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

Coinage Metal Compounds With 4-Methoxy-Diphenylphosphane Benzoate Ligand Inhibit Female Cancer Cell Growth

In the continuous effort to find new metal-based compounds as alternatives to platinum related anticancer drugs, 11th group metal phosphane compounds have been thoroughly considered. Tris-arylphosphane metal derivatives have been extensively considered heteroleptic metal compounds exhibiting remarkable cytotoxic activities. Functional groups in the aryl moieties modulate the activity reinforcing or eliminating it. Previous works have highlighted that the presence of hydrophilic groups in the phosphane ligands, such as COOH or OH, hampers the anticancer activity of gold azolate/PPh3 compounds. To increase the polarity of the triarylphosphane ligand without affecting the activity, we considered the preparation of esters starting from the 4-diphenylphosphanebenzoic acid. The resulting phosphanes are poorer donators than the PPh3, leading to poly-phosphane M(I) compounds, and they exhibit intense emissive properties. A homologous series of L3MX-type compounds (where M = Au and X = Cl, M = Cu and X = BF4, and M = Ag and X = PF6) were obtained with the 4-methoxy-diphenylphosphane benzoate. The homologous metal compounds have been characterized by analytical and spectroscopic methods and, remarkably, their formation was associated with high frequencies of 31P NMR chemical shift variations (5–35 ppm in CDCl3). The new complexes and the ligand were evaluated on sensitive and cisplatin-resistant human tumor cell lines. The ligand is ineffective on cells while the complexes exert a notable antiproliferative effect. The homologous series of the L3MX complexes were able to significantly reduce the cell viability of human triple-negative breast cancer cells (MDAMB- 231), representing the most aggressive subtype of breast cancer, and of ovarian carcinoma (A2780). Among these coinage metal compounds, L3AgPF6 results the most interesting, showing the lowest GI50 values in all cell lines. Interestingly, this silver complex is more cytotoxic than cisplatin, taken as a reference drug. The investigation of the mechanism of action of L3AgPF6 in A2780 cells highlighted the induction of the apoptotic pathway, the depolarization of the mitochondrial inner membrane, and a significant accumulation in cells

Further characterization of agmatine binding to mitochondrial membranes: involvement of imidazoline I2 receptor.

Agmatine, a divalent diamine with two positive charges at physiological pH, is transported into the matrix of liver mitochondria by an energy-dependent mechanism, the driving force of which is the electrical membrane potential. Its binding to mitochondrial membranes is studied by applying a thermodynamic treatment of ligand-receptor interactions on the analyses of Scatchard and Hill. The presence of two mono-coordinated binding sites S(1) and S(2), with a negative influence of S(2) on S(1), has been demonstrated. The calculated binding energy is characteristic for weak interactions. S(1) exhibits a lower binding capacity and higher binding affinity both of about two orders of magnitude than S(2). Experiments with idazoxan, a ligand of the mitochondrial imidazoline receptor I(2), demonstrate that S(1) site is localized on this receptor while S(2) is localized on the transport system. S(1) would act as a sensor of exogenous agmatine concentration, thus modulating the transport of the amine by its binding to S(2)

From Monoamine Oxidase Inhibition to Antiproliferative Activity: New Biological Perspectives for Polyamine Analogs

: Monoamine oxidases (MAOs) are well-known pharmacological targets in neurological and neurodegenerative diseases. However, recent studies have revealed a new role for MAOs in certain types of cancer such as glioblastoma and prostate cancer, in which they have been found overexpressed. This finding is opening new frontiers for MAO inhibitors as potential antiproliferative agents. In light of our previous studies demonstrating how a polyamine scaffold can act as MAO inhibitor, our aim was to search for novel analogs with greater inhibitory potency for human MAOs and possibly with antiproliferative activity. A small in-house library of polyamine analogs (2-7) was selected to investigate the effect of constrained linkers between the inner amine functions of a polyamine backbone on the inhibitory potency. Compounds 4 and 5, characterized by a dianiline (4) or dianilide (5) moiety, emerged as the most potent, reversible, and mainly competitive MAO inhibitors (Ki < 1 μM). Additionally, they exhibited a high antiproliferative activity in the LN-229 human glioblastoma cell line (GI50 < 1 μM). The scaffold of compound 5 could represent a potential starting point for future development of anticancer agents endowed with MAO inhibitory activity

Synthesis and reactivity of cytotoxic platinum(II) complexes of bidentate oximes: a step towards the functionalization of bioactive complexes

