Total Syntheses of the Telomerase Inhibitors Dictyodendrin B, C, and E

Concise and flexible total syntheses of the pyrrolo[2,3-c]carbazole alkaloids dictyodendrin B (2), C (3), and E (5) are described. These polycyclic telomerase inhibitors of marine origin derive from the common intermediate 18 which was prepared on a multigram scale by a sequence comprising a TosMIC cycloaddition with formation of the pyrrole A-ring, a titanium-induced reductive oxoamide coupling reaction to generate an adjacent indole nucleus, and a photochemical 6π-electrocyclization/aromatization tandem to forge the pyrrolocarbazole core. Conversion of 18 into dictyodendrin C required selective manipulations of the lateral protecting groups and oxidation with peroxoimidic acid to form the vinylogous benzoquinone core of the target. Zinc-induced reductive cleavage of the trichloroethyl sulfate ester then completed the first total synthesis of 3. Its relatives 2 and 5 also originate from compound 18 by a selective bromination of the pyrrole entity followed by elaboration of the resulting bromide 27 via metal−halogen exchange or cross-coupling chemistry, respectively. Particularly noteworthy in this context is the generation of the very labile p-quinomethide motif of dictyodendrin E by a palladium-catalyzed benzyl cross-coupling reaction followed by vinylogous oxidation of the resulting product 41 with DDQ. The Suzuki step could only be achieved with the aid of the borate complex 40 formed in situ from p-methoxybenzylmagnesium chloride and 9-MeO-9-BBN, whereas alternative methods employing benzylic boronates, -trifluoroborates, or -stannanes met with failure

Total Synthesis of Dictyodendrin B

A concise total synthesis of dictyodendrin B (1) is reported, a scarce marine alkaloid endowed with promising telomerase inhibitory activity. Key steps of the chosen route are a reductive cyclization of ketoamide 11 to indole 12 mediated by low-valent titanium (from TiCl₃ and KC₈) followed by a photochemical 6π-electrocyclization, which was performed in the presence of Pd/C and nitrobenzene to effect concomitant dehydrogenation/aromatization of the product initially formed. Regioselective bromination of the resulting pyrrolocarbazole 13 followed by lithium/bromine exchange and quenching of the resulting organolithium species with p-methoxybenzaldehyde installed the side chain at C2. Oxidation of the benzylic alcohol 15 thus obtained to ketone 17 was best achieved with catalytic amounts of tetra-n-propylammonium perruthenate (TPAP) and N-methylmorpholine-N-oxide (NMO) in dilute CH₂Cl₂ solution to avoid the formation of undue amounts of the unsymmetrical dimer 16. Ketone 17 was elaborated into the natural product by selective cleavage of the isopropyl ether with BCl₃, introduction of the sulfate moiety with the aid of trichloroethyl chlorosulfuric acid ester, deprotection of all lateral methyl ether groups, and final reductive cleavage of the trichloroethyl ester moiety. The spectroscopic data of synthetic dictyodendrin B thus formed matched those of an authentic sample in all regards. Moreover, it was shown that global deprotection of the peripheral −OH groups in pyrrolo[2,3-c]carbazole 13 is accompanied by spontaneous air-oxidation to form the quinone core of dictyodendrin C

Les Cetotheriidae (Mammalia, Cetacea, Mysticeti) de la Formation Pisco (Miocène inférieur Pliocène inférieur) de la côte péruvienne. Relations phylogénétiques et affinités des Cetotheriidae

Les mysticètes à fanons comprennent généralement quatre familles actuelles et une famille fossile: les Cetotheriidae s.l. Dépourvus des synapomorphies des mysticètes actuels, ces fossiles sont un groupe paraphylétique peu étudié. La description de trois nouveaux taxons fossiles (Piscobalaena nana et deux nouveaux genres) de la Formation Pisco (Néogène, Pérou) a mis en évidence de nouveaux caractères morphologiques. Les Balaenopteridae ont une stratégie de nutrition très particulière à laquelle sont associés des caractères morphologiques du crâne et du dentaire. Six taxons fossiles présentent certains de ces caractères. Ils pourraient donc être phylogénétiquement proches des ces derniers et avoir utilisé la même stratégie nutritionnelle. L'analyse cladistique de 54 caractères (crâne, région auditive et dentaire) de 25 taxons suggère que huit des 15 taxons fossiles étudiés forment un clade : les Cetotheriidae s.s. Son groupe-frère comprend les taxons actuels et cinq fossiles.Baleen mysticetes traditionally comprise four living families and a fifth exclusively fossil family: the Cetotheriidae s.l.. New material (Piscobalaena nana and two new genera) from the Neogene Pisco Formation of Peru, yield new morphological data. Balaenopteridae have a peculiar feeding behaviour associated with some morphological characters of the skull and dentary. Six fossil taxa present similar morphologies. Thus they could be phylogenetically close to Balaenopteridae and could have used the same feeding behaviour. The cladistic analysis of 54 characters (skull, auditory area, dentary) of 25 taxa suggests that eight of the 15 studied Cetotheriidae s.l. constitute a clade: the Cetotheriidae s.s. Its sister-group includes the extant taxa and five fossil taxa.PARIS-Museum Hist.Naturelle (751052304) / SudocSudocFranceF

Genetic analysis of sudden unexpected death cases: evaluation of library preparation methods to handle heterogeneous sample material

