surface of the complexes facilitates approach to negatively charged DNA phosphate groups.
ADMET predictions via SwissADME revealed favorable pharmacokinetic profiles. Both complexes are orally bioavailable, with high gastrointestinal absorption and no brain barrier penetration, making them suitable for systemic delivery. They are P-glycoprotein substrates but do not exhibit neurotoxicity risk. Their lipophilicity (Log Po/w ≈ +1.0) supports oral administration, contrasting with hydrophilic clinical platinum drugs like cisplatin.RPAIN Antibody In Vitro The Bioavailability Radar plots confirmed that both complexes fall within optimal ranges for size, polarity, and solubility, classifying them as drug-like molecules.PMID:34929057
In vitro cytotoxicity assays against the MCF-7 breast cancer cell line demonstrated significant antiproliferative effects. After 72 hours of incubation, IC₅₀ values were 25 μM and 40 μM for [Pt(bpy)(IPG)]NO₃ and [Pt(bpy)(TPG)]NO₃, respectively—comparable to carboplatin and oxaliplatin. Although the IPG derivative showed slightly stronger activity, the difference was marginal, suggesting that side-chain branching does not drastically alter potency. Importantly, no significant difference was observed after 48 hours, indicating similar early-stage cytotoxicity.
In conclusion, these novel platinum complexes exhibit strong DNA-binding affinity, favorable biophysical and pharmacological properties, and potent anticancer activity. The tert-pentylglycine derivative shows superior DNA interaction due to enhanced hydrophobic and entropic contributions, while the iso-pentylglycine analog displays slightly better cellular efficacy. Together, they represent promising candidates for further development as orally available platinum-based anticancer agents with reduced side-effect profiles.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com