Studies on DNA interaction of organotin(IV) complexes of meso-tetra(4-sulfonatophenyl)porphine that show cellular activity

Abstract

The interaction of the diorgano-and triorganotin(IV) derivatives of meso-tetra-(4-sulfonatophenyl)porphine (Me2Sn)2TPPS, (Bu2Sn)2TPPS, (Me3Sn)4TPPS and (Bu3Sn)4TPPS to natural DNA was analysed (together with free meso-tetra-(4-sulfonatophenyl)porphine (H4TPPS) for comparison purposes). Particular attention was paid to (Bu3Sn)4TPPS, a species that shows significant cellular action. Preliminary tests were done on the solution properties of the organotin(IV) compounds (pKA and possible self-aggregation). Spectrophotometric and spectrofluorometric experiments showed that all the investigated organotin(IV) derivatives strongly interact with DNA, the binding energy depending on the dye steric hindrance. In all cases experimental data concur in indicating that external binding mode prevails. Interestingly, fluorescence quenching and viscosity experiments show that the Bu-containing species, and in particular (Bu3Sn)4TPPS, are able to noticeably alter the DNA conformation.

Dibutyltin(IV) and Tributyltin(IV) Derivatives of meso-Tetra(4-sulfonatophenyl)porphine Inhibit the Growth and the Migration of Human Melanoma Cells

“…In melanoma cells the treatment with nanomolar concentrations of (Bu 2 Sn) 2 TPPS and (Bu 3 Sn) 4 TPPS is mostly associated, although with different outcomes, to a significant decrease of the expression of integrin and CAM adhesion receptors and especially to the consequent inhibition of the cellular motility. The lipophilicity of the butyl moieties [15] enables (Bu 2 Sn) 2 TPPS and (Bu 3 Sn) 4 TPPS to cross and to intercalate the lipid bilayer of the membrane, to bind phospholipids, glycoproteins and receptors, thus modifying the structure and functionality of the membranes [52], could explain the reported results. Therefore, the decreased expression of integrin and CAM adhesion receptors in treated melanoma cells, could inhibit not only the cellular motility, but also the homologous and heterologous interactions between melanoma and endothelial cells thus preventing the cells from assembling in clumps and the melanoma intravasation, extravasation and metastatic spread.…”

“…Furthermore, the A375, HT-144 and M74 human melanoma cell lines harbouring the mutation V600E of BRAF, also express the mutated form of several common and different proteins such as ATM in HT-144 cells, instead, in A375 and M74 cells the promoter of TERT is mutated [32][33][34], thus eliciting the reported different sensitivity to the treatment with (Bu 2 Sn) 2 TPPS and (Bu 3 Sn) 4 TPPS. Indeed, the hydrophobic butyl components of the (Bu 2 Sn) 2 TPPS and the (Bu 3 Sn) 4 TPPS, can directly interact with DNA and in particular, the tin of the organotin(IV) compounds can bind not only to the DNA bases but also the functional groups of the DNA grooves and the phosphate of the DNA phosphodiester backbones [11][12][13]15]. Therefore, the high DNA binding affinity of these organotin(IV) compounds and mostly of (Bu 3 Sn) 4 TPPS, elicits the alteration of the DNA conformation [15] and the induction of DNA damage suggested by the increased expression of the full-length PARP-1 as well as by the inhibition of the growth and by the blockage of the cell cycle that we showed in treated melanoma cells.…”

“…Indeed, the hydrophobic butyl components of the (Bu 2 Sn) 2 TPPS and the (Bu 3 Sn) 4 TPPS, can directly interact with DNA and in particular, the tin of the organotin(IV) compounds can bind not only to the DNA bases but also the functional groups of the DNA grooves and the phosphate of the DNA phosphodiester backbones [11][12][13]15]. Therefore, the high DNA binding affinity of these organotin(IV) compounds and mostly of (Bu 3 Sn) 4 TPPS, elicits the alteration of the DNA conformation [15] and the induction of DNA damage suggested by the increased expression of the full-length PARP-1 as well as by the inhibition of the growth and by the blockage of the cell cycle that we showed in treated melanoma cells. In particular, our hypothesis is that (Bu 3 Sn) 4 TPPS has a higher DNA backbone affinity compared to (Bu 2 Sn) 2 TPPS and therefore the higher alteration of the DNA conformation could explain the earlier stop of the cell cycle reported in (Bu 3 Sn) 4 TPPS treated cells.…”

“…Indeed, tin-based compounds can bind some membrane and cytoplasmic proteins such as receptors and glycoproteins, can cross lipid bilayer membranes and reach the nucleus, where they can directly interact with the DNA bases through intercalation, can also interact with the functional groups of the DNA grooves and with the phosphate of the DNA phosphodiester backbones as anchoring sites for the tin [11][12][13]. The consequences of these interactions are both the structural and functional alterations of the membranes and the induction of DNA damage that leads to the blockage of cell division and cell growth of organotin(IV)-treated cancer cells [6,[8][9][10][14][15][16]. Moreover, the ligand molecules of the organotin(IV) complexes, modifying the reactivity, the lipophilicity, the configuration and the molecular structure of the complexes and therefore their binding activity and functions, play a significant role in modulating the anti-tumour activity of the organotin(IV) moieties [12,17].…”

Triorganotin complexes in cancer chemotherapy: Mechanistic insights and future perspectives

“…Aydinoglu et al reported that the interaction between DNA and porphyrin‐based tri ‐n‐ butyltin and trimethyltin(IV) derivatives containing meso‐tetra‐(4‐sulfonatophenyl)porphine ( 119 and 120 ) could be due to a synergistic effect resulting from the affinity of tin for phosphates and hydrophobic interactions. [ 143 ] The authors suggested that this interaction could potentially cause DNA conformation changes. A study by Naz et al described the DNA interaction with triorganotin(IV) derivatives of 2,4‐dichlorophenoxyacetic acid ( 121 and 122 ).…”