Synthesis, characterisation and in vitro cytotoxicity of mixed ligand Pt(ii) oxadiazoline complexes with hexamethylenetetramine and 7-nitro-1,3,5-triazaadamantane

Abstract

trans-Platinum(ii) oxadiazoline complexes with 7-nitro-1,3,5-triazaadamantane (NO-TAA) or hexamethylenetetramine (hmta) ligands have been synthesised from trans-[PtCl(PhCN)] via cycloaddition of nitrones to one of the coordinated nitriles, followed by exchange of the other nitrile by NO-TAA or hmta. Stoichiometric control allows for the selective synthesis of mono- and dinuclear complexes where 7-NOTAA and hmta act as mono- and bidentate ligands, respectively. Precursors and the target complexes trans-[PtCl(hmta)(oxadiazoline)], trans-[PtCl(NO-TAA)(oxadiazoline)] and trans-[{PtCl(oxadiazoline)}(hmta)] were characterised by elemental analysis, IR and multinuclear (H, C,Pt) NMR spectroscopy. DFT (B3LYP/6-31G*/LANL08) and AIM calculations suggest a stronger bonding of hmta with the [PtCl(oxadiazoline)] fragment, in agreement with the experimentally observed reactivity in the ligand exchange (hmta > 7-NOTAA). Replacement of the nitrile by hmta is predicted to be more exothermic than that with 7-NO-TAA, although the activation barriers are similar. Protonation of the non-coordinated N atoms is anticipated to weaken the Pt-N bond and lower the activation barrier for ligand exchange. This effect might help activate these compounds in a slightly acidic environment such as some tumour tissues. Ten of the new compounds were tested for their in vitro cytotoxicity in the human cancer cell lines HeLa and A549. Some of the mononuclear complexes are more potent than cisplatin, and their activity is still high in A549 where cisplatin shows little effect. The dinuclear complexes are inactive, presumably due to their lipophilicity and reduced solubility in water.

Facile construction of the all-bridge-position-functionalized 2,4,6,8-tetraazaadamantane skeleton and conversion of its N-functionalities

“…, daphodhamine B 1 and terengganensine A 2 ), drugs 3 ( e.g. , antiemetics, 4 antivirals, 5 bactericidals, 3 c ,6 analgesics, 7 and anticancer drugs 8 ), energetic materials, 9 organocatalysts, 10 organoligands, 11 organic redox mediators, 12 etc . Considerable progress has also been made in the post-synthesis of azaadamantanes.…”

trans‐Platinum(II) Thionate Complexes: Synthesis, Structural Characterization, and in vitro Biological Assessment as Potent Anticancer Agents

“…Trans ‐configured Pt(II) complexes have been introduced as a strategy to potentially overcome the drawbacks and diminish severe side effects, drug resistance, poor selectivity and serious toxicity of cisplatin . They have displayed considerable in vitro antiproliferative effects against a wide range of cancer cells . The unique cytotoxicity profiles of trans ‐Pt(II) complexes with bulky planar ligands are attributed to their different structural and DNA‐binding properties in comparison with cisplatin analogues .…”

“…[10] They have displayed considerable in vitro antiproliferative effects against a wide range of cancer cells. [11] The unique cytotoxicity profiles of trans-Pt(II) complexes with bulky planar ligands are attributed to their different structural and DNA-binding properties in comparison with cisplatin analogues. [12] Sterically hindered Pt(II) complexes would have reduced reactivity in a substitution reaction with all potential targets, i. e., nucleophiles on DNA, proteins and small molecules.…”