Pharmacological and Structure-Activity Relationship Evaluation of 4-aryl-1-Diphenylacetyl(thio)semicarbazides

This article describes the synthesis of six 4-aryl-(thio)semicarbazides (series a and b) linked with diphenylacetyl moiety along with their pharmacological evaluation on the central nervous system in mice and computational studies, including conformational analysis and electrostatic properties. All thiosemicarbazides (series b) were found to exhibit strong antinociceptive activity in the behavioural model. Among them, compound 1-diphenylacetyl-4-(4-methylphenyl)thiosemicarbazide 1b was found to be the most potentan algesic agent, whose activity is connected with the opioid system. For compounds from series a significant anti-serotonergic effect, especially for compound 1-diphenylacetyl-4- (4-methoxyphenyl)semicarbazide 2b was observed. The computational studies strongly support the obtained results

1-(3-Chloro­phen­yl)-3-(1-p-tolyl­imidazolidin-2-yl­idene)urea

In the crystal structure of the title compound, C17H17ClN4O, the existence of only one 2-imino–oxo of the five possible N-amino–imino/O-keto–hydr­oxy tautomers is observed and the dihedral angle between the aromatic rings is 29.78 (11)°. The mol­ecular conformation is stabilized by intra­molecular C—H⋯N, N—H⋯O and C—H⋯O hydrogen bonds, in each case generating a six-membered ring. In the crystal structure, the glide-plane-related mol­ecules are linked into C(4) amide chains by inter­molecular N—H⋯O hydrogen bonds, and an inter­molecular C—H⋯O link also occurs

Non-interventional study evaluating the response to treatment in patients with chronic lymphocytic leukaemia (CLL) depending on rituximab-chemotherapy regimen

A multicenter, prospective, observational, non-interventional study evaluated the response to treatment in patients with chronic lymphocytic leukemia (CLL) depending on the rituximab-chemotherapy (R-chemo) regimen used in routine clinical practice in Poland. The primary endpoint was the overall response rate (ORR) regarding the R-chemo regimen. The secondary endpoints were complete remission (CR), partial remission (PR), progressive disease (PD) and stable disease (SD) rates. A total of 400 CLL patients were enrolled in 20 sites in Poland. Data were collected on-line using eCRF during 6-months rituximab treatment. There were 150 treatment-naive patients (37.5%) and 250 patients with recurrent disease (62.5%) enrolled to the study. The overall ORR in R-FC-treated patients was 87.28%, 78.57% for the R-COP regimen, and for other regimens – 51.72%. Complete remission was achieved in 141 patients (36.25%), including 16.40% in patients receiving first-line treatment and 11.76% in relapsed disease. Partial remission was achieved in 166 patients (42.67%), including 38.4% in patients on first-line treatment and 38.56% in patients treated for recurrence. Complete or partial responses were achieved in 78.92% in total. No new safety signals were detected in comparison to safety profile described in Summary of Product Characteristics

Helicene grafting on halloysite nanotubes for drug delivery: layer structure, surface selectivity and pH triggered drug release

Halloysite nanotubes (HNTs) have recently emerged as promising candidates for targeted drug delivery [1]. HNTs are low-toxic and low-cost aluminosilicate clays with nanotubular structure, presenting a positively charged Al(OH)3 inner lumen and a negatively charged SiO2 outer surface, which can support a selective functionalization of the two surfaces. In this work, we investigated the loading and release mechanisms of the tetrathia[7]helicene (7-TH) derivative linked via an imine bond to HNTs. The 7-TH scaffold displays promising intercalation properties for DNA, with a high degree of enantioselective recognition [2]. Moreover, a 7-TH derivative showed potent inhibitory activity against telomerase, demonstrating the great potential of 7-TH as therapeutic cytotoxic molecules [2,3]. We analyzed functionalized HNTs as well as Al2O3 and SiO2 layers, as models of the inner and outer surfaces, by means of surface-sensitive synchrotron-based techniques (XPS, UPS and NEXAFS spectroscopies). The oxide surfaces were analyzed both before and after functionalization with helicene derivatives through a (3-aminopropyl)triethoxysilane (APTES) linker [4]. Furthermore, the effect of a treatment in acidic conditions was investigated to prove the release of the helicene moiety from the oxide carrier at the extracellular pH of tumor cells. The surface state and atomic ratios of key elements within the organic layer determined by XPS proved the successful coupling of the helicene aldehyde to the APTES-functionalized films, clarifying differences in the reactivity of the two oxides. The sulfur peak confirmed the results obtained on the model films, supporting the reliability of the two adopted model surfaces. Moreover, NEXAFS results provided indication of a preferential orientation of helicene moieties at the oxide surface, which is lacking in APTES-functionalized layers. A further confirmation of the complete release of helicene moieties upon treatment in mild acidic conditions was given by NEXAFS spectra, showing a random orientation of the C and N functional groups after the release treatment. Preliminary in vitro toxicity tests on cancer cell lines characterized by different extracellular pH values show data consistent with a pH-triggered release of the 7-TH moiety, as also supported by kinetics data about the release in various physiological conditions. Work is currently under way to achieve a selective functionalization of the inner and outer surfaces by orthogonal functionalization strategies