Spectroscopic, X-ray crystallographic and preliminary biological screening study of unsymmetrical diphosphinoamine (PNP’) and monodentate aminophosphine (PNH) ligands coordinated to Pt(II)

Abstract

An efficient and simple synthetic route to a new class of unsymmetrical diphosphinoamine {PNP'=(o-Tol)2P'N(R1)P(R2)2} and monophosphinoamine {(o-Tol)2P(R1)NH} ligands are presented, which allowed the manipulation of the R1 substituents on the amine as well as the cyclic R2 substituents on the phosphorus atom. The unsymmetrical (o-Tol)2P'N(R1)P(R2)2 ligands {R1 = p-MePh (A), o-MePh (B), p-ClPh (C) or p-FPh (D)} and their coordination to a Pt(II) metal center as [Pt{κ2-(P,P')(PNP')}Cl2] (3N; N = A, C, D) type of complexes are presented. In addition, monophosphinoamine ligands {(o-Tol)2P(R1)NH} are described, yielding the cisplatin analogue cis-[Pt((o-Tol)2P(p-MePh)NH)2Cl2] (2A), and trans-[Pt((o-Tol)2P(o-MePh)NH)2Cl2] (2B). Five single crystal X-ray studies are reported (2A, 2B, 3A, 3C, 3D), together with a detailed 31P NMR spectroscopy study. The electrostatic and steric repulsions on the ortho-CH3 on these types of ligands induces restricted rotation as seen by solution NMR spectra of all free ligands. The presence of two stable conformers (syn,syn,anti) and (syn,syn,syn) for the free PNP' ligands is illustrated, both in solution and solid state (31P MAS NMR). Moreover, in the synthesis, a scrambling/disproportionation of the unsymmetrical PNP' ligand is observed, yielding some 20% of the corresponding symmetrical PNP nucleophiles. However, the (syn,syn,anti)-conformer disappear upon coordination to the Pt(II), as required by the cis-[Pt(PNP')Cl2] complexes. The two Pt-PN complexes cis-[Pt((o-Tol)2P(p-MePh)NH)2Cl2] (2A) and trans-[Pt((o-Tol)2P(o-MePh)NH)2Cl2] (2B) were evaluated for biological activity to ascertain whether the stereo chemistry on these would show more activity as analogous cisplatin and derivatives. Additionally, 2A and 2B were also screened for antimicrobial activity. Significant microbial inhibition against Gram-positive Staphylococcus aureus and two Fungi Cryptococcus neoformans and Candida albicans was found for complex trans-[Pt(p-MePh-PNH)2Cl2] (2A), while the cytotoxicity evaluation of 2A against HEK293 human embryonic kidney cells displayed a moderate activity CC50 of 18.1 μM.