An Improved Biomimetic Formal Synthesis of Abyssomicin C and atrop-Abyssomicin C

Biomimetic approaches towards the synthesis of abysssomicin C and atrop-abyssomicin C are based on a powerful intramolecular Diels–Alder reaction (IMDA) of a butenolide derivative attached to a keto-triene side chain, where the stereogenic centers and the carbon framework are established in one step. The synthesis of the IMDA precursor is based on an ionic coupling of methyl γ-methylene-β-tetronate with various aldehydes. However, the low yields of the coupling and the high sensitivity of the precursor hampered the efficiency of the developed routes and should be met. In the present work, a modified aldehyde is coupled with methyl γ-methylene-β-tetronate, in a substantially higher yield. Asymmetric synthesis of this aldehyde is based on the use of the widely available and cheap Amano lipase AK. In addition, the development of a highly convenient one-pot oxidation-IMDA reaction protocol obviates the isolation of the sensitive IMDA-precursor and augments the yield towards the carbocyclic skeleton of abysssomicin C and atrop-abyssomicin C. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinhei

Aqueous Solubility Enhancement for Bioassays of Insoluble Inhibitors and QSPR Analysis: A TNF-α Study

The aim of this study is to improve the aqueous solubility of a group of compounds without interfering with their bioassay as well as to create a relevant prediction model. A series of 55 potential small-molecule inhibitors of tumor necrosis factor–alpha (TNF-α; SPD304 and 54 analogues), many of which cannot be bioassayed because of their poor solubility, was used for this purpose. The solubility of many of the compounds was sufficiently improved to allow measurement of their respective dissociation constants (K d ). Parameters such as dissolution time, initial state of the solute (solid/liquid), co-solvent addition (DMSO and PEG3350), and sample filtration were evaluated. Except for filtration, the remaining parameters affected aqueous solubility, and a solubilization protocol was established according to these. The aqueous solubility of the 55 compounds in 5% DMSO was measured with this protocol, and a predictive quantitative structure property relationship model was developed and fully validated based on these data. This classification model separates the insoluble from the soluble compounds and predicts the solubility of potential small-molecule inhibitors of TNF-α in aqueous solution (containing 5% DMSO as co-solvent) with an accuracy of 81.2%. The domain of applicability of the model indicates the type of compounds for which estimation of aqueous solubility can be confidently predicted. © 2017, © 2017 Society for Laboratory Automation and Screening

Discovery of Small-Molecule Inhibitors of Receptor Activator of Nuclear Factor-κB Ligand with a Superior Therapeutic Index

Receptor activator of nuclear factor-κB ligand (RANKL) constitutes the master mediator of osteoclastogenesis, while its pharmaceutical inhibition by a monoclonal antibody has been approved for the treatment of postmenopausal osteoporosis. To date, the pursuit of pharmacologically more favorable approaches using low-molecular-weight inhibitors has been hampered by low specificity and high toxicity issues. This study aimed to discover small-molecule inhibitors targeting RANKL trimer formation. Through a systematic screening of 39 analogues of SPD-304, a dual inhibitor of tumor necrosis factor (TNF) and RANKL trimerization, we identified four compounds (1b, 3b, 4a, and 4c) that selectively inhibited RANKL-induced osteoclastogenesis in a dose-dependent manner, without affecting TNF activity or osteoblast differentiation. Based on structure-activity observations extracted from the most potent and less toxic inhibitors of RANKL-induced osteoclastogenesis, we synthesized a focused set of compounds that revealed three potent inhibitors (19a, 19b, and 20a) with remarkably low cell-toxicity and improved therapeutic indexes as shown by the LC50 to IC50 ratio. These RANKL-selective inhibitors are an excellent starting point for the development of small-molecule therapeutics against osteolytic diseases.

Synthesis and biological evaluation of potential small molecule inhibitors of tumor necrosis factor

Inhibition of tumor necrosis factor (TNF) production or function by small molecules has become a major focus in the pharmaceutical industry for the treatment of rheumatoid arthritis. In this study, a series of 39 novel SPD-304 analogs were designed, synthesized and evaluated as TNF inhibitors. Our results show that small structural changes produce ligands with similar binding affinities (K-d) for TNF, but significantly different potencies in a L929 cell-based assay. In addition, contrary to the high affinity of compounds 4e, 8c and 10e for TNF in vitro, the potency of these compounds was determined to be low. We propose that these differences can partly be explained by the physicochemical characteristics of the synthesized SPD-304 analogs. Our findings were supplemented by molecular docking studies on the TNF dimer. These synthesized analogs may serve as a starting point for developing novel TNF inhibitors

Nuove oxazinine dai mitili contaminati del Mar Adriatico

L???aumento delle intossicazioni, dovute all???ingestione di molluschi contaminati, determina non solo gravi problemi sanitari, ma anche ingenti perdite economiche all???industria marina. L???avvelenamento dei molluschi è connesso alla produzione di biotossine marine da parte di microalghe. I mitili, infatti, filtrando il plancton marino, possono accumulare livelli di tossine tali da poter essere letali per l???uomo. Per minimizzare tale rischio, è nata la necessità di continui controlli dei molluschi raccolti nelle aree più a rischio. A tal scopo, il nostro gruppo di ricerca ha intrapreso da diversi anni un programma di monitoraggio dei mitili provenienti dalle coste del Mar Adriatico Settentrionale, dove si concentra il 90 % della produzione nazionale. Nel corso di queste analisi abbiamo isolato biotossine di tipo DSP (Diarrhetic Shellfish poisoning)1 e delle yessotossine, alcune delle quali sembrano essere peculiari dei nostri mari. In aggiunta a queste classiche biotossine marine, seguendo la tossicità delle frazioni isolate, sono stati trovati e caratterizzati da un punto di vista stereostrutturale anche altri composti citotossici, appartenenti alla classe dei clorosolfolipidi3 e delle oxazinine4. Il ritrovamento di queste sostanze aggrava ulteriormente i rischi sanitari collegati al consumo dei molluschi. Recentemente, l???analisi di una partita di mitili (Mytilus galloprovincialis) raccolta dalle acque di Cesenatico nel 2002 ha permesso di isolare delle nuove oxazinine citotossiche, la cui determinazione stereostrutturale è stata effettuata attraverso una dettagliata analisi spettroscopica NMR. La loro attività citotossica è stata valutata calcolando la percentuale di inibizione di crescita su linee cellulari WEHI 164 e J774. 1. Fattorusso, E.; Ciminiello, P.; Costantino, V.; Magno, S.; Mangoni, A.; Milandri, A.; Poletti, R.; Pompei, M.; Viviani, R. Mar. Poll. Bull.1992, 24, 234. 2. Ciminiello, P.; Fattorusso, E.; Forino, M.; Poletti, R.; Viviani, R. Chem. Res. in Toxicology. 2000, 13, 770. 3. Ciminiello, P.; Fattorusso, E.; Forino, M.; Di Rosa, M.; Ianaro, A.; Poletti, R. J. Org. Chem. 2001, 66, 578. 4. Ciminiello, P.; Dell???Aversano, C.; Fattorusso, E.; Forino, M.; Magno, S.; Ianaro, A.; Di Rosa, M. Eur. J. Org. Chem.2001, 1, 49