Current therapy against melanoma relies on surgical treatment
or,
in alternative, on conventional drug therapy. Often these therapeutic
agents are ineffective due to the development of resistance phenomena.
For this purpose, chemical hybridization emerged as an effective strategy
to overcome the development of drug resistance. In this study, a series
of molecular hybrids were synthesized combining the sesquiterpene
artesunic acid with a panel of phytochemical coumarins. Cytotoxicity,
antimelanoma effect, and cancer selectivity of the novel compounds
were evaluated by MTT assay on primary and metastatic cells and on
healthy fibroblasts as a reference. The two most active compounds
showed lower cytotoxicity and higher activity against metastatic melanoma
than paclitaxel and artesunic acid. Further tests, including cellular
proliferation, apoptosis, confocal microscopy, and MTT analyses in
the presence of an iron chelating agent, were conducted with the aim
of tentatively addressing the mode of action and the pharmacokinetic
profile of selected compounds.
The synthesis of both enantiomers of a key intermediate in the synthesis of halofuginone was accomplished by Candida antarctica lipase B-catalyzed kinetic resolution of the corresponding racemate. When the resolution was carried out in the versatile and eco-friendly solvent cyclopentyl methyl ether (CPME) using PCPB (p-chlorophenylbutyrate) as the acylating reagent, the highest enantiomeric ratio (E) values were measured and highly enantioenriched (95% ee) compounds could be obtained in a single iteration. As an example, one of the two enantiomers was used as a starting material to prepare (+)-halofuginone in a three-step procedure.
Quinol derivatives of estrogens are effective pro-drugs in steroid replacement therapy. Here, we report that these compounds can be synthesized in one-pot conditions and high yield by blue LED-driven photo-oxygenation of parent estrogens. The oxidation was performed in buffer and eco-certified 2-methyltetrahydrofuran as the two-liquid-phase reaction solvent, and in the presence of meso-tetraphenyl porphyrin as the photosensitizer. Two steroidal prodrugs 10β, 17β-dihydroxyestra-1,4-dien-3-one (DHED) and 10β-Hydroxyestra-1,4-diene-3,17-dione (HEDD) were obtained with high yield and selectivity.
BackgroundAcute Kidney Injury (AKI) is a very frequent condition, occurring in about one in three patients admitted to an intensive care unit (ICU). AKI is a syndrome defined as a sudden decrease in glomerular filtration rate. However, this unified definition does not reflect the various mechanisms involved in AKI pathophysiology, each with its own characteristics and sensitivity to therapy. In this study, we aimed at developing an innovative machine learning based method able to subphenotype AKI according to its pattern of risk factors.MethodsWe adopted a three-step pipeline of analyses. First, we looked for factors associated with AKI using a generalized additive model. Second, we calculated the importance of each identified AKI related factor in the estimated AKI risk to find the main risk factor for AKI, at the single patient level. Lastly, we clusterized AKI patients according to their profile of risk factors and compared the clinical characteristics and outcome of every cluster. We applied this method to a cohort of severe COVID-19 patients hospitalized in the ICU of the Geneva University Hospitals.ResultsAmong the 248 patients analyzed, we found 7 factors associated with AKI development. Using the individual expression of these factors, we identified three groups of AKI patients, based on the use of Lopinavir/Ritonavir, baseline eGFR, use of dexamethasone and AKI severity. The three clusters expressed distinct characteristics in terms of AKI severity and recovery, metabolic patterns and hospital mortality.ConclusionWe propose here a new method to phenotype AKI patients according to their most important individual risk factors for AKI development. When applied to an ICU cohort of COVID-19 patients, we were able to differentiate three groups of patients. Each expressed specific AKI characteristics and outcomes, which probably reflect a distinct pathophysiology.
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