Two new platinum(II) complexes bearing triphenylphosphine and bidentate oxime ligands [Pt(Cl)(PPh3){(κ2-N,O)-(1{C(R)=N(OH)-2(O)C10H6})}] (R = H, Me) were synthesized in good yields from trans-[PtCl(μ-Cl)(PPh3)]2. The structure of [Pt(Cl)(PPh3){(κ2-N,O)-(1{CH=N(OH)-2(O)C10H6})}] was determined by single-crystal X-ray diffraction. Both complexes showed good antiproliferative properties in vitro against HeLa, A2780, and A2780cis cancer cell lines. They reacted cleanly with alkylating agents in the presence of aqueous bases under phase-transfer catalysis conditions to afford the corresponding O-alkylation products [Pt(Cl)(PPh3){(κ2-N,O)-(1{HC=N(OR′)-2(O)C10H6})}] [R′ = CH2CH2Cl, CH2Ph, (CH2)4Br] in good yields

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

Anticancer gold(III) peptidomimetics: from synthesis to in vitro and ex vivo biological evaluation

Five new Au(III)‐peptidodithiocarbamato complexes of the type [AuIIIBr2(dtc‐AA1‐AA2‐OR] (AA1=Sar, L/D‐Pro; AA2=L/D‐Ala, Aib; R=OtBu, TEG), differing in the amino acidic sequence and/or the chiral amino acid configuration, were designed to enhance the tumor selectivity and bioavailability. The gold(III)‐based moiety was functionalized to exploit the targeting properties of the peptidomimetic ligand towards two peptide transporters (namely, PEPT1 and PEPT2), up‐regulated in several tumor cells. The compounds were synthesized and fully characterized, mainly by means of elemental analysis, mono‐ and bidimensional NMR spectroscopy, FT‐IR and UV‐Vis spectrophotometries. The crystal structures of three compounds were also solved by X‐ray diffraction. In vitro cytotoxicity studies using a panel of human tumor cell lines (A549, MCF‐7, A2780, H1975, H460 and A431) showed that the dtc‐Pro‐Aib‐OtBu derivative is very effective, with GI50 values much lower than those of Cisplatin. It was thus selected for evaluating the stability under physiological conditions and possible interaction with serum albumin as well as for PARP‐1 enzyme inhibition assays and preliminary ex vivo toxicity experiments on healthy rat tissues

Cytotoxic Acetogenins from the Roots of Annona purpurea

Annona purpurea, known in Mexico as "cabeza de negro" or "ilama", belongs to the Annonaceae family. Its roots are employed in folk medicine in several regions of Mexico. Taking that information into account, a chemical and biological analysis of the components present in the roots of this species was proposed. Our results demonstrated that the dichloromethane (DCM) extract was exclusively constituted by a mixture of five new acetogenins named annopurpuricins A-E (1-5). These compounds have an aliphatic chain of 37 carbons with a terminal \u3b1,\u3b2 unsaturated \u3b3-lactone. Compounds 1 and 2 belong to the adjacent bis-THF (tetrahydrofuran) \u3b1-monohydroxylated type, while compounds 3 and 4 belong to the adjacent bis-THF \u3b1,\u3b1'-dihydroxylated type; only compound 5 possesses a bis-epoxide system. Complete structure analysis was carried out by spectroscopy and chemical methods. All compounds were evaluated for their antiproliferative activity on three human tumor cell lines (MSTO-211H, HeLa and HepG2). Compounds 1-4 inhibited significantly the growth of HeLa and HepG2 cells, showing GI50 values in the low/subnanomolar range, while 5 was completely ineffective under the tested conditions. The investigation of the mechanism of action responsible for cytotoxicity revealed for the most interesting compound 1 the ability to block the complex I activity on isolated rat liver mitochondria (RLM)

Bidirectional fluxes of spermine across the mitochondrial membrane.

The polyamine spermine is transported into the mitochondrial matrix by an electrophoretic mechanism having as driving force the negative electrical membrane potential (DW). The presence of phosphate increases spermine uptake by reducingDpH and enhancingDW. The transport system is a specific uniporter constituted by a protein channel exhibiting two asymmetric energy barriers with the spermine binding site located in the energy well between the two barriers. Although spermine transport is electrophoretic in origin, its accumulation does not follow the Nernst equation for the presence of an efflux pathway. Spermine efflux may be induced by different agents, such as FCCP, antimycin A and mersalyl, able to completely or partially reduce theDWvalue and, consequently, suppress or weaken the force necessary to maintain spermine in the matrix. However this efflux may also take place in normal conditions when the electrophoretic accumulation of the polycationic polyamine induces a sufficient drop inDWable to trigger the efflux pathway. The release of the polyamine is most probably electroneutral in origin and can take place in exchange with protons or in symport with phosphate anion. The activity of both the uptake and efflux pathways induces a continuous cycling of spermine across the mitochondrial membrane, the rate of which may be prominent in imposing the concentrations of spermine in the inner and outer compartment. Thus, this event has a significant role on mitochondrial permeability transition modulation and consequently on the triggering of intrinsic apoptosis