Cytotoxic hydrophilic iminophosphorane coordination compounds of d8 metals. Studies of their interactions with DNA and HSA

Abstract

The synthesis and characterization of a new water-soluble N,N-chelating iminophosphorane ligand TPA=N-C(O)-2-NC5H4 (N,N-IM) (1) and its d8 (AuIII, PdII and PtII) coordination complexes are reported. The structures of cationic [AuCl2(N,N-IM)] ClO4 (2) and neutral [MCl2(N,N-IM)] M = Pd (3), Pt(4) complexes were determined by X-ray diffraction studies or by means of density-functional calculations. While the Pd and Pt compounds are stable in mixtures of DMSO/H2O over 4 days, the gold derivative (2) decomposes quickly to TPA=O and previously reported neutral gold(III) compound [AuCl2(N,N-H)] 5 (containing the chelating N,N- fragment HN-C(O)-2-NC5H4). The cytotoxicities of complexes 2–5 were evaluated in vitro against human Jurkat-T acute lymphoblastic leukemia cells and DU-145 human prostate cancer cells. Pt (4) and Au compounds (2 and 5) are more cytotoxic than cisplatin to these cell lines and to cisplatin-resistant Jurkat sh-Bak cell lines and their cell death mechanism is different from that of cisplatin. All the compounds show higher toxicity against leukemia cells when compared to normal human T-lymphocytes (PBMC). The interaction of the Pd and Pt compounds with calf thymus and plasmid (pBR322) DNA is different from that of cisplatin. All compounds bind to human serum albumin (HSA) faster than cisplatin (measured by fluorescence spectroscopy). Weak and stronger binding interactions were found for the Pd (3) and Pt (4) derivatives by isothermal titration calorimetry. Importantly, for the Pt (4) compounds the binding to HSA was reversed by addition of a chelating agent (citric acid) and by a decrease in pH.

Luminescent iminophosphorane gold, palladium and platinum complexes as potential anticancer agents

“…24 The distances Au-N(1), Au-M(2), Au-Cl(1) and Au-Cl(2) in 3 are similar to the ones obtained by X-ray crystallographic analysis or DFT calculations for [AuCl 2 (Ph 2 PyP=NC(O)-Ph)]ClO 4 , 32 [(Ph 3 P=N-CH 2 -2-NC 5 H 4 )AuCl 2 ]ClO 4 , 32 [AuCl 2 (TPA=N-C(O)-2-NC 5 H 4 )]ClO 4 22 [({Cp-P(Ph 2 )=N-CH 2 -2-NC 5 H 4 }AuCl 2 ) 2 Fe](ClO 4 ) 2 24 and [{(Cp-P(Ph 2 )=N-CH 2 -2-NC 5 H 4 )AuCl 2 }Fe(Cp)]ClO 4 . 24 The distances P=N are shorter than in compounds which incorporate a carbonyl group bonded to the iminic nitrogen (due to a smaller delocalized charge density as compared to the CO group).…”

“…The main distances M-N(1) or M-N(iminic) and M-N(2) found for the Pd complex 4 are similar to that in related iminophosphorane complexes like [PdCl 2 (TPA=N-C(O)-2-NC 5 H 4 )], 22 [Pd{k 2 -C,N-C 6 H 4 (PPh 2 =NC 6 H 4 Me-4′)-2}{μ-OAc)}] 2 , 30 [Pd{k 2 -C,N-C 6 H 4 (PPh 2 =NC 6 H 4 Me-4′)-2}(tmeda)]ClO 4 , 30 [Pd(C 6 H 4 CH 2 NMe 2 )(Ph 3 PNC(O)-2-NC 5 H 4 )]ClO 4 , 31 [({Cp-P(Ph 2 )=N-CH 2 -2-NC 5 H 4 }PdCl 2 ) 2 Fe] 24 and [{(Cp-P(Ph 2 )=N-CH 2 -2-NC 5 H 4 )PdCl 2 }Fe(Cp)]. 24 The distances Au-N(1), Au-M(2), Au-Cl(1) and Au-Cl(2) in 3 are similar to the ones obtained by X-ray crystallographic analysis or DFT calculations for [AuCl 2 (Ph 2 PyP=NC(O)-Ph)]ClO 4 , 32 [(Ph 3 P=N-CH 2 -2-NC 5 H 4 )AuCl 2 ]ClO 4 , 32 [AuCl 2 (TPA=N-C(O)-2-NC 5 H 4 )]ClO 4 22 [({Cp-P(Ph 2 )=N-CH 2 -2-NC 5 H 4 }AuCl 2 ) 2 Fe](ClO 4 ) 2 24 and [{(Cp-P(Ph 2 )=N-CH 2 -2-NC 5 H 4 )AuCl 2 }Fe(Cp)]ClO 4 .…”

“…24 The distances P=N are shorter than in compounds which incorporate a carbonyl group bonded to the iminic nitrogen (due to a smaller delocalized charge density as compared to the CO group). 22–24,32 …”

“…21 We have also reported on the cytotoxicity of coordination and organometallic Pt(II) and Pd(II) complexes with water-soluble iminophosphorane ligands. 22,23 Interestingly, we observed that some of these Pt and Pd compounds ( b – d ) were more cytotoxic than cisplatin to leukemia cell lines (both T-Jurkat and cisplatin-resistant Jurkat sh-Bak) by a mode of action different to that of cisplatin. 22,23 …”

Synthesis, characterization and interaction with bovine serum albumin of cyclometallated Pd(II) complexes containing arylimine and salicylaldimine co-ligands

“…A similar effect (more than one binding site) was observed in the interaction of cyclometallated iminophosphorane complexes and HSA as well [6]. Moreover this same effect was observed in a quantitative way (by isothermal calorimetry ITC) with other coordination palladium iminophosphorane complexes [35].…”