GC/MSn analysis of the crude reaction mixtures from Friedel–Crafts acylation: Unambiguous identification and differentiation of 3-aroylbenzofurans from their 4- and 6-regioisomers

Rationale: 3-Aroylbenzofurans and their 2-nitrophenyl derivatives constitute fundamental intermediates for the synthesis of target compounds with pharmaceutical properties. However, their preparation via the Friedel–Crafts acylation of 2-phenylbenzofurans, using Lewis acid as catalyst, often leads to mixtures of regioisomeric aroylbenzofurans that can be challenging to distinguish, thus preventing the reaction characterization. Method: We report a method for the unambiguous identification and differentiation of the desired 3-benzoyl isomers from their 4- and 6-regioisomers in a crude reaction mixture using gas chromatography coupled to multiple-stage mass spectrometric (GC/MSn) analysis performed in collision-induced dissociation (CID) mode. Results: Upon electron ionization, each set of isomers displayed nearly identical mass spectra. MSn revealed fragmentation patterns that varied in the location of the benzoyl group on the benzofuran scaffold: CID experiments performed on the molecular ion allowed the distinction of the 3-acyl isomers from the 4- and 6-regioisomers; CID experiments on the [M − Ar]+ ion allowed the distinction of the 4-benzoyl from the 6-benzoyl regioisomer, when the nitro group is located on the 2-phenyl ring. Moreover, the unusual loss of OH• radical allowed ascertaining the position of the nitro group in 3-acyl regioisomers bearing the NO2 group. The origin of the diagnostic OH• loss was investigated through MSn experiments using 18O-labelled 3-benzoyl derivatives. Conclusions: The method allows the rapid characterization of crude reaction mixtures of benzoylbenzofurans using solely GC/MSn analysis, simplifying the workflow of extensive isolation and purification for structure elucidationThe present work was partially supported by FIR (Fondo Integrativo per la Ricerca – annualità 2018 and 2019), University of CagliariS

Biocompatible Polyhydroxyethylaspartamide-based Micelles with Gadolinium for MRI Contrast Agents

Biocompatible poly-[N-(2-hydroxyethyl)-d,l-aspartamide]-methoxypoly(ethyleneglycol)-hexadecylamine (PHEA-mPEG-C16) conjugated with 1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid-gadolinium (DOTA-Gd) via ethylenediamine (ED) was synthesized as a magnetic resonance imaging (MRI) contrast agent. Amphiphilic PHEA-mPEG-C16-ED-DOTA-Gd forms micelle in aqueous solution. All the synthesized materials were characterized by proton nuclear magnetic resonance (1H NMR). Micelle size and shape were examined by dynamic light scattering (DLS) and atomic force microscopy (AFM). Micelles with PHEA-mPEG-C16-ED-DOTA-Gd showed higher relaxivities than the commercially available gadolinium contrast agent. Moreover, the signal intensity of a rabbit liver was effectively increased after intravenous injection of PHEA-mPEG-C16-ED-DOTA-Gd

Boron microlocalization in oral mucosal tissue: implications for boron neutron capture therapy

