Development of Anticancer Activity of the Pt(II) Complex with N-Heterocyclic Amine: Its In Vitro Pharmacokinetics with Thiol and Thio-Ethers, DNA and BSA Binding, and Cell Cycle Arrest

Abstract

A dichloro Pt­(II) complex with N-heterocyclic amine cis-Pt­(PIEAM)­Cl2, C-1 (where PIEAM = 1-(2-aminoethyl)­piperidine) was synthesized and hydrolyzed to the corresponding [Pt­(PIEAM)­(OH2)2]2+ C-2 to explore its bioactivity and cytotoxic property. Biorelevant sulfur-containing small tripeptide glutathione (GSH)- and amino acid dl-methionine (dl-meth)-substituted complexes [Pt­(PIEAM)­(GSH)] C-3 and [Pt­(PIEAM)­(dl-meth)]+2 C-4 were synthesized and characterized. In vitro pharmacokinetic reactions of complex C-2 → C-3 and C-4 with GSH and dl-meth, respectively, were studied under pseudo-first-order reaction conditions. The high and negative entropy of activation (ΔS ⧧) and low and positive enthalpy of activation (ΔH ⧧) values were deduced from the Eyring equation to propose an associative mechanism. To find out the biotransformation of complex C-1, C-2, and Pt­(II)–S chelates C-3 and C-4 to Pt­(II)-DNA adducts, DNA binding affinity of C-1–C-4 was examined by UV–visible spectroscopy, fluorescence quenching, and gel electrophoresis methods. BSA binding activity of these complexes was emphasized for their biological importance and the “drug reservoir” activity. Anticancer activity of these complexes on HEp 2 (laryngeal), MDA-MB-231 (breast), and A549 (lung) cancer cell lines was found to be remarkable as compared to the recognized anticancer drugs such as cisplatin, carboplatin, and oxaliplatin. Cell cycle arrest was also explored on HEp 2 cells of the complexes at a concentration corresponding to IC50 value and displayed significant cell death at the sub-G1 phase.

Anticancer activity and biomolecular interaction of Pt(II) complexes: Their synthesis, characterisation and DFT study

“…The characteristic nature of ln(A ∞ À A t ) versus time (t) plot (Figures S17a and S18a) indicates a two-step reaction pathway for both the substitution reactions. [54,55] From the plot, we can concede that two labile H 2 O from Complex 2 are substituted in two consecutive steps, as shown in Scheme 4.…”

New Apoptosis Inducers Containing Anti-inflammatory Drugs and Pnictogen Derivatives: A New Strategy in the Development of Mitochondrial Targeting Chemotherapeutics

“…The interaction of the metallodrugs and DNA was also evaluated by fluorescence spectroscopy. Ethidium bromide (EB) emits intense fluorescent light in the presence of DNA as a result of its strong intercalation between the adjacent DNA base pairs. ,, The fluorescence spectra of the CT-DNA-EB complex with increasing concentrations of 1 – 4 (0–250 μM) are shown in Figure and Figure S43.…”

“…Among the direct methods (X-ray crystallography, NMR spectroscopy, mass spectrometry, etc.) with which the metal compound interactions with DNA are studied is the measurement of the DNA solution viscosity. − The DNA length changes when interacting with a metallodrug as a result of the different conformations that DNA helix obtains . [i] In the case of an intercalation mode, the relative viscosity of the DNA-agent solution is significantly increased because of the unwinding and elongation of the double helix .…”

Oxidative DNA cleavage mediated by a new unexpected [Pd(BAPP)][PdCl4] complex (BAPP = 1,4-bis(3-aminopropyl)piperazine): crystal structure, DNA binding and cytotoxic behavior

“…complex exhibited a sharp peak at 236 nm and 300 nm which could be assignable to the transitions of an electron from s (bonding orbital)/s* (antibonding) orbital and the nonbonding orbital/s* of the amine in the BAPP ligand. 50 The similarity between the absorption bands of the BAPP ligand and the [Pd(BAPP)][PdCl 4 ] complex reects that the spectrum of the complex was predominated mainly by ligand transitions. Besides, only the complex displayed one broadband as a shoulder in the region of 389-489 nm due to a combination of nitrogen-Pd(II) charge transfer (L-M) and Pd(II) d-d bands 51 as expected for the square planar geometry through the involvement of the BAPP ligand in the coordination to the Pd(II) ion.…”