Synthesis of 13C-labelled, bicyclic mimetics of natural enediynes

Using a versatile synthesis with 13CH3PPh3I and CH313CO2Et as 13C sources, the first examples of nine membered chromophores, which have been differentially labelled with 13C in their carbocyclic enediyne cores, are described

Total synthesis and biomimetic studies of nine-membered enediynes

The kedarcidin and C1027 chromophores are formidable targets of total synthesis. During our 20-year study of these nine-membered enediyne chromophores, several powerful, yet chemoselective methods have been developed: stereoselective epoxyalkyne formation, atropselective Pd/Cu-Sonogashira coupling, 2-deoxy-α-glycosylation, CeX3-mediated enediyne cyclisation, and SmI2-based reductive olefination. Besides their total syntheses, application of these methods to the biomimetic study of the putative enediyne-precursors of the cyanosporasides, sporolides, and fijiolides will be presented. In particular, we disclose biomimetic evidence of a p-benzyne diradical species reacting in either a radical mode (hydrogen abstraction) or ionic mode (chloride attack) at the same sterically exposed site, leading to either monochlorinated cyanosporaside A/F or cyanosporaside B–E, respectively. The ionic monochlorination of the cycloaromatized p-benzyne of the C1027 enediyne core to generate the fijiolide aglycon framework will also be presented

A Convergent Total Synthesis of the Kedarcidin Chromophore: 20-Years in the Making

The kedarcidin chromophore is a formidible target for total synthesis. Herein, we 19 describe a viable synthesis of this highly unstable natural product. This entailed the early 20 introduction and gram-scale synthesis of 2-deoxysugar conjugates of both L-mycarose and L21 kedarosamine. Key advances include: (1) stereoselective allenylzinc keto-addition to form an 22 epoxyalkyne; (2) -selective glycosylations with 2-deoxy thioglycosides (AgPF6/DTBMP) 23 and Schmidt donors (TiCl4); (3) Mitsunobu aryl etherification to install a hindered 1,2-cis24 configuration; (4) atropselective and convergent Sonogashira-Shiina cyclization sequence; 25 (5) Ohfune-based amidation protocol for naphthoic acid; (6) Ce(III)-mediated nine26 membered enediyne cyclization and ester/mesylate derivatisation; (7) SmI2-based reductive 27 olefination and global HF-deprotection end-game. The longest linear sequence from gram28 scale intermediates is 17-steps, and HRMS data of the synthetic natural product was obtained 29 for the first tim

Transcriptomic Analysis of Ciguatoxin-Induced Changes in Gene Expression in Primary Cultures of Mice Cortical Neurons

Ciguatoxins are polyether marine toxins that act as sodium channel activators. These toxins cause ciguatera, one of the most widespread nonbacterial forms of food poisoning, which presents several symptoms in humans including long-term neurological alterations. Earlier work has shown that both acute and chronic exposure of primary cortical neurons to synthetic ciguatoxin CTX3C have profound impacts on neuronal function. Thus, the present work aimed to identify relevant neuronal genes and metabolic pathways that could be altered by ciguatoxin exposure. To study the effect of ciguatoxins in primary neurons in culture, we performed a transcriptomic analysis using whole mouse genome microarrays, for primary cortical neurons exposed during 6, 24, or 72 h in culture to CTX3C. Here, we have shown that the effects of the toxin on gene expression differ with the exposure time. The results presented here have identified several relevant genes and pathways related to the effect of ciguatoxins on neurons and may assist in future research or even treatment of ciguatera. Moreover, we demonstrated that the effects of the toxin on gene expression were exclusively consequential of its action as a voltage-gated sodium channel activator, since all the effects of CTX3C were avoided by preincubation of the neurons with the sodium channel blocker tetrodotoxinThe research leading to these results has received funding from the following FEDER cofounded-grants. From CDTI and Technological Funds, supported by Ministerio de Economía, Industria y Competitividad, AGL2014-58210-R, AGL2016-78728-R (AEI/FEDER, UE), ISCIII/PI16/01830 and RTC-2016-5507-2. From CDTI under ISIP Programme, Spain, IDI-20130304 APTAFOOD and ITC-20161072. From European Union POCTEP 0161-Nanoeaters -1-E-1, and Interreg AlertoxNet EAPA-317-2016. ABJ is recipient of a predoctoral fellowship from the Spanish Ministry of EducationS

Addressing the analytical challenges for the detection of ciguatoxins using an electrochemical biosensor

The importance of ciguatoxins (CTXs) in seafood safety and their emerging occurrence in locations far away from tropical areas highlight the need for simple and low-cost methods for the sensitive and rapid detection of these potent marine toxins to protect seafood consumers. Herein, an electrochemical immunosensor for the detection of CTXs is presented. A sandwich configuration is proposed, using magnetic beads (MBs) as immobilisation supports for two capture antibodies, with their combination facilitating the detection of CTX1B, CTX3C, 54-deoxyCTX1B and 51-hydroxyCTX3C. PolyHRP-streptavidin is used for the detection of the biotinylated detector antibody. Experimental conditions are first optimised using colorimetry, and these conditions are subsequently used for electrochemical detection on electrode arrays. Limits of detection at the pg/mL level are achieved for CTX1B and 51-hydroxyCTX3C. The applicability of the immunosensor to the analysis of fish samples is demonstrated, attaining detection of CTX1B at contents as low as 0.01 µg/kg, and providing results in correlation with those obtained using mouse bioassay (MBA) and cell-based assay (CBA), as well as liquid chromatography coupled to high-resolution mass spectrometry (LC-ESI-HRMS). This user-friendly bioanalytical tool for the rapid detection of CTXs can be used to mitigate ciguatera risk and contribute to the protection of consumer health.info:eu-repo/semantics/acceptedVersio

Synthesis of the entire carbon framework of the kedarcidin chromophore aglycon

In advanced studies directed toward the total synthesis of the kedarcidin chromophore, we have successfully achieved the late-stage installation of the nine-membered diyne ring in the presence of the highly functionalised ansamacrocyclic bridge

Efficient construction of the kedarcidin chromophore ansamacrolide

The streamlined assembly of the ansamacrolide framework of the kedarcidin chromophore via an efficient atropselective Sonogashira coupling step is described. To this end, two newly improved practical syntheses of the cyclopentene and dine fragments have been developed, which feature 0.2 mol % catalytic loadings for an RCM step and i-PrMgCl/CH2I2 as a new entry to gem-disubstituted epoxides from ketones, both being applicable to 49-g scales

Convenient route to derivatives of the 2-deoxysugar subunits of the kedarcidin chromophore: L-mycarose and L-kedarosamine

An efficient and practical synthesis of mycarose and kedarosamine derivatives has been devised from ethyl (S)-lactate v/a a versatile (E)-alkene intermediate. Noteworthy transformations include a highly trans-selective one-pot Julia olefination protocol and intramolecular cyclisation of a 2,3-epoxy carbamate