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Fluorinated Cycloplatinated(II) Complexes Bearing Bisphosphine Ligands as Potent Anticancer Agents.

ABSTRACT: A family of cationic cycloplatinated(II) complexes [Pt(dfppy)(P^P)]Cl, dfppy = 2-(2,4-difluorophenyl)pyridine, incorporating bisphosphine ligands, P^P = bis(diphenylphosphino)methane (1, dppm), 1,2-bis(diphenylphosphino)ethane (2, dppe) and 1,2-bis(diphenylphosphino)benzene (3, dppbz), was prepared. The complexes were characterized by means of several analytical and spectroscopic methods. These complexes displayed acceptable stability in the biological environments which was confirmed by NMR, HR ESI-MS and UV-vis techniques. The antiproliferative properties of these complexes were evaluated by National Cancer Institute (NCI) at National Institutes of Health (NIH) against 60 different human tumor cell lines such as leukemia, melanoma, lung, colon, brain, ovary, breast, prostate and kidney. These complexes showed higher cytotoxicity than cisplatin against a wide variety of cancer cell lines such as K-562 (leukemia), HOP-92 (lung), HCT-116 (colon), OVCAR-8 (ovarian), PC-3 (prostate), MDA-MB-468 (breast), and melanoma cancer cell lines. Complex 3 as the most potent compound in this study furnished an excellent anti-proliferative activity compared to the cisplatin against Hela, SKOV3, and MCF-7 cancer cell lines. The main mode of the interaction of 1-3 with DNA was also determined using molecular docking studies.

SUBMITTER: Shahsavari HR

PROVIDER: S-EPMC8320711 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Chelating phosphines are effective additives and supporting ligands for a wide array of iron-catalyzed cross-coupling reactions. While recent studies have begun to unravel the nature of the in situ-formed iron species in several of these reactions, including the identification of the active iron species, insight into the origin of the differential effectiveness of bisphosphine ligands in catalysis as a function of their backbone and peripheral steric structures remains elusive. Herein, we report a spectroscopic and computational investigation of well-defined FeCl2(bisphosphine) complexes (bisphosphine = SciOPP, dpbz, (tBu)dppe, or Xantphos) and known iron(I) variants to systematically discern the relative effects of bisphosphine backbone character and steric substitution on the overall electronic structure and bonding within their iron complexes across oxidation states implicated to be relevant in catalysis. Magnetic circular dichroism (MCD) and density functional theory (DFT) studies demonstrate that common o-phenylene and saturated ethyl backbone motifs result in small but non-negligible perturbations to 10Dq(Td) and iron-bisphosphine bonding character at the iron(II) level within isostructural tetrahedra as well as in five-coordinate iron(I) complexes FeCl(dpbz)2 and FeCl(dppe)2. Notably, coordination of Xantphos to FeCl2 results in a ligand field significantly reduced relative to those of its iron(II) partners, where a large bite angle and consequent reduced iron-phosphorus Mayer bond orders (MBOs) could play a role in fostering the unique ability of Xantphos to be an effective additive in Kumada and Suzuki-Miyaura alkyl-alkyl cross-couplings. Furthermore, it has been found that the peripheral steric bulk of the SciOPP ligand does little to perturb the electronic structure of FeCl2(SciOPP) relative to that of the analogous FeCl2(dpbz) complex, potentially suggesting that differences in the steric properties of these ligands might be more important in determining in situ iron speciation and reactivity.

Project description:We report the synthesis, characterization, and antiproliferative activity of 15 iridium(III) half-sandwich complexes of the type [(?5-Cp*)Ir(2-(R'-phenyl)-R-pyridine)Cl] bearing either an electron-donating (-OH, -CH2OH, -CH3) or electron-withdrawing (-F, -CHO, -NO2) group at various positions on the 2-phenylpyridine (2-PhPy) chelating ligand giving rise to six sets of structural isomers. The X-ray crystal structures of [(?5-Cp*)Ir(2-(2'-fluorophenyl)pyridine)Cl] (1) and [(?5-Cp*)Ir(2-(4'-fluorophenyl)pyridine)Cl] (2) exhibit the expected "piano-stool" configuration. DFT calculations showed that substituents caused only localized effects on the electrostatic potential surface of the chelating 2-PhPy ligand of the complexes. Hydrolysis of all complexes is rapid, but readily reversed by addition of NaCl. The complexes show preferential binding to 9-ethylguanine over 9-methyladenine and are active catalysts for the oxidation of NADH to NAD+. Antiproliferative activity experiments in A2780 ovarian, MCF-7 breast, A549 lung, and HCT116 colon cancer cell lines showed IC50 values ranging from 1 to 89 ?M, with the most potent complex, [(?5-Cp*)Ir(2-(2'-methylphenyl)pyridine)Cl] (13) (A2780 IC50 = 1.18 ?M), being 10× more active than the parent, [(?5-Cp*)Ir(2-phenylpyridine)Cl], and 2× more active than [(?5-CpxPh)Ir(2-phenylpyridine)Cl]. Intriguingly, contrasting biological activities are observed between structural isomers despite exhibiting similar chemical reactivity. For pairs of structural isomers both the nature and position of the functional group can affect the hydrophobicity of the complex. An increase in hydrophobicity resulted in enhanced cellular-iridium accumulation in A2780 ovarian cells, which generally gave rise to an increase in potency. The structural isomers [(?5-Cp*)Ir(2-(4'-fluorophenyl)pyridine)Cl] (2) and [(?5-Cp*)Ir(2-phenyl-5-fluoropyridine)Cl] (4) preferentially localized in the cytosol > membrane and particulate > nucleus > cytoskeleton. This work highlights the strong dependence of biological behavior on the nature and position of the substituent on the chelating ligand and shows how this class of organometallic anticancer complexes can be fine-tuned to increase their potency without using extended cyclopentadienyl systems.

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Fluorinated Cycloplatinated(II) Complexes Bearing Bisphosphine Ligands as Potent Anticancer Agents.

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