Clinical studies of the treatment of glioma and cutaneous melanoma using boron neutron capture therapy (BNCT) are currently taking place in the USA, Europe and Japan. New BNCT clinical facilities are under construction in Finland, Sweden, England and California. The observation of transient acute effects in the oral mucosa of a number of glioma patients involved in the American clinical trials, suggests that radiation damage of the oral mucosa could be a potential complication in future BNCT clinical protocols, involving higher doses and larger irradiation field sizes. The present investigation is the first to use a high resolution surface analytical technique to relate the microdistribution of boron-10 (10B) in the oral mucosa to the biological effectiveness of the 10B(n,α)7Li neutron capture reaction in this tissue. The two boron delivery agents used clinically in Europe/Japan and the USA, borocaptate sodium (BSH) and p-boronophenylalanine (BPA), respectively, were evaluated using a rat ventral tongue model. 10B concentrations in various regions of the tongue mucosa were estimated using ion microscopy. In the epithelium, levels of 10B were appreciably lower after the administration of BSH than was the case after BPA. The epithelium:blood 10B partition ratios were 0.2:1 and 1:1 for BSH and BPA respectively. The 10B content of the lamina propria was higher than that measured in the epithelium for both BSH and BPA. The difference was most marked for BSH, where 10B levels were a factor of six higher in the lamina propria than in the epithelium. The concentration of 10B was also measured in blood vessel walls where relatively low levels of accumulation of BSH, as compared with BPA, was demonstrated in blood vessel endothelial cells and muscle. Vessel wall:blood 10B partition ratios were 0.3:1 and 0.9:1 for BSH and BPA respectively. Evaluation of tongue mucosal response (ulceration) to BNC irradiation indicated a considerably reduced radiation sensitivity using BSH as the boron delivery agent relative to BPA. The compound biological effectiveness (CBE) factor for BSH was estimated at 0.29 ± 0.02. This compares with a previously published CBE factor for BPA of 4.87 ± 0.16. It was concluded that variations in the microdistribution profile of 10B, using the two boron delivery agents, had a significant effect on the response of oral mucosa to BNC irradiation. From a clinical perspective, based on the findings of the present study, it is probable that potential radiation-induced oral mucositis will be restricted to BNCT protocols involving BPA. However, a thorough high resolution analysis of 10B microdistribution in human oral mucosal tissue, using a technique such as ion microscopy, is a prerequisite for the use of experimentally derived CBE factors in clinical BNCT. © 2000 Cancer Research Campaig

Paramagnetic and fluorescent liposomes for target-specific imaging and therapy of tumor angiogenesis

Angiogenesis is essential for tumor growth and metastatic potential and for that reason considered an important target for tumor treatment. Noninvasive imaging technologies, capable of visualizing tumor angiogenesis and evaluating the efficacy of angiostatic therapies, are therefore becoming increasingly important. Among the various imaging modalities, magnetic resonance imaging (MRI) is characterized by a superb spatial resolution and anatomical soft-tissue contrast. Revolutionary advances in contrast agent chemistry have delivered versatile angiogenesis-specific molecular MRI contrast agents. In this paper, we review recent advances in the preclinical application of paramagnetic and fluorescent liposomes for noninvasive visualization of the molecular processes involved in tumor angiogenesis. This liposomal contrast agent platform can be prepared with a high payload of contrast generating material, thereby facilitating its detection, and is equipped with one or more types of targeting ligands for binding to specific molecules expressed at the angiogenic site. Multimodal liposomes endowed with contrast material for complementary imaging technologies, e.g., MRI and optical, can be exploited to gain important preclinical insights into the mechanisms of binding and accumulation at angiogenic vascular endothelium and to corroborate the in vivo findings. Interestingly, liposomes can be designed to contain angiostatic therapeutics, allowing for image-supervised drug delivery and subsequent monitoring of therapeutic efficacy

Enantiospecific sp(2)-sp(3) coupling of secondary and tertiary boronic esters

The cross-coupling of boronic acids and related derivatives with sp² electrophiles (the Suzuki–Miyaura reaction) is one of the most powerful C–C bond formation reactions in synthesis, with applications that span pharmaceuticals, agrochemicals and high-tech materials. Despite the breadth of its utility, the scope of this Nobel prize-winning reaction is rather limited when applied to aliphatic boronic esters. Primary organoboron reagents work well, but secondary and tertiary boronic esters do not (apart from a few specific and isolated examples). Through an alternative strategy, which does not involve using transition metals, we have discovered that enantioenriched secondary and tertiary boronic esters can be coupled to electron-rich aromatics with essentially complete enantiospecificity. As the enantioenriched boronic esters are easily accessible, this reaction should find considerable application, particularly in the pharmaceutical industry where there is growing awareness of the importance of, and greater clinical success in, creating biomolecules with three-dimensional architectures