To
replace dimethylformamide (DMF) in fluorenylmethoxycarbonyl
(Fmoc) solid-phase peptide synthesis, we explored the application
of mixtures of green solvents (green solvents mixtures for solid-phase
peptide synthesis (GM-SPPS)) as combinations of Cyrene (dihydrolevoglucosenone),
sulfolane, or anisole with dimethyl carbonate or diethyl carbonate,
in different proportions. Their ability to swell differently functionalized
polystyrene and polyethylene glycol resins was explored, and solubility
of amino acids and coupling reagents was studied. Moreover, the synthesis
of the model peptide Aib-enkephalin was performed in the new green
mixtures, confirming the possibility to fully replace DMF all over
SPPS. The two established best green protocols were then successfully
applied to the synthesis of a longer peptide (Aib-ACP). Finally, the
green solvent-based procedure was applied to the synthesis of the
reduced form of the active pharmaceutical ingredient (API) Octreotide.
After oxidative cyclization and a single high-pressure column chromatography,
the pharmaceutical-grade compound was isolated in comparable high
yield to that obtained with the standard procedures.
Combretastatin A-4, a potent tubulin polymerization inhibitor, caused us to synthesize a novel series of 2-amino-4-(3′,4′,5′-trimethoxyphenyl)-5-aryl thiazoles with the goal of evaluating the effects of substituents on the phenyl at the 5-position of the thiazole skeleton on biological activities. An ethoxy group at the para-position produced the most active compound in the series, with IC50 values of 0.03–0.9 nM against five of seven cancer cell lines. The most active compounds retained full activity in multidrug resistant cancer cells and acted through the colchicine site of tubulin. Treated cells were arrested in the G2/M phase of the cell cycle, with cell death proceeding through an apoptotic pathway that was only partially caspase-dependent. Preliminary results suggest that, in addition to cell death by apoptosis, cells were also killed via mitotic catastrophe as an alternative cell death mechanism.
This study shows that rhinosinusal infections are common in asthmatic children. Moreover, nasal endoscopy might represent a fruitful tool in the management of asthmatic children.
Autosomal recessive autoinflammatory disorder caused by mutations of the mevalonate kinase gene (MVK), leading to mild, incomplete MK enzyme deficiency (MKD), has been known so far as Hyper-IgD and periodic fever syndrome (HIDS) and regarded as mostly occurring in Northern Europe. Here we report the results of the molecular characterization of the first Italian series of patients affected with autoinflammatory disorders and periodic fever. A total of 13 different mutations, scattered throughout the MVK coding region, were identified in either homozygous or compound heterozygous state in 15 patients. The mutation leading to the V377I amino-acid change, already described also in other series, resulted the most common with a frequency of 50% of all MKD alleles. Among the other mutations, eight had never been described before, including an interstitial deletion of 19 nucleotides in exon 2. In addition to these nucleotide changes, private and polymorphic MVK variants have been detected in the patients under analysis and checked also in a set of control individuals. Clinical features are reported for each of the 15 MKD patients, and life-threatening infections and systemic amyloidosis presented as unexpected MKDrelated complications. Our study demonstrates that MKD is a common cause of recurrent fever also in the Italian population, where it is associated with both a wide spectrum of previously unreported MVK mutations and peculiar phenotypic features.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.