Luminescent mono(pentafluorophenyl) cycloplatinated complexes [Pt(C^N-κC,N)(HC^N-κN)(C6F5)] [HC^N = Hthpy (2-(2-thienyl)pyridine) 2a, Hbt (2-phenylbenzothiazole) 2b, Hpq (2-phenylquinoline) 2c] have been prepared by C–H activation of a HC^N ligand in the corresponding [Pt(HC^N-κN)2(C6F5)2] (1a, 1b, 1c) complexes. Complexes 2 evolve in DMSO solution into solvate complexes and we present here successful routes for the synthesis of [Pt(C^N)(C6F5)(DMSO)] (C^N = thpy 3a, bt 3b). They have been fully characterized (X-ray for 1a, 1c, 2b, 3a and 3b), their electronic absorption and emission properties have been investigated and DFT and TD-DFT calculations for 1a, 1c, 2b and 3a have been carried out. Complexes 3a, 3b and [Pt(ppy)(C6F5)(DMSO)] 4 (Hppy = 2-phenylpyridine) show remarkable stability in a mixed DMSO-cellular medium and their cytotoxicity towards the human lung tumor (A549) and bronchial epithelial non-tumorigenic (NL20) cell lines has been evaluated by MTS assays. Their cellular localization in A549 and NL20 human cells and in mouse embryonic fibroblasts obtained from lungs (LMEFs) has also been investigated by fluorescence microscopy.

Two series of neutral luminescent pentafluorophenyl cycloplatinated­(II) complexes [Pt­(C^N)­(C6F5)­L] [C^N = C-deprotonated 2-phenylpyridine (ppy; a), 2-(2,4-difluorophenylpyridine (dfppy; b)] incorporating dimethyl sulfoxide [L = DMSO for 1 (1a reported by us in ref )] or biocompatible phosphine [L = PPh2C6H4COOH (dpbH; 2), PPh2C6H4CONHCH2COOMe (dpbGlyOMe; 3), P­(C6H4SO3Na)3 (TPPTS; 4)] ligands have been prepared and characterized and their optical properties studied. Their cytotoxic activities against tumor A549 (lung carcinoma), HeLa (cervix carcinoma), and nontumor NL-20 (lung epithelium) cell lines, as well as the ability to interact with DNA (plasmid pBR322), were evaluated. Complexes 2 exhibit higher cytotoxicity (IC50 3.89–20.29 μM) than compounds 1 (9.03–20.50 μM), whereas the activities of complexes 3 and 4 are negligible. All cytotoxic complexes show low selective toxicities toward cancer cells. Interestingly, except 1a, these complexes do not show evidence of DNA intercalation. Along the same lines, fluorescence costaining with Hoechst (2,5′-bi-1H-benzimidazole, 2′-(4-ethoxyphenyl)-5-(4-methyl-1-piperazinyl), a nuclear DNA stain) reveals that all complexes easily internalize, being mainly localized in the cytoplasm. In order to deepen the mechanism of biological action, the effect of the most cytotoxic complex 2b toward the dynamics of tubulin was explored. This complex displays tubulin depolymerization activity, exhibiting more potent inhibition of microtubule formation in A549 than in HeLa cells, in accordance with its higher antiproliferative activity (IC50 6.98 vs 12.45 μM), placing this complex as a potential antitubulin agent.

Cycloplatinated complexes based on 2-(4-substituted)benzothiazole ligands of type [Pt(R-PBT-κC,N)Cl(L)] (PBT=2-phenylbenzothiazole; R=Br (1), Me N (2); L=dimethyl sulfoxide (DMSO; a), 1,3,5- triaza-7-phosphaadamantane (PTA; b), triphenylphosphine 3,3',3''-trisulfonate (TPPTS; c)) and [Pt(Br-PBT-κC)Cl(PTA) ] (3) are presented. On the basis of the photophysical data and time-dependent (TD)-DFT calculations (1 a and 2 a), the low-lying transitions (absorption and emission) were associated with ligand-center (LC) charge transfer, with minor metal-to-ligand charge transfer (MLCT), and intraligand charge transfer (ILCT) [Me N-PBT→PBT] excited states, respectively. Simultaneous fluorescence/phosphorescence bands were found in fluid solutions (and also in the solid state for 2 a), which become dominated by triplet emission bands in rigid media at 77 K. The effect of the concentration on emissive behavior of 2 a, b indicated the occurrence of aggregation-induced luminescence properties related to the occurrence of metal-metal and π⋅⋅⋅π interactions, which are more enhanced in 2 a because of the less bulky DMSO ligand. The behavior of 2 a toward para-toluenesulfonic acid (PTSA) in aerated acetonitrile and to hydrogen chloride gas in the solid state has been evaluated, thus showing a clear reversible change between the ILCT and LC/ MLCT states due to protonation of the NMe group (theoretical calculations on 2 a-H ). Solid 2 a undergoes a surprising oxidation of the Pt center to Pt with concomitant deoxygenation of DMSO, under prolonged reaction with hydrogen chloride gas to afford the Pt /dimethyl sulfide complex (mer-[Pt(Me N-PBT-κC,N)Cl (SMe )]; mer-4), which evolves in solution to fac-4, as confirmed by X-ray studies. Cytotoxic activity studies on A549 and HeLa cell lines indicated cytotoxic activity of 1 b and 2 a, b. In addition, fluorescent cell microscopy revealed cytoplasmic staining, more visible in perinuclear areas. Inhibition of tubulin polymerization by 1 b in both cells is presented as a preliminary mechanism of its cytotoxic action.

Insulin-like growth factor type 1 receptor (IGF1R) is a ubiquitously expressed tyrosine kinase that regulates cell proliferation, differentiation and survival. It controls body growth and organ homeostasis, but with specific functions depending on developmental time and cell type. Human deficiency in IGF1R is involved in growth failure, microcephaly, mental retardation and deafness, and its overactivation is implicated in oncogenesis. Igf1r-deficient mice die at birth due to growth retardation and respiratory failure. Although multiple Igf1r tissue-specific mutant lines have been analyzed postnatally, using Igf1r-floxed (Igf1r (fl/fl) ) mice mated with diverse cell-type recombinase Cre-expressing transgenics, no mouse models for the study of generalized Igf1r deficiency in adults have been reported. To this end we generated UBC-CreERT2; Igf1r (fl/fl) transgenic mice with an inducible deletion of Igf1r activated by tamoxifen. Tamoxifen administration to 4 week-old prepuberal male mice delayed their growth, producing a distinct impact on organ size 4 weeks later. Whereas testes were smaller, spleen and heart showed an increased organ to body weight ratio. Mosaic Igf1r genomic deletions caused a significant reduction in Igf1r mRNA in all organs analyzed, resulting in diverse phenotypes. While kidneys, spleen and cochlea had unaltered gross morphology, testes revealed halted spermatogenesis, and liver and alveolar lung parenchyma showed increased cell proliferation rates without affecting apoptosis. We demonstrate that UBC-CreERT2 transgenic mice efficiently delete Igf1r upon postnatal tamoxifen treatment in multiple mouse organs, and corroborate that IGF1R function is highly dependent on cell, tissue and organ type.

Herein, we demonstrate by the first time that the Igf1r plays an important role in murine asthma, mediating both AHR and mucus secretion after HDM exposure. Thus, our study identifies IGF1R as a potential therapeutic target, not only for asthma but also for hypersecretory airway diseases.