New trans dichloro (triphenylphosphine)platinum(II) complexes containing N-(butyl),N-(arylmethyl)amino ligands: Synthesis, cytotoxicity and mechanism of action

Some new platinum(II) complexes have been prepared, of general formula trans-[PtCl2(PPh3)NH(Bu)CH2Ar], where the dimension of the Ar residue in the secondary amines has been varied from small phenyl to large pyrenyl group. The obtained complexes, tested in vitro towards a panel of human tumor cell lines showed an interesting antiproliferative effect on both cisplatin-sensitive and -resistant cells. For the most cytotoxic derivative 2a the investigation on the mechanism of action highlighted the ability to induce apoptosis on resistant cells and interestingly, to inhibit the catalytic activity of topoisomerase II

New insights in the structure-activity relationships of 2-phenylamino-substituted benzothiopyrano[4,3-d]pyrimidines as kinase inhibitors

Inhibition of angiogenesis via blocking vascular endothelial growth factor receptor (VEGFR) signaling pathway emerged as an established approach in anticancer therapy. So far, many monoclonal antibodies and ATP-competitive small molecule inhibitors have been clinically validated and approved. In this study, structure-activity relationships (SAR) within the 2-phenylamino-substituted benzothiopyrano[4,3-d]pyrimidine class of kinase inhibitors were further refined by the synthesis and biological evaluation of new compounds 1â\u80\u9321 featuring different substitution patterns on the pendant phenyl moiety, combined with H, OCH3, or Cl at 8-position. Most compounds showed a promising human kinase insert domain receptor (KDR) inhibition profile, with IC50values in the submicromolar/low nanomolar range, and promising antiproliferative activity on human umbilical vein endothelial cells (HUVECs) as well as on a panel of three human tumor cell lines. The angio-kinase selectivity profile was assessed for the most promising compound 16 against a set of six human kinases. Finally, computational studies allowed clarifying at molecular level the interaction pattern established by the compounds with KDR, highlighting key stable cation-Ï\u80 interactions, and thus providing the basis for further designing novel inhibitors

Antiproliferative activity of platinum(II) complexes containing triphenylphosphine: correlation between structure and biological activity.

none6A series of neutral complexes of platinum(II) of general formula [PtCl2L(PPh3)] [L = Et2NC(Me)NH, SOMe2, CO, Et2NH, (HOCH2CH2)2NH, Bz2NH, N-morpholine] was prepared starting from suitable precursors. The syntheses and spectroscopic characterizations of the two new complexes trans-[PtCl2(N-morpholine)(PPh3)] and cis-[PtCl2(SOMe2)(PPh3)] are described as well as their X-ray structures. The antiproliferative activity of all the available compounds was tested in vitro against HeLa, H460 and A549 human tumor cell lines. A brief discussion regarding the structure–activity correlation is presented.restrictedBelli Dell’Amico, Daniela; Dalla Via, Lisa; García-Argáez, Aída Nelly; Labella, Luca; Marchetti, Fabio; Samaritani, SimonaBelli Dell’Amico, Daniela; DALLA VIA, Lisa; GARCIA ARGAEZ, AIDA NELLY; Labella, Luca; Marchetti, Fabio; Samaritani, Simon

The antioxidant, aged garlic extract, exerts cytotoxic effects on wild-type and multidrug-resistant human cancer cells by altering mitochondrial permeability

Aged garlic extract (AGE) has been shown to possess therapeutic properties in cancer; however its mechanisms of action are unclear. In this study, we demonstrate by MTT assay that AGE exerts an anti-proliferative effect on a panel of both sensitive and multidrug-resistant (MDR) human cancer cell lines and enhances the effects of hyperthermia (42C) on M14 melanoma cells. The evaluation of the mitochondrial activity in whole cancer cells treated with AGE, performed by cyto-fluorimetric analysis in the presence of the lipophilic cationic fluorochrome JC-1, revealed the occurrence of dose-dependent mitochondrial membrane depolarization. Membrane potential was measured by the TPP+selective electrode. In order to shed light on its mechanisms of action, the effects of AGE on isolated rat liver mitochondria were also examined. In this regard, AGE induced a mitochondrial membrane hyperpolarization of approximately 15 mV through a mechanism that was similar to that observed with the ionophores, nigericin or salinomycin, by activating an exchange between endogenous K+with exogenous H+. The prolonged incubation of the mitochondria with AGE induced depolarization and matrix swelling, indicative of mitochondrial permeability transition induction that, however, occurs through a different mechanism from the well-known one. In particular, the transition pore opening induced by AGE was due to the rearrangement of the mitochondrial membranes following the increased activity of the K+/H+exchanger. On the whole, the findings of this study indicate that AGE exerts cytotoxic effects on cancer cells by altering mitochondrial permeability. In particular, AGE in the mitochondria activates K+/H+exchanger, causes oxidative stress and induces mitochondrial permeability transition (MPT)

Boehmeriasin A as new lead compound for the inhibition of topoisomerases and SIRT2

Two synthetic approaches to boehmeriasin A are described. A gram scale racemic preparation is accompanied by an efficient preparation of both the pure enantiomers using the conformationally stable 2-piperidin-2-yl acetaldehyde as starting material. The anti-proliferative activity in three cancer cell lines (CEM, HeLa and L1210) and two endothelial cell lines (HMEC-1, BAEC) indicates promising activity at the nanomolar range. Topoisomerases and SIRT2 are identified as biological targets and the experimental data has been supported by docking studies.publisher: Elsevier articletitle: Boehmeriasin A as new lead compound for the inhibition of topoisomerases and SIRT2 journaltitle: European Journal of Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.ejmech.2015.01.038 content_type: article copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.status: publishe