Conjugation of testosterone modifies the interaction of mono-functional cationic platinum(ii) complexes with DNA, causing significant alterations to the DNA helix

Abstract

Previously a range of androgen conjugates with non-conventional platinum(II) complexes have been synthesised with the aim of enhancing cellular delivery, and which have shown increased cytotoxic activity compared with non-steroidal compounds (M. J. Hannon et al., Dalton Trans., 2010, DOI: 10.1039/c0dt00838a). To further study this, the complexes have been assessed for their ability to bind to and alter the structure of DNA. All platinum(II) complexes studied herein bind to model nucleo-bases and DNA, but to our surprise, testosterone-based complexes caused the DNA helix to undergo significant unwinding and bending, whereas non-steroidal control complexes caused minimal structural alterations. These effects are similar to those cisplatin induces on DNA structure despite the fact that these compounds produce a monofunctional lesion. This ability attributed to interactions between the DNA helix and bulky steroidal skeleton of testosterone, coupled with the enhanced cellular delivery induced by the steroid make the steroid approach an exciting way to explore non-conventional platinum drug delivery.

Synthesis of a DNA-targeting nickel (II) complex with testosterone thiosemicarbazone which exhibits selective cytotoxicity towards human prostate cancer cells (LNCaP)

“…These testosterone-based complexes also caused the DNA helix to undergo unwinding and bending. These reported effects are similar to those induced by cisplatin on DNA structure [20]. Furthermore, a Schiff base containing testosterone and a thiosemicarbazone molecule was prepared by Al-Bayati et al and the antimicrobial property of this compound was reported [21].…”

Understanding trans platinum complexes as potential antitumor drugs beyond targeting DNA

“…In particular our design was aimed to create a testosterone conjugates of a non-conventional platinum(II) structures. The conjugation of steroids to platinum fragments showed a clear advantage on the delivery of the drug inside the cell [44,45]. The results showed that the linkage of a steroid moieties to the platinum units produce not only increased the cytotoxicity compared with the non-steroidal complex but also higher uptake.…”

“…The results showed that the linkage of a steroid moieties to the platinum units produce not only increased the cytotoxicity compared with the non-steroidal complex but also higher uptake. Finally, although the correlation of the activity with the AR status of the cell is complicated and we must be cautious in this regard, the specificity of the new complexes is higher than cisplatin and the non-steroidal controls [44,45].…”

Disturbance of DNA conformation by the binding of testosterone-based platinum drugs via groove-face and intercalative interactions: a molecular dynamics simulation study

“…Especially, the groove-face and intercalative interactions could greatly stabilize the distorted DNA molecule via hydrogen bonds and hydrophobic interactions, etc [17,18,20,21]. Therefore, some pioneering strategies toward improving the ligand properties of monofunctional platinum agents have emerged [15,23-27]. However, the systematic studies on the relationship between the ligand properties of platinum agents and interaction modes in the platinum + DNA adducts have not yet been clearly detailed so far.…”