Two new series of pyran‐ or coumarin‐substituted thiazolyl‐pyrazole‐chromen‐2‐one derivatives 10a–10d and 11a–11d were efficiently synthesized under environmentally friendly reaction conditions through a convenient one‐pot multicomponent reaction of a heterocyclic bromoacetyl derivative 3 or 4 with thiosemicarbazide and a substituted 3‐(acetoacetyl)coumarin derivative 5a–5d in anhydrous ethanol. The reaction proceeds through Hantzsch thiazole and Knorr pyrazole syntheses in refluxing ethanol. The key features of this approach are its operational simplicity, the quick access to the desired products, and the good to excellent yields. The structures of the newly synthesized compounds were established by IR spectroscopy, 1H, 13C, and 2D NMR spectroscopy, and mass spectrometry.
Imaging the enhanced permeation and retention effect by ultrasound is hindered by the large size of commercial ultrasound contrast agents (UCAs). To obtain nanosized UCAs, triblock copolymers of poly(ethylene glycol)-polylactide-poly(1 H,1 H,2 H,2 H-heptadecafluorodecyl methacrylate) (PEG-PLA-PFMA) with distinct numbers of perfluorinated pendant chains (5, 10, or 20) are synthesized by a combination of ring-opening polymerization and atom transfer radical polymerization. Nanocapsules (NCs) containing perfluorooctyl bromide (PFOB) intended as UCAs are obtained with a 2-fold increase in PFOB encapsulation efficiency in fluorinated NCs as compared with plain PEG-PLA NCs thanks to fluorous interactions. NC morphology is strongly influenced by the number of perfluorinated chains and the amount of polymer used for formulation, leading to peculiar capsules with several PFOB cores at high PEG-PLA-PFMA amount and single-cored NCs with a thinner shell at low fluorinated polymer amount, as confirmed by small-angle neutron scattering. Finally, fluorinated NCs yield higher in vitro ultrasound signal compared with PEG-PLA NCs, and no in vitro cytotoxicity is induced by fluorinated polymers and their degradation products. Our results highlight the benefit of adding comb-like fluorinated blocks in PEG-PLA polymers to modify the nanostructure and enhance the echogenicity of nanocapsules intended as UCAs.
We have synthesized novel fluorinated polyesters and formulated them into nanocapsules of perfluorohexane as ultrasound contrast agents. This nanosystem has been thoroughly characterized by several techniques and we show that fluorination of the biodegradable polymer favors the encapsulation of perfluorohexane without producing further reduction of cell viability. Contrary to nanocapsules of perfluoroctyl bromide formulated with the fluorinated polymers [32], the presence of the fluorinated moieties leads to an increase of echogenicity that is dependent of the length of the fluorinated moiety. Morevover, the ability of nanocapsules to explode when submitted to focused ultrasound also depends on the length of the fluorinated chain. These results pave the way to theranostic perfluorohexane nanocapsules co-encapsulating a drug for precision delivery using focused ultrasound.
SummaryThe synthesis of ω-di-(trideuteromethyl)-trisnorsqualenic acid has been achieved from natural squalene. The synthesis features the use of a Shapiro reaction of acetone-d
6 trisylhydrazone as a key step to implement the terminal isopropylidene-d
6 moiety. The obtained squalenic acid-d
6 has been coupled to gemcitabine to provide the deuterated analogue of squalenoyl gemcitabine, a powerful anticancer agent endowed with self-assembling properties. The Raman spectra of both deuterated and non-deuterated squalenoyl gemcitabine nanoparticles displayed significant Raman scattering signals. They revealed no differences except from the deuterium peak patterns in the silent spectral region of cells. This paves the way for label-free intracellular trafficking studies of squalenoyl nanomedicines.
A controllable method for the functionalization of XantPhos Pd-G3 precatalyst with thiosugars and thiols has been established. Under mild and operationally simple reaction conditions through just mixing of precatalyst and thiosugars (α- or β-mono-, di- and poly-thiosugar derivatives) in water at 25 °C for 20 min, a series of 1-aminobiphenyl thioglycosides that are difficult to synthesize by classical methods has been synthesized in very high yields.
The first enantioselective total syntheses of two marine sesquiterpenes, natural (1S)-suberosanone and (1S)-suberosenol A, are achieved leading to the assignment of the absolute configuration of natural suberosenol A. A new access to (1S)-suberosenone from a key tricyclic enone was also developed leading to an overall improvement of the synthesis, allowing an efficient route to suberosenol A. Hyperbaric asymmetric Michael addition and a highly efficient silver trifluoroacetate mediated α-alkylation for the formation of ring A completed the key steps of the synthesis. Regrettably, synthetic (1S)-suberosanone did not retain the reported picomolar cytotoxic activity displayed by the natural product, the reason for which remains to be elucidated.
We have synthesized polylactide (PLA) polymers containing five distinct lengths of fluorinated end-groups (from C 3 F 7 to C 13 F 27). The influence of fluorinated end-groups length and their dynamics in chlorinated solvents (chloroform and dichloromethane) was investigated as a function of the presence of perfluohexane (PFH) and related to the morphology of capsules of PFH obtained using these fluorinated polylactides. 19 F spin-spin relaxation time (T 2) measurements revealed a reduced mobility of the fluorinated units with dependency on fluorinated chain length in the order C 3 F 7 >C 8 F 17 >C 13 F 27. The presence of perfluorohexane (PFH) led to a further decrease on the segmental mobility, indicating the existence of fluorous interactions. The T 2 relaxation time of the CF 3 resonance of PLA-C 3 F 7 decreased from 540±50 ms in CDCl 3 to 81±15 ms after the addition of PFH. Due to these fluorous interactions, PLA polymers containing short fluorinated groups (C 3 F 7 and C 6 F 13) led to microcapsules with core-shell morphologies, whereas those formulated with long F-units (C 8 F 17 , C 11 F 23 and C 13 F 27) favored the formation of multinucleated capsules as observed by confocal microscopy.
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