Solid-phase synthesis of peptides containing reverse-turn mimetic bicyclic lactams

The solid-phase synthesis and characterization of a series of peptides (4-15) containing reverse-turn mimetic bicyclic lactams is reported. The bicyclic lactams (1a, 1b) possess high structural similarity to the two central residues of a Pturn. Amino acid conjugates of these bicyclic lactams were synthesized on solid supports following a g-fluorenylmethoxycarbonyl (FMOC) protection strategy on WangMerrifield resin. Coupling between amino acids was accomplished by means of diisopropylcarbodiimide (DIC)/ hydroxyazabenzotriazole (HOAt). Coupling between amino acids and the mimics was performed with the potent Carpino's reagent O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramelhyluronium hexafluorophosphate (HATU). The final compounds were cleaved from the resin and obtained as N-acetylated methyl esters or benzyl amides

The role of the amygdala in ictal central apnea: insights from brain MRI morphometry

Objective: Ictal central apnea (ICA) is a frequent correlate of focal seizures, particularly in temporal lobe epilepsy (TLE), and regarded as a potential electroclinical biomarker of sudden unexpected death in epilepsy (SUDEP). Aims of this study are to investigate morphometric changes of subcortical structures in ICA patients and to find neuroimaging biomarkers of ICA in patients with focal epilepsy.Methods: We prospectively recruited focal epilepsy patients with recorded seizures during a video-EEG long-term monitoring with cardiorespiratory polygraphic recordings from April 2020 to September 2022. Participants were accordingly subdivided into two groups: patients with focal seizures with ICA (ICA) and without (noICA). A pool of 30 controls matched by age and sex was collected. All the participants underwent MRI scans with volumetric high-resolution T1-weighted images. Post-processing analyses included a whole-brain VBM analysis and segmentation algorithms performed with FreeSurfer.Results: Forty-six patients were recruited (aged 15-60 years): 16 ICA and 30 noICA. The whole-brain VBM analysis showed an increased gray matter volume of the amygdala ipsilateral to the epileptogenic zone (EZ) in the ICA group compared to the noICA patients. Amygdala sub-segmentation analysis revealed an increased volume of the whole amygdala, ipsilateral to the EZ compared to controls [F(1, 76) = 5.383, pFDR = 0.042] and to noICA patients ([F(1, 76) = 5.383, pFDR = 0.038], specifically of the basolateral complex (respectively F(1, 76) = 6.160, pFDR = 0.037; F(1, 76) = 5.121, pFDR = 0.034). Interpretation: Our findings, while confirming the key role of the amygdala in participating in ictal respiratory modifications, suggest that structural modifications of the amygdala and its subnuclei may be valuable morphological biomarkers of ICA

Novel SMAC-mimetics synergistically stimulate melanoma cell death in combination with TRAIL and Bortezomib

BACKGROUND: XIAP (X-linked inhibitor of apoptosis protein) is an anti-apoptotic protein exerting its activity by binding and suppressing caspases. As XIAP is overexpressed in several tumours, in which it apparently contributes to chemoresistance, and because its activity in vivo is antagonised by second mitochondria-derived activator of caspase (SMAC)/direct inhibitor of apoptosis-binding protein with low pI, small molecules mimicking SMAC (so called SMAC-mimetics) can potentially overcome tumour resistance by promoting apoptosis. METHODS: Three homodimeric compounds were synthesised tethering a monomeric SMAC-mimetic with different linkers and their affinity binding for the baculoviral inhibitor repeats domains of XIAP measured by fluorescent polarisation assay. The apoptotic activity of these molecules, alone or in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and/or Bortezomib, was tested in melanoma cell lines by MTT viability assays and western blot analysis of activated caspases. RESULTS: We show that in melanoma cell lines, which are typically resistant to chemotherapeutic agents, XIAP knock-down sensitises cells to TRAIL treatment in vitro, also favouring the accumulation of cleaved caspase-8. We also describe a new series of 4-substituted azabicyclo[5.3.0] alkane monomeric and dimeric SMAC-mimetics that target various members of the IAP family and powerfully synergise at submicromolar concentrations with TRAIL in inducing cell death. Finally, we show that the simultaneous administration of newly developed SMAC-mimetics with Bortezomib potently triggers apoptosis in a melanoma cell line resistant to the combined effect of SMAC-mimetics and TRAIL. CONCLUSION: Hence, the newly developed SMAC-mimetics effectively synergise with TRAIL and Bortezomib in inducing cell death. These findings warrant further preclinical studies in vivo to verify the anticancer effectiveness of the combination of these agents

Biosynthesis of mycophenolic acid. Oxidation of 6-farnesyl-5,7-dihydroxy-4- methylphthalide in a cell-free preparation from Penicillium brevicompactum

The conversion of 6-farnesyl-5,7-dihydroxy-4-methylphthalide (5) into mycophenolic acid (1) proceeds through the hydroxy-ketone (11) by oxidation of the central double bond

Synthesis of 8,5-fused bicyclic lactam by stereo- and regioselective radical cyclization

A conformationally restricted dipeptide mimetic was synthesized via a regio- and stereoselective radical cyclization of an \u3b1-N-acetyl acrylamide

TITANIUM TETRACHLORIDE-MEDIATED ENANTIOSELECTIVE SYNTHESIS OF TRANS BETA-LACTONES

Pharmacologically interesting trans beta-lactones 11 and 16 were synthesized using a titanium tetrachloride-mediated enantioselective aldol reaction as the key synthetic step (see Scheme 2)

Chiral acyl anion equivalents: asymmetric synthesis of 11-deoxy-ent-prostaglandin intermediates

Conjugate addition of the chiral formyl anion equivalent p-tolyl p-tolylthiomethyl sulphoxide (+)-(S)-(1) to the cyclopentenone derivative (2a) leads to the adduct (3a) in 45% yield with high diastereoselectivity. Reduction of (3a) gives the dithioacetal (4a), an interesting optically pure intermediate in the synthesis of 11-deoxy-ent-prostanoids. The high selectivity, contrasting with a lower selectivity observed using cyclopentenone, is to be ascribed to more severe steric demands in the transition state

A total synthesis of mycophenolic acid, some analogues and some biogenetic intermediates

Mycophenolic acid (28) has been obtained by a convergent synthesis starting from methyl 6-bromo-4-methylhex-4-enoate (13) and 5,7-dihydroxy-4-methylphthalide (24). For the total synthesis of 5,7-dihydroxy-4-methylphthalide, 1-carbethoxy-2,3-dimethylcyclohexa-4,6-dione (14) was aromatized and transformed into 4,6-dimethoxy-2,3-dimethylbenzamide. The photolysis of the corresponding N-chloroamide and subsequent hydrolysis gave 5,7-dimethoxy-4-methylphthalide which was hydrolysed to 5,7-dihydroxy-4-methylphthalide (24). The bromoester (13) was obtained starting from geraniol. Condensation between 13 and 24 with silver oxide in dioxane afforded the methyl ester of nor-O-methyl mycophenolic acid. Selective methylation and hydrolysis furnished mycophenolic acid. \ua9 1972