Impact of Hydrophobic Chains in Five-Coordinate Glucoconjugate Pt(II) Anticancer Agents

Abstract

This study describes new platinum(II) cationic five-coordinate complexes (1-R,R’) of the formula [PtR(NHC)(dmphen)(ethene)]CF3SO3 (dmphen = 2,9-dimethyl-1,10-phenanthroline), containing in their axial positions an alkyl group R (methyl or octyl) and an imidazole-based NHC-carbene ligand with a substituent R’ of variable length (methyl or octyl) on one nitrogen atom. The Pt–carbene bond is stable both in DMSO and in aqueous solvents. In DMSO, a gradual substitution of dmphen and ethene is observed, with the formation of a square planar solvated species. Octanol/water partitioning studies have revealed the order of hydrophobicity of the complexes (1-Oct,Me > 1-Oct,Oct > 1-Me,Oct > 1-Me,Me). Their biological activity was investigated against two pairs of cancer and non-cancer cell lines. The tested drugs were internalized in cancer cells and able to activate the apoptotic pathway. The reactivity of 1-Me,Me with DNA and protein model systems was also studied using UV–vis absorption spectroscopy, fluorescence, and X-ray crystallography. The compound binds DNA and interacts in various ways with the model protein lysozyme. Remarkably, structural data revealed that the complex can bind lysozyme via non-covalent interactions, retaining its five-coordinate geometry.

Exploring the Impact of Head Group Modifications on the Anticancer Activities of Fatty-Acid-like Platinum(IV) Prodrugs: A Structure–Activity Relationship Study

“…This new study focuses on exploring the structure-activity relationship of FALP derivatives (1-9 in Figure 1A), with a specific emphasis on how modifications of the carboxylic head group's hydrophobicity influence their anticancer activity and cellular responses (Figure 2A). Understanding the impact of hydrophobicity on the uptake of therapeutic molecules is widely recognized as a crucial factor in drug development [36,[47][48][49][50][51][52][53]. Remarkably, contrary to the widely accepted notion that increased hydrophobicity enhances the cellular uptake of therapeutic molecules, the primary findings of this study demonstrate that FALPs with hydrophilic modifications exhibit exceptional penetration into cancer cells and mitochondria.…”

Development of Cytotoxic GW7604-Zeise’s Salt Conjugates as Multitarget Compounds with Selectivity for Estrogen Receptor- Positive Tumor Cells

“…There are already numerous reports in the literature on the linking of metal complexes with macromolecules or other drugs via various alkyl chains. In most cases, a spacer was used to increase the hydrophobicity. − This study, however, aims to find a suitable spacer that minimizes the influence of the PtCl 3 unit on the interaction of GW7604 with its preferred target. It is thought that the selectivity of GW7604-Alk-PtCl 3 for hormone-dependent tumor cells and their cellular uptake is mediated through binding of the GW7604 moiety to the membrane-associated ER (mER).…”

Frontiers in New Drug Discovery: From Molecular Targets to Preclinical Trials

“…Their biological activity was investigated against two pairs of cancer and non-cancer cell lines. The tested drugs were internalized in cancer cells and were able to activate the apoptotic pathway [1]. The regio-and diastereoselective synthesis of novel pyrrolidine-fused spiro-dihydrophosphacoumarins were presented in [2].…”