Off-target effects of an insect cell-expressed influenza HA-pseudotyped Gag-VLP preparation in limiting postinfluenza Staphylococcus aureus infections.

Clinical and historical data underscore the ability of influenza viruses to ally with Staphylococcus aureus and predispose the host for secondary bacterial pneumonia, which is a leading cause of influenza-associated mortality. This is fundamental because no vaccine for S. aureus is available and the number of antibiotic-resistant strains is alarmingly rising. Hence, this leaves influenza vaccination the only strategy to prevent postinfluenza staphylococcal infections. In the present work, we assessed the off-target effects of a Tnms42 insect cell-expressed BEI-treated Gag-VLP preparation expressing the HA of A/Puerto Rico/8/1934 (H1N1) in preventing S. aureus superinfection in mice pre-infected with a homologous or heterologous H1N1 viral challenge strain. Our results demonstrate that matched anti-hemagglutinin immunity elicited by a VLP preparation may suffice to prevent morbidity and mortality caused by lethal secondary bacterial infection. This effect was observed even when employing a single low antigen dose of 50 ng HA per animal. However, induction of anti-hemagglutinin immunity alone was not helpful in inhibiting heterologous viral replication and subsequent bacterial infection. Our results indicate the potential of the VLP vaccine approach in terms of immunogenicity but suggest that anti-HA immunity should not be considered as the sole preventive method for combatting influenza and postinfluenza bacterial infections.

Hydrolysis and cytotoxic properties of osmium(II)/(III)-DMSO-azole complexes. Short communication.

The antiproliferative properties of the osmium(II) complexes cis,fac-[Os(II)Cl(2)(DMSO)(3)(L)] and trans,cis,cis-[Os(II)Cl(2)(DMSO)(2)(L)(2)] (L = 1H-pyrazole, 1H-imidazole) were studied in three human cancer cell lines, namely 41M (ovary), SK-BR-3 (breast), and SW480 (colon). Their activities were compared with those of osmium(III) and ruthenium(III) NAMI-A type complexes on HT-29 (colon) and SK-BR-3 cancer cell lines. While IC(50) values of all the Os(II) complexes were found to be >1000 microM in all cell lines, Os and Ru-NAMI-A type complexes showed remarkable antiproliferative activity. The marginal in vitro cytotoxicity of the Os(II) compounds is presumably attributed to their resistance to hydrolysis. However, the Os-NAMI-A complexes, which are also kinetically stable in aqueous solution, showed reasonable antiproliferative activity in vitro when compared with the analogous Ru compounds and with the Os(II)-DMSO-azole species, indicating that hydrolysis might be not a prerequisite for the antitumor activity of Os-NAMI-A type complexes.

Synthesis, structure, spectroscopic properties, and antiproliferative activity in vitro of novel osmium(III) complexes with azole heterocycles.

Reactions of (H 2azole) 2[OsCl 6], where Hazole = pyrazole, Hpz, ( 1), indazole, Hind, ( 2), imidazole, Him, ( 3) and benzimidazole, Hbzim, ( 4) with the corresponding azole heterocycle in 1:4 molar ratio in boiling isoamyl alcohol or hexanol-1 afforded novel water-soluble osmium(III) complexes of the type trans-[OsCl 2(Hazole) 4]Cl, where Hazole = Hpz ( 5a), Hind ( 6a), Him ( 7a), and Hbzim ( 9a) in 50-70% ( 5a, 7a, 9a) and 5% ( 6a) yields. The synthesis of 7a was accompanied by a concurrent reaction which led to minor formation (<4%) of cis-[OsCl 2(Him) 4]Cl ( 8). The complexes were characterized by elemental analysis, IR spectroscopy, UV-vis spectroscopy, ESI mass spectrometry, cyclic voltammetry, and X-ray crystallography. 5a, 7a, and 9a were found to possess remarkable antiproliferative activity in vitro against A549 (non-small cell lung carcinoma), CH1 (ovarian carcinoma), and SW480 (colon carcinoma) cells, which was compared with that of related ruthenium compounds trans-[RuCl 2(Hazole) 4]Cl, where Hazole = Hpz (5b), Hind (6b), Him (7b), and Hbzim (9b).

Osmium NAMI-A analogues: synthesis, structural and spectroscopic characterization, and antiproliferative properties.

The osmium(III) complex [(DMSO)2H][trans-OsIIICl4(DMSO)2] (1) has been prepared via stepwise reduction of OsO4 in concentrated HCl using N2H(4).2HCl and SnCl(2).2H2O in DMSO. 1 reacts with a number of azole ligands, namely, indazole (Hind), pyrazole (Hpz), benzimidazole (Hbzim), imidazole (Him), and 1H-1,2,4-triazole (Htrz), in organic solvents, affording novel complexes (H2ind)[OsIIICl4(Hind)(DMSO)] (2), (H2pz)[OsIIICl4(Hpz)(DMSO)] (3), (H2bzim)[OsIIICl4(Hbzim)(DMSO)] (4), (H2im)[OsIIICl4(Him)(DMSO)] (6), and (H2trz)[OsIIICl4(Htrz)(DMSO)] (7), which are close analogues of the antimetastatic complex NAMI-A. Metathesis reaction of 4 with benzyltriphenylphosphonium chloride in methanol led to the formation of (Ph3PCH2Ph)[OsIIICl4(Hbzim)(DMSO)] (5). The complexes were characterized by IR, UV-vis, ESI mass spectrometry, 1H NMR spectroscopy, cyclic voltammetry, and X-ray crystallography. In contrast to NAMI-A, 2-4, 6, and 7 are kinetically stable in aqueous solution and resistant to hydrolysis. Surprisingly, they show reasonable antiproliferative activity in vitro in two human cell lines, HT-29 (colon carcinoma) and SK-BR-3 (mammary carcinoma), when compared with analogous ruthenium compounds. Structure-activity relationships and the potential of the prepared complexes for further development are discussed.