Theoretical investigations and density functional theory based quantitative structure-activity relationships model for novel cytotoxic platinum(IV) complexes

Abstract

Octahedral platinum(IV) complexes are promising candidates in the fight against cancer. In order to rationalize the further development of this class of compounds, detailed studies on their mechanisms of action, toxicity, and resistance must be provided and structure-activity relationships must be drawn. Herein, we report on theoretical and QSAR investigations of a series of 53 novel bis-, tris-, and tetrakis(carboxylato)platinum(IV) complexes, synthesized and tested for cytotoxicity in our laboratories. The hybrid DFT functional wb97x was used for optimization of the structure geometry and calculation of the descriptors. Reliable and robust QSAR models with good explanatory and predictive properties were obtained for both the cisplatin sensitive cell line CH1 and the intrinsically cisplatin resistant cell line SW480, with a set of four descriptors.

Figure 1

Scheme of the mechanism of action of platinum-based cytostatics.

Figure 2

Schematic formulas of the investigated complexes.

Figure 3

Comparative diagram of the cytotoxicity (IC₅₀ values, logarithmic scale) of some Pt(IV) complexes from the series in the CH1 cell line, depending on their equatorial ligands (y axis) and the terminal moieties of the axial ligands (x axis), and the clinically approved Pt(II) drugs: cisplatin, carboplatin, oxaliplatin, and nedaplatin.

Figure 4

ESP color mapped electron density for complexes 22 (left) and 36 (right).

Figure 5

NPA charge at the Pt atom (in au), calculated for complexes 1–53. A scheme of the coordination sphere of subsets 1 and 2 is presented on the right.

Figure 6

Frontier orbitals (with their energies) of complexes 22 (top) and 38 (bottom).

Figure 7

Scheme of possible reduction reactions to pentacoordinated Pt complex for M1 (bottom) and M2 (top).

Figure 8

Predicted (with the selected four-variable model) vs experimental cytotoxicity in the cell line CH1. The coloring is based on the subtypes containing the same equatorial ligands.

Figure 9

Scoring plot derived from PCA on the four descriptors (MW, E_eas′, H_don, and H_acc) used in the proposed model for cytotoxicity in the CH1 cells: cluster I, esters from subset 1; cluster II, esters from subset 2; cluster III, amides and free carboxylic acids from subset I and nedaplatin derivatives (48–50); cluster IV, amides and free carboxylic acids from subset 2 and complexes 17 and 18 from subset 1; cluster V, compounds with terminal CH₂OH groups in the axial ligands.

Figure 10

Predicted (with the selected four-variables model) vs experimental cytotoxicity in the SW480 cell line: top, model 1; middle, model 2; bottom, model 3. The coloring is based on the subtypes containing the same equatorial ligands.

Figure 11

Score plot derived from PCA using four descriptors (E_i, E_ea, E_eas, and H_don), applied for modeling the cytotoxicity in SW480 cells (model 3): cluster I, compounds with a terminal free CH₂OH group in the axial ligands; cluster II, amides and free carboxylic acids from subset 1; cluster III, amides and free carboxylic acids from subset 2 and 17 and 18 from subset 1; cluster IV, esters from subset 1 (without the EtNH₂ derivatives); cluster V, esters from subset 1/the EtNH₂ derivatives; cluster VI, esters from subset 2.