Ionic liquid as plasticizer for europium(III)-doped luminescent poly(methyl methacrylate) films

Flexible luminescent polymer films were obtained by doping europium(III) complexes in blends of poly(methyl methacrylate) (PMMA) and the ionic liquid 1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [C(6)mim][Tf2N]. Different europium(III) complexes have been incorporated in the polymer/ionic liquid matrix: [C(6)mim][Eu(nta)(4)], [C(6)mim][Eu(tta)(4)], [Eu(tta)(3)(phen)] and [choline](3)[Eu(dpa)(3)], where nta is 2-naphthoyltrifluoroacetonate, tta is 2-thenoyltrifluoroacetonate, phen is 1,10-phenanthroline, dpa is 2,6-pyridinedicarboxylate ( dipicolinate) and choline is the 2-hydroxyethyltrimethyl ammonium cation. Bright red photoluminescence was observed for all the films upon irradiation with ultraviolet radiation. The luminescent films have been investigated by high-resolution steady-state luminescence spectroscopy and by time-resolved measurements. The polymer films doped with beta-diketonate complexes are characterized by a very intense D-5(0) -> F-7(2) transition ( up to 15 times more intense than the D-5(0) -> F-7(1)) transition, whereas a marked feature of the PMMA films doped with [choline](3)[Eu(dpa)(3)] is the long lifetime of the D-5(0) excited state (1.8 ms).

The vascular targeting agent combretastatin-A4 and a novel cis-Restricted {beta}-Lactam Analogue, CA-432, induce apoptosis in human chronic myeloid leukemia cells and ex vivo patient samples including those displaying multidrug resistance

Combretastatin-A4 (CA-4) is a natural derivative of the African willow tree Combretum caffrum. CA-4 is one of the most potent antimitotic components of natural origin, but it is, however, intrinsically unstable. A novel series of CA-4 analogs incorporating a 3,4-diaryl-2-azetidinone (β-lactam) ring were designed and synthesized with the objective to prevent cis -trans isomerization and improve the intrinsic stability without altering the biological activity of CA-4. Evaluation of selected β-lactam CA-4 analogs demonstrated potent antitubulin, antiproliferative, and antimitotic effects in human leukemia cells. A lead β-lactam analog, CA-432, displayed comparable antiproliferative activities with CA-4. CA-432 induced rapid apoptosis in HL-60 acute myeloid leukemia cells, which was accompanied by depolymerization of the microtubular network, poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Bcl-2 cleavage. A prolonged G(2)M cell cycle arrest accompanied by a sustained phosphorylation of mitotic spindle checkpoint protein, BubR1, and the antiapoptotic proteins Bcl-2 and Bcl-x(L) preceded apoptotic events in K562 chronic myeloid leukemia (CML) cells. Molecular docking studies in conjunction with comprehensive cell line data rule out CA-4 and β-lactam derivatives as P-glycoprotein substrates. Furthermore, both CA-4 and CA-432 induced significantly more apoptosis compared with imatinib mesylate in ex vivo samples from patients with CML, including those positive for the T315I mutation displaying resistance to imatinib mesylate and dasatinib. In summary, synthetic intrinsically stable analogs of CA-4 that display significant clinical potential as antileukemic agents have been designed and synthesized.