Previous studies in the field of beta-adrenergic drugs had supported the hypothesis of the existence of a bioisosterism between the [(methyleneamino)oxy]methyl moiety (C = NOCH2, MAOMM) of type B beta-blocking drugs and the aryl (Ar) of type A beta-blocking agents. In the MAOMM, however, the carbon of the CH2 linked to the oximic oxygen possesses a hybridization (sp3) and a geometry different from those of the corresponding carbon of Ar which possesses an sp2 hybridization. Furthermore, in the MAOMM, in its preferred conformation, the unsaturated portion (C = N) is situated in a spatial area which does not correspond exactly to the area occupied by Ar. The formal inversion of the atomic sequence C = NOCH2 of the MAOMM leads to a different type of group, the [(methyloxy)imino]methyl moiety (CH2ON = C, MOIMM), which, in the E configuration, appears to present greater steric and electronic analogies with an Ar, with respect to the MAOMM. On the basis of these observations, some completely aliphatic (E)-N-(3-amino-2- hydroxypropylidene)(alkyloxy)amino derivatives of type C (11a,b and 12a, b) were synthesized, the their beta-adrenergic properties were compared with those of the corresponding [(methyleneamino)oxy]-methyl isomers of type B (19a, b and 20a, b). The similar beta-adrenergic properties of 11, 12 and 19, 20 evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations, are discussed on the basis of considerations regarding the spatial correspondences and electronic analogies between the MOIMM and the MAOMM.
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Glioblastoma multiforme (GBM) has a dismal outcome of approximately 12 months. Less than 5% of patients (long-term survivors-LTS) survives more than 5-years, including IDH-mutant gliomas. Nevertheless, the molecular fingerprint of LTS remains largely uncharted. DNA methylation (DNAm) is an epigenetic modification, altered in cancer and used to classify brain tumors. In this multicentric study sponsored by Alleanza Contro il Cancro (ACC) network, we aimed to molecularly characterize LTS vs standard survival GBM (CTR) by DNAm/Copy Number Variation (CNV) and mutation profiling. We analyzed 51 IDHwt GBM samples (27LTS/24CTR) by Illumina EPIC beadChip and AmpliSeq Comprehensive Cancer Panel. We ran methylation data through the brain tumor classifiers v11b4 and v12.5, performed multidimensional scaling analysis and investigated differentially methylated regions (DMR) correlating them with survival. According to v11b4, cases were classified as: 43 GBM IDHwt (22LTS/21CTR), 27 with a calibrated score >0.84 (16LTS); Plexus Tumor with low scores (2LTS/3CTR); 3 LTS samples did not match. A diagnostic refinement was observed by the v12.5, with 48 cases classifying as GBM IDHwt (25LTS/23CTR) and 35 (19LTS) with optimal score. The LTS group was more heterogeneous, with 4 cases matching in the pedHGG subtypes, including 2 cases in young adults, one with high tumor mutational burden and MSH6 mutation. No specific DNAm genomic profile was observed for LTS patients but we identified 18 significant DMRs, 4 associated with survival probability. At CNV analysis, most cases showed classical alterations (Chr7 gain with or w/o EGFR amplification, 9p21 loss, Chr10 loss) while pedHGG were associated with PDGFRA amplification, 1q gain, 13q loss. NGS identified at least 1 pathogenic variant in 40 cases (22CTR/18LTS) and showed a higher prevalence of mutation negative cases among LTS. No significant difference between the 2 groups was observed in terms of prevalence of mutated genes or number of VUS per sample.
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