Cytotoxic hydrophilic iminophosphorane coordination compounds of d⁸ metals. Studies of their interactions with DNA and HSA.
The synthesis and characterization of a new water-soluble N,N-chelating iminophosphorane ligand TPAN-C(O)-2-NC(5)H(4) (N,N-IM) (1) and its d(8) (Au(III), Pd(II) and Pt(II)) coordination complexes are reported. The structures of cationic [AuCl(2)(N,N-IM)]ClO(4) (2) and neutral [MCl(2)(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/H(2)O over 4 days, the gold derivative (2) decomposes quickly to TPAO and previously reported neutral gold(III) compound [AuCl(2)(N,N-H)] 5 (containing the chelating N,N-fragment HN-C(O)-2-NC(5)H(4)). 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.
Department of Chemistry, Brooklyn College and The Graduate Center, The City University of New York, Brooklyn, NY 11210, USA.
Monica
M
Carreira
Rubén
R
Calvo-Sanjuán
Mercedes
M
Sanaú
Xiangbo
X
Zhao
Richard S
RS
Magliozzo
Isabel
I
Marzo
María
M
Contel
D000970:Antineoplastic Agents / Q000737:chemistry*; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D002945:Cisplatin / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D008670:Metals / Q000737:chemistry*; D010753:Phosphoranes / Q000737:chemistry*; D012709:Serum Albumin / Q000737:chemistry*; D013050:Spectrometry, Fluorescence; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction
D000970:Antineoplastic Agents; D008670:Metals; D010753:Phosphoranes; D012709:Serum Albumin; D004247:DNA; D002945:Cisplatin