Synthetic studies on alotamide A: construction of N‐demethylalotamide A

Financiado para publicación en acceso aberto: Universidade de Vigo/CISUGSeveral approaches to the synthesis of cyclodepsipeptide natural product alotamide A are described, eventually affording a very advanced N-demethylated analogue of the targeted natural product. The difficulties found in our endeavors on the synthesis of alotamide A have allowed us to gather some valuable information regarding the most convenient synthetic step for each key transformation. The intramolecular Csp2−Csp2 Stille cross-coupling and the macrolactam formation were found to be reliable protocols for the final construction of the alotamide A skeleton.Agencia Estatal de Investigación | Ref. PID2019-107855RB−I00Xunta de Galicia | Ref. ED431 C 2021/45Xunta de Galicia | Ref. ED431G/0

Total synthesis of homo- and heterodimeric bispyrrolidinoindoline dioxopiperazine natural products

Total synthesis and structural confirmation of homo- and heterodimeric bispyrrolidinoindoline dioxopiperazine alkaloids isolated from fungi and bacteria, namely, ditryptoleucine A, ditryptoleucine B (11), the N,N′-bis-demethylated analogue (+)-12, (−)-dibrevianamide F (13), (−)-SF-5280-451 (14), tetratryptomycin A (15), (−)-tryprophenaline (17), and (−)-SF-5280-415 (18), has been carried out starting from the corresponding bispyrrolidinoindolines derived from tryptophan. Our efforts to synthesize all possible diastereomers of the natural ditryptoleucine isolates uncovered structural factors that determine the rate and efficiency of dioxopiperazine ring formation, leading in some cases to mixtures of diastereomers by concomitant epimerization, to the formation of their putative monomeric dioxopiperazine dipeptide biogenetic precursors, and to the alternative formation of a dimer with a fused 1,3,5-triazepan-6-one heterocycle.Financiado para publicación en acceso aberto: Universidade de Vigo/CISUGMinisterio de Economía y Competitividad | Ref. SAF2016-77620-RXunta de Galicia | Ref. ED-431G/02 INBIOMED-FEDERXunta de Galicia | Ref. ED431C 2017/6

Apo-14´-Carotenoic acid is a novel endogenous and bioactive apo-carotenoid

Carotenoids can be metabolized to various apo-carotenoids and retinoids. Apo-15´-carotenoic acid (retinoic acid, RA) is a potent activator of the retinoic acid receptor (RAR) in its all-trans- (ATRA) and 9-cis- (9CRA) forms. In this study we show firstly, that apo-14´-carotenoic acid (A14CA), besides retinoic acids, is present endogenously and with increased levels in the human organism after carrot juice supplementation rich in β-carotene. All-trans-A14C (ATA14CA) is just a moderate activator of RAR-transactivation in reporter cell lines but can potently activate retinoic acid response element (RARE)-mediated signalling in DR5/RARE-reporter mice and potently increase retinoid-reporter target gene expression in ATA14CA-supplemented mice and treated MM6 cells. Further metabolism to all-trans-13,14-dihydroretinoic acid (ATDHRA) may be the key for its potent effects on retinoid target gene activation in ATA14CA-treated MM6 cells and in liver of supplemented mice. We conclude that besides RAs, there are alternative ways to activate RAR-response pathways in the mammalian organism. ATA14CA alone and in combination with its metabolite ATDHRA may be an alternative pathway for potent RAR-mediated signalling.Ministerio de Economía y Competitividad (España) | Ref. SAF2016-77620-R-FEDERXunta de Galicia | Ref. GRC ED431C 2017/6

Bioactivity-guided mapping and navigation of chemical space

The structure- and chemistry-based hierarchical organization of library scaffolds in tree-like arrangements provides a valid, intuitive means to map and navigate chemical space. We demonstrate that scaffold trees built using bioactivity as the key selection criterion for structural simplification during tree construction allow efficient and intuitive mapping, visualization and navigation of the chemical space defined by a given library, which in turn allows correlation of this chemical space with the investigated bioactivity and further compound design. Brachiation along the branches of such trees from structurally complex to simple scaffolds with retained yet varying bioactivity is feasible at high frequency for the five major pharmaceutically relevant target classes and allows for the identification of new inhibitor types for a given target. We provide proof of principle by identifying new active scaffolds for 5-lipoxygenase and the estrogen receptor ERa

Analysis of Outcomes in Ischemic vs Nonischemic Cardiomyopathy in Patients With Atrial Fibrillation A Report From the GARFIELD-AF Registry

IMPORTANCE Congestive heart failure (CHF) is commonly associated with nonvalvular atrial fibrillation (AF), and their combination may affect treatment strategies and outcomes