Anticancer C,N-cycloplatinated(II) complexes containing fluorinated phosphine ligands: synthesis, structural characterization, and biological activity.
A series of potent C,N-cycloplatinated(II) phosphine antitumor complexes containing fluorous substituents in the cyclometalated or the ancillary phosphine ligands [Pt(C-N)(PR3)Cl] or both have been synthesized and characterized. The crystal structure of [Pt(dmba){P(C6H4CF3-p)3}Cl]·2CH2Cl2 (dmba = dimethylaminomethyl)phenyl) has been established by X-ray diffraction. Values of IC50 of the new platinum complexes were calculated toward a panel of human tumor cell lines representative of ovarian (A2780 and A2780cisR) and breast cancers (T47D). Complexes containing P(C6H4CF3-p)3 as ancillary ligand (with a bulky and electronegative CF3 substituent in para position) were the most cytotoxic compounds in all the tested cancer cell lines. In some cases, the IC50 values were 16-fold smaller than that of cisplatin and 11-fold smaller than the non-fluorous analogue [Pt(dmba)(PPh3)Cl]. On the other hand, very low resistance factors (RF) in A2780cisR (cisplatin-resistant ovarian carcinoma) at 48 h were observed (RF ≈ 1) for most of the new compounds. Analysis of cell cycle was done for the three more active compounds in A2780. They arrest cell growth in G0/G1 phase in contrast to cisplatin (S phase) with a high incidence of late-stage apoptosis. They are also good cathepsin B inhibitors (an enzyme implicated in a number of cancer related events).
Departamento de Química Inorgánica and Regional Campus of International Excellence "Campus Mare Nostrum", Universidad de Murcia and Instituto Murciano de Investigación Biosanitaria (IMIB) , E-30071 Murcia, Spain.
Natalia
N
Cutillas
Alexandra
A
Martínez
Gorakh S
GS
Yellol
Venancio
V
Rodríguez
Ana
A
Zamora
Mónica
M
Pedreño
Antonio
A
Donaire
Christoph
C
Janiak
José
J
Ruiz
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002401:Cathepsin B / Q000378:metabolism; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D005260:Female; D054879:Halogenation; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D010053:Ovary / Q000187:drug effects / Q000473:pathology; D010720:Phosphines / Q000737:chemistry* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; D010720:Phosphines; D002401:Cathepsin B; C044646:phosphine