Over the past years, next-generation sequencing (NGS) technologies revolutionized the possibilities in a broad range of application areas. Also in the field of forensic genetics, NGS continuously gained in importance and attentiveness. A significant number of sudden cardiac deaths (SCD) in the young is due to heritable arrhythmia syndromes emphasizing the need of examining the genetic basis in these cases also with regard to the identification of relatives and/or patients being at risk. As a result, high-throughput methods became of increasing value in molecular autopsy investigations enabling the analysis of a broad spectrum of genes. Most standard protocols are optimized for high-quality samples and frequently not directly applicable to challenging forensic sample material. In the present study, we intended to examine a comprehensive gene panel associated with SCD and inherited arrhythmogenic disorders. We compared three different hybridization-based library preparation technologies in order to implement a suitable NGS workflow for heterogeneous, forensic as well as diagnostic sample material. The results obtained indicated, that the Illumina technologies Nextera DNA Flex and TruSeq were compatible with samples exhibiting varying levels of degradation. In comparison, the TruSight method also resulted in good sequencing data, but seemed to be more dependent on DNA integrity. The preparation protocols evaluated in our study are not restricted to molecular autopsy investigations and might be helpful for and transferrable to further forensic research applications

Post-mortem genetic investigation of cardiac disease–associated genes in sudden infant death syndrome (SIDS) cases

The sudden infant death syndrome (SIDS) is one of the leading causes of postneonatal infant death. It has been shown that there exists a complex relationship between SIDS and inherited cardiac disease. Next-generation sequencing and surveillance of cardiac channelopathy and cardiomyopathy genes represent an important tool for investigating the cause of death in SIDS cases. In the present study, targeted sequencing of 80 genes associated with genetic heart diseases in a cohort of 31 SIDS cases was performed. To determine the spectrum and prevalence of genetic heart disease associated mutations as a potential monogenic basis for SIDS, a stringent variant classification was applied and the percentage of rare (minor allele frequency ≤ 0.2%) and ultra-rare variants (minor allele frequency ≤ 0.005%) in these genes was assessed. With a minor allele frequency of ≤ 0.005%, about 20% of the SIDS cases exhibited a variant of uncertain significance (VUS), but in only 6% of these cases, gene variants proved to be “potentially informative.” The present study shows the importance of careful variant interpretation. Applying stringent criteria misinterpretations are avoided, as the results of genetic analyses may have an important impact of the family members involved

Synthesis-driven mapping of the dictyodendrin alkaloids

The dictyodendrin alkaloids have been described as the first telomerase inhibitors of marine origin. As such they represent interesting lead compounds in the quest for small molecule inhibitors of this tumor-marker enzyme. Described herein is the preparation of a collection of dictyodendrin-like compounds that hinges on the formation of their indole subunit by reductive cyclization of appropriate keto-amide precursors mediated by low valent titanium. It is shown that the underlying concept can be extended from the synthesis of heterocycles to the preparation of phenol and aniline derivatives using oxo-acid, oxo-nitrile or oxo-lactam derivatives as the substrates; such arene formations can even be carried out in cascade. Exploratory studies into the closure of the B-ring of the dictyodendrins with the aid of electrophilic reagents such as Ph3PAuCl/AgSbF6 or I+ revealed the bias of these polycyclic heteroarenes to undergo unusual skeletal rearrangements. It is demonstrated that the individual dictyodendrins and analogues are capable of cleaving double stranded DNA under oxidative conditions, provided that they exhibit at least one unprotected phenol group in their periphery

Clinical utility gene card for: Long-QT syndrome

Background/objectives!#!In the recently introduced GLIM diagnosis of malnutrition (Global Leadership Initiative on Malnutrition), details of how to classify inflammation as an etiologic criterion are lacking. This study aimed to determine at what level of serum C-reactive protein (CRP) the risk of low food intake increases in acutely ill older hospitalized patients.!##!Subjects/methods!#!A total of 377 patients, who were consecutively admitted to a geriatric acute care ward, were analyzed. Nutritional intake was determined using the food intake item of Nutritional Risk Screening and the plate diagram method and patients were grouped into three categories as >75%, 50-75% and ≤50% of requirements. CRP was analyzed according to standard procedures and patients were classified into different CRP groups as follows: 0.0-0.99 mg/dl, 1.0-1.99 mg/dl, 2.0-2.99 mg/dl, 3.0-4.99 mg/dl, 5.0-9.99 mg/dl and ≥10.0 mg/dl.!##!Results!#!Of the total population (mean age of 82.2 ± 6.6 years; 241 females), 82 (22%) had intake <50% of requirements and 126 (33%) demonstrated moderate to severe inflammation. Patients with food intake <50% of requirements had a significantly higher median CRP level compared to patients with food intake >75% of requirements (P < 0.001). The group with serum-CRP levels above 3.0 mg/dl had a markedly higher proportion of patients with low food intake; i.e., <50% and <75% of the requirements.!##!Conclusion!#!A serum-CRP of 3.0 mg/dl appears to be a reasonable threshold of acute inflammation leading to reduced food intake to serve as an orientation with regard to the inflammation criterion of the GLIM diagnosis in acutely ill older patients

Catalysis-based enantioselective total synthesis of the macrocyclic spermidine alkaloid isooncinotine

A concise and efficient total synthesis of the spermidine alkaloid (-)-isooncinotine (1) incorporating a 22-membered lactam ring is outlined. The approach is largely catalysis-based, involving a selective iron-catalyzed alkyl–aryl cross-coupling reaction of a difunctionalized pyridine substrate, a heterogeneous asymmetric hydrogenation step to set the chiral center of the target, and a highly integrated ring-closing metathesis/hydrogenation sequence to forge the saturated macrocyclic edifice in a single operation