BODIPY-Appended Pt(II) Complexes with High Toxicities and Anti-chemoresistance Performances in a Cisplatin Resistant In Vivo Model

Abstract

Two novel fluorophore (BODIPY)-bearing complexes, pyriplatin (mCBP) and pyrimidine-chelated cisplatin (dCBP), were synthesized and characterized. The additional BODIPY-pyridine/pyridimine motifs of the two Pt(II) complexes resulted in stronger interactions with DNA in comparison with those of cisplatin. mCBP and cisplatin caused relative decreases in life span and body length in a cisplatin resistant in vivo model, N2 (wild-type) Caenorhabditis elegans. In contrast, dCBP resulted in a dramatic reduction in the two physiological parameters in N2 C. elegans, indicating high toxicity and sensitivity. The resistance factors (RF) of cisplatin, mCBP, and dCBP were determined to be 2.46, 1.04, and 0.91, respectively. The increasing RF folds for mCBP and dCBP against cisplatin were 2.36 and 2.70, respectively. This suggested they were featured with improved anti-chemoresistance capabilities. It is noteworthy that dCBP showed lowest lethal concentration (LC 50 ) values of 0.56 and 0.61 mM in cisplatin resistant and sensitive in vivo models, respectively. Upregulation of several evolutionary conservation genes that regulate cisplatin chemoresistance through cisplatin effluxing, the DNA damage response, the unfolded protein response, and detoxification (asna-1, parp-1, enpl-1, and skn-1) was observed upon exposure to cisplatin but not to mCBP and dCBP. This could explain the improved anti-chemoresistance performances of synthesized Pt(II) complexes.

Computational Analysis of the Behavior of BODIPY Decorated Monofunctional Platinum(II) Complexes in the Dark and under Light Irradiation

“…From a comparison between the values obtained for dCBP and its parent Pyrim , it appears that the presence of the appended BODIPY does not play a significant role at this stage and the more sterically hindered structure of the binuclear Pt complex, regardless the presence of the BODIPY moiety, penalizes the second guanine attack. According to the enhanced experimentally observed loss of DNA helical structure for dCBP , , it can be inferred from such results that, in analogy to phenanthriplatin, , the first attack to a guanine base causes an initial DNA double helix distortion. Such a distortion could lead to a rearrangement of the real DNA flexible structure more favorable to the second guanine attack and, therefore, to cross-linking.…”

“…In addition, it has been hypothesized that the binuclear dCBP complex is able to cause enhanced DNA damage due to its DNA cross-linking capability. 16 Quantum mechanical DFT and time dependent DFT calculations have been used to carry out a detailed investigation of some aspects of the cytotoxic activity of such complexes by examining the key steps of the mechanism of action of Pt(II)-based drugs and photophysical properties and how such properties are influenced by the substitution of the chlorido ligand with water and by the interactions established with DNA bases.…”

“…Unlike cisplatin, nonetheless, only a single bond can be formed with DNA, as in such drugs only one labile ligand is bound to the metal center, and due to additional interactions and steric hindrance, cellular repair ability via transcription is reduced and apoptosis is induced with a different mechanism. , Aiming at enhancing the efficacy of monofunctional anticancer agents, dual-action complexes have been designed by appending a suitable photosensitizer (PS) to the ligand bound to platinum­(II). Two-component systems of this kind have recently received increasing attention due to the possibility to combine the DNA cross-linking ability of the complex bearing a labile anionic ligand, generally a chloride, with the photodynamic therapy (PDT) effect of a PS. − PDT is an alternative treatment for the control of malignant diseases based on the uptake of a photosensitizing molecule which, upon being excited by light of proper wavelength, reacts with oxygen and generates oxidant species in target tissues, leading to cell death. , The PS, in the photodynamic process, is promoted from its ground singlet state to an excited one. The excitation is followed by an intersystem crossing (ISC) transition to a lower triplet state, being a usually forbidden nonradiative process that can take place if the relativistic spin–orbit coupling (SOC) between the two states is large enough and the involved states are close in energy to permit the process to be efficient.…”

“…Given such premises and due to the prominent place that dual-action drugs are occupying in the scientific landscape of cancer research thanks to the possibility to combine different therapeutic strategies within one molecule, we have carefully examined both the photophysical properties and the key steps of the mechanism of action of two BODIPY-appended monofunctional Pt­(II) complexes recently synthesized and tested for their cytotoxicity. , The structures of the two investigated complexes named in the original papers mCBP {[ cis -Pt­(NH 3 ) 2 Cl]-8-( p -pyridinemethylene),1,3,5,7-tetramethyldipyrrinborondifluoride} + and dCBP {[ cis -Pt­(NH 3 ) 2 Cl] 2 -8-(1,3-pyrimidine-5-methylene),1,3,5,7-tetramethyldipyrrinborondifluoride} 2+ , are shown in Scheme , with the latter being a binuclear Pt­(II) complex. For both compounds, it is reported that they show promising ROS generating capability under light irradiation reinforcing the classical chemo-therapic action in the dark caused by DNA distortion.…”

“…For both compounds, it is reported that they show promising ROS generating capability under light irradiation reinforcing the classical chemo-therapic action in the dark caused by DNA distortion. In addition, it has been hypothesized that the binuclear dCBP complex is able to cause enhanced DNA damage due to its DNA cross-linking capability …”