Density Functional Theory Characterization and Descriptive Analysis of Cisplatin and Related Compounds

Abstract

Quantum and nonquantum descriptors clearly related to physicochemical features and predictors of the trends to evolve along different stages of a known mechanism of action were determined for a set of square-planar compounds of general formula [M(II)A(1)A(2)L(1)L(2)] (M(II) = Pt(II)/Pd(II); A(i)/L(i) = carrier/labile ligands), structurally related to the anticancer agent Cisplatin. Selected compounds have been sorted and classified by Ward's Cluster Analysis and Principal Components Analysis data-mining techniques using seventeen 1D and two 3D of such theoretical descriptors calculated at the DFT level (PCM-B3LYP/LANL2DZ/6-31G*). A rationale emerging from the study is that whereas most significant differences come from substitution of Cisplatin ligands, cis/trans isomerism, and exchange of M(II) introduce minor alterations in the electronic/geometrical structure. This provides theoretical support to the assay of transplatinum compounds as potential anticancer drugs, a fact already pointed out by empirical evidence. Similarly, the little geometrical/electronic differences triggered by switching M(II) from Pt to Pd enable us to devise a rational path to propose new compounds with expected good anticancer profiles, tuning alterations introduced by simultaneously changing both metal and ligands. Current results serve thus to enlarge the Cleare-Hoeschele guides for Pt(II) square-planar anticancer potential drugs to Pd(II) compounds, both using cis/trans scaffolds.

Aromatic amine N-oxide organometallic compounds: searching for prospective agents against infectious diseases

“…As pointed out by the aforementioned features of the "HOMO/LUMO" frontier KS orbitals of the new M-dppf-mpo species and their corresponding energy gaps (1.95 vs. 2.44 eV for M = Pd and Pt, respectively), whereas the palladium derivative appears as intrinsically more reactive and more prone to be reduced at the metal center M (consistent with the comparative behaviour found for other Pd/Pt pairs of prospective square planar cytotoxic agents 61,62 ) both species display the same tendency to undergo oxidation at the ferrocene moiety forming oxidized open-shell derivatives at the dppf ligand that could contribute to their biological action. Connected to the fact that Pt-dppf-mpo consistently displayed higher activity against both parasites and mammalian cells together with a lower selectivity, all these chemical features would be indicative of the involvement of multiple mechanisms and targets in the biological action of the M-dppf-mpo species.…”

Evaluation of cytotoxic effect of the combination of a pyridinyl carboxamide derivative and oxaliplatin on NCI-H1299 human non-small cell lung carcinoma cells

“…From the values listed in Table 1, one can infer that LabMol-12 is more lipophilic and less polar than oxaliplatin, probably because the latter presents an oxalate' leaving group in its structure and is known that its hydrophobicity was improved adding the diaminocyclohexane ring to its structure. In fact, the oxaliplatin mechanism of action is uncommon, and the literature describes a link between its efficacy against colorectal cancer and particularities involving its interaction with proteins from diverse transport system through the cell membrane [44][45][46].…”

Quantum Mechanics in Structure‐Based Ligand Design

“…For example, many theoretical studies have been performed on the structure, binding, reactivity, and toxicity of cisplatin and similar anti-cancer drugs. [61,62,63] Likewise this approach has been tested for the binding of M-arene-PTA ligands to cathepsin B (M = Ru II , Os II , Rh III , or Ir III ). [63,64,65] It was shown that a correlation of r 2 = 0.52 could be obtained between calculated and experimental affinities, including only the firstsphere ligands of the metal.…”