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We have synthesized and characterized a novel copper(II) complex of the fluoroquinolone antibacterial drug N-propyl-norfloxacin (Hpr-norf) in the presence of 1,10-phenanthroline (Phen) and studied its biological properties as antitumor antibiotic and antimicrobial agent. Human acute myeloid leukemia cell line HL-60, MTT assay, and Trypan blue assay were used to test the antileukemic, the cell viability, and the structural integrity of the cell membrane and cell proliferation properties of (chloro)(Phen)( N-propyl-norfloxacinato)copper(II) (complex 1), respectively. We found that the proliferation rate and viability of HL-60 cells decreased after treatment with complex 1, leading to cell death through apoptosis in a time-dependent manner. The antimicrobial activity of complex 1 has been tested, revealing an increased potency in comparison to the free Hpr-norf. Complex 1 proved to be capable of acting as an independent nuclease by inducing nicking of supercoiled pUC19 plasmid. Our results suggest that 1 may provide a valuable tool in cancer chemotherapy.

We have elaborated a versatile mitotropic nanocarrier; furthermore, using this platform, we have developed a mitochondrial-doxorubicin formulation with exceptional cytocidal properties, even in nanomolar concentrations.

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Substantial evidence over the last decades has implicated uncontrolled angiogenesis with various pathological states, including cancer. Vascular endothelial growth factor (VEGF) plays a critical role in its regulation. Because the tyrosine kinase VEGF receptor-2 (VEGFR-2) is the major mediator of the mitogenic, angiogenic, and permeability-enhancing effects of VEGF, it has become one of the most profound anti-angiogenesis targets. Inspired by the anthranilamide class of VEGFR-2 inhibitors, we performed a computational analysis of some potent representative members, using docking and molecular dynamics calculations. Based on the observations drawn from introducing the effect of the receptor's flexibility in implicit aqueous environment, we designed, synthesized, and characterized several new analogues of related scaffolds with modifications in their steric and electronic characteristics. In vitro evaluation of these compounds revealed several novel VEGFR-2 inhibitors that are less cytotoxic and more potent than the parent compounds.

Cytotoxicity and cell growth inhibition studies were performed for five distinct cobalt(ll) [Co2(acac)tpmc](ClO4)3, [Co2(dibzac)tpmc](ClO4)3, [Co2(hfac)tpmc](CIO4)2, [Co2(tmhd)tpmc](CIO4)3 and [Co2(ox)tpmc](CIO4)2.3H20 and five molybdenum(Vl) complexes, [MoO2(pipdtc)2], [MoO2(morphdtc)], [MoO2(timdtc)2], [MoO2(pzdtc)2] and [MoO2(N-Mepzdtc)2]. The former were tested in two leukemia cell lines: chronic myelogenic leukemia (K562) and human promyelocytic cell line (U937). They showed to have relatively high toxicity in K562 cells and a relatively low cytotoxicity in U937 cells, as assessed by both MTT and Trypan Blue assays. The five molybdenum complexes were tested in human promyelotic U937 cell line and they showed to have high toxicity.

the glomerular capillaries, often abnormal lipid profile, proteinuria, and progressive kidney failure (1, 2). The relapse of LPG following kidney transplantation in LPG patients (3, 4) has suggested that factors outside the kidney should be crucial for the disease pathogenesis. One such factor has been proposed to be mutated apoE, because LPG has been related with inherited mutations within the apoE gene that act in a dominant way but with incomplete penetrance (1, 2, 5, 6). ApoE is a major protein component of the lipoprotein transport system and plays critical roles in dyslipidemia and atherosclerosis (7, 8). Human apoE has three common isoforms, the apoE2, apoE3, and apoE4, each differing in the amino acid positions 112 and 158 (9). The polymorphic background and mutations in the apoE gene have been linked with the pathogenesis of several diseases related to lipid metabolism, such as type III hyperlipoproteinemia, atherosclerosis, diabetic dyslipidemia, and LPG, as well as of neurodegenerative disorders, such as Alzheimer's disease (5, 6, 8, 10, 11). ApoE is highly helical with labile tertiary structure (12) that can undergo significant conformational changes during its physiological functions that include lipid binding, protein-protein interactions, and other processes (10, 13-16). Lipid-free apoE is folded into two structural domains, an N-terminal and a carboxyl-terminal, connected with a hinge region (10, 13-16). Crystal structure analysis of the N-terminal domain of apoE showed that this domain folds as a four-helix bundle of amphipathic -helices (17). NMR analysis of full-length apoE also showed a four-helix bundle in the N-terminal domain, as well as two helices in the hinge region and three helices in the carboxyl-terminal Abstract Lipoprotein glomerulopathy (LPG) is a rare renal disease, characterized by lipoprotein thrombi in glomerular capillaries. A series of apoE mutations have been associated with LPG development. We previously showed that three mutants based on apoE3 sequence, in which an arginine was substituted by proline, are thermodynamically destabilized and aggregation-prone. To examine whether other LPGassociated apoE3 mutations induce similar effects, we characterized three nonproline LPG-associated apoE3 mutations, namely, R25C (apoE Kyoto), R114C (apoE Tsukuba), and A152D (apoE LasVegas). All three apoE3 variants are found to have significantly reduced helical content and to be thermodynamically destabilized, both in lipid-free and lipoprotein-associated form, and to expose a larger portion of hydrophobic surface to the solvent compared with WT apoE3. Furthermore, all three apoE3 variants are aggregation-prone, as shown by dynamic light-scattering measurements and by their enhanced capacity to bind the amyloid probe thioflavin T. Overall, our data suggest that the LPG-associated apoE3 mutations R25C, R114C, and A152D induce protein misfolding, which may contribute to protein aggregation in glomerular capillaries. The similar effects of both LPG-associated proline and nonproline mutati...