Organelle movement is essential for proper function of living cells. In plants, these movements generally depend on actin filaments, but the underlying mechanism unknown. Here, in Arabidopsis , we identify associations short filaments along chloroplast periphery plasma membrane side associated with photorelocation and anchoring to membrane. We have termed chloroplast-actin (cp-actin filaments). Cp-actin emerge from edge exhibit rapid turnover. The presence cp-actin depends an actin-binding...

Full details of the first total synthesis (−)-muraymycin (MRY) D2 and its epimer, antibacterial nucleoside natural product, are described. Key strategic elements approach include preparation urea dipeptide moiety found in muraymycins containing an l-epi-capreomycidine via a nitrene C−H insertion sulfamate 10 fully protected muraymycin skeleton at late stage by Ugi four-component reaction. Thus, with mol % Rh2(esp)2 catalyst gave cyclic sulfamates 11a 11b 47% yield (11a:11b = 1:2.0)....

The systematic structure–activity relationship (SAR) of the muraymycins (MRYs) using an Ugi four-component reaction (U4CR) was investigated. impact lipophilic substituent on antibacterial activity significant, and analogues 8 9 having a side chain exhibited good against range Gram-positive bacterial pathogens, including MRSA VRE. Further investigation compounds revealed these to be selective inhibitors MraY transferase nontoxic HepG2 cells. SAR accessory urea–peptide moiety indicated that it...

Abstract Novel antibacterial agents are needed to address the emergence of global antibiotic resistance. MraY is a promising candidate for development because it target five classes naturally occurring nucleoside inhibitors with potent activity. Although these natural products share common uridine moiety, their core structures vary substantially and they exhibit different activity profiles. An incomplete understanding structural mechanistic basis inhibition has hindered translation compounds...

Key derivatives and analogues of fostriecin were prepared examined that revealed a fundamental role for the unsaturated lactone confirmed essential nature phosphate monoester. Thus, an identical 200-fold reduction in protein phosphatase 2A (PP2A) inhibition is observed with either saturated (7) or analogue lacks entire (15). This increase PP2A attributable to potentially may be due reversible C269 alkylation within PP β12−β13 active site loop accounting PP2A/4 potency selectivity.

The first total synthesis of the potent antitumor agent fostriecin (CI-920) is described, confirming relative and absolute stereochemistry assignments. Fostriecin a unique phosphate monoester which exhibits weak topoisomerase II inhibition (IC(50) = 40 microM) more selective protein phosphatase 2A 4 (PP2A PP4) 40-3 nM 1.5 nM), resulting in mitotic entry checkpoint inhibition. Phase I clinical trials with fostriecin, were to explore potential this novel mechanism action, halted even before...

TB and anti-TB: Two key steps in the synthesis of caprazol (1), a core structure antituberculosis antibiotics, are introduction an aminoribose moiety by β-selective ribosylation without use neighboring-group participation construction diazepanone moiety. Supporting information for this article (experimental details characterization data 3–16 synthetic 2) is available on WWW under http://www.wiley-vch.de/contents/jc_2002/2005/z462439_s.pdf or from author. Please note: The publisher not...

Synthesis of palmitoyl caprazol 7, which possesses a simple fatty acyl side chain at the 3' ''-position diazepanone moiety, was carried out and their antibacterial activity evaluated. The key elements our approach include improved synthesis 5'-β-O-aminoribosyl-glycyluridine derivative, installation to cyclization precursor, construction by an intramolecular reductive amination. second generation (+)-caprazol also established. Palmitoyl 7 exhibited against Mycobacterium smegmatis ATCC607 (MIC...

The rational simplification of the caprazamycin (CPZ) class nucleoside natural products was carried out to address their molecular complexity. First, analogues 6-8, where diazepanone ring CPZ removed and a lipophilic side chain attached either C-7' or N(6') atom, were used investigate conformation-activity relationship. On basis this relationship, we designed oxazolidine-containing uridine derivatives 18-21 by restricting conformation 6-8. As result, (t)Bu ester 20 found be most active...

Peptides can be converted to highly active compounds by introducing appropriate substituents on the suitable amino acid residue. Although modifiable residues in peptides systematically identified peptide scanning methodologies, there is no practical method for optimization at "scanned" position. With purpose of using derivatives not only but also as a starting point further chemical functionalization, we herein report "scanning and direct derivatization" strategy through chemoselective...

Abstract MraY (phospho- N -acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive molecules as candidates for a new class of antibacterial agents to combat antimicrobial-resistant bacteria. Structural optimization these is required improve their drug-like properties therapeutic use. However, chemical modifications painstaking tasks due complex synthetic processes, which bottleneck in advancing the clinic. Here, we develop strategy comprehensive situ evaluation...

The first total synthesis of the nucleoside antibiotic herbicidin B (1b) was achieved, where a novel aldol-type C-glycosidation reaction promoted by samarium diiodide (SmI2) used as key step. Treatment methyl 3,4-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanediyl)-1-phenylthio-2-ulos-β-d-glucuronate (13) with SmI2 in THF regioselectively gave corresponding 1-enolate, which readily trapped 1-β-d-xylosyladenine 5'-aldehyde derivative 7 to afford product 19a,b an anomeric mixture. Dehydration...

Full details of the total syntheses thiocoraline (1) and BE-22179 (2), C2 symmetric bicyclic octadepsipeptides possessing two pendant 3-hydroxyquinoline chromophores, are described in which their relative absolute stereochemistry were established. Key elements approach include late-stage introduction chromophore, symmetrical tetrapeptide coupling, macrocyclization 26-membered octadepsipeptide conducted at single secondary amide site following disulfide formation, a convergent assemblage...

Full details of the total synthesis (+)-caprazol are described. The key elements our approach include early stage introduction aminoribose in a highly β-selective manner, using steric hindrance transition state and construction diazepanone by modified intramolecular reductive amination. 5'-C-glycyluridine derivative 9, which was prepared stereoselectively via Sharpless asymmetric aminohydroxylation, ribosylated with 2,3-O-alkylidene ribofuranosyl donors. It revealed that increasing size...

Triazole-cross-linked oligodeoxynucleotides were synthesized with use of the Cu(I) catalyzed alkyne−azide cycloaddition (CuAAC) possessing N-3-(azidoethyl)thymidine and N-3-(propargyl)thymidine at 3'- 5'-termini. The newly thermally stable their global structures retained those non-cross-linked oligodeoxynucleotides. dumbbell showed excellent stability against snake venom phosphodiesterase (3'-exonuclease) high thermal stability, which are necessary for decoy molecules to achieve biological...

Muraymycin analogues with a lipophilic substituent were synthesized using an Ugi four-component assemblage. This approach provides ready access to range of simply by altering the aldehyde component. The impact on antibacterial activity was very large, and 7b−e 8b−e exhibited good against Gram-positive bacterial pathogens including methicillin-resistant Staphylococcus aureus vancomycin-resistant Enterococcus faecium. study also showed that accessory urea-dipeptide motif contributes MraY...

The effect of the solvent on diastereoselectivity Joullié-Ugi three-component reaction (JU-3CR) using an α-substituted five-membered cyclic imine is revisited. cis and trans isomers were generated in toluene HFIP, respectively. Hammett analysis JU-3CR suggests presence two mechanisms.

Abstract The development of new antibacterial drugs with different mechanisms action is urgently needed to address antimicrobial resistance. MraY an essential membrane enzyme required for bacterial cell wall synthesis. Sphaerimicins are naturally occurring macrocyclic nucleoside inhibitors and considered a promising target in discovery. However, developing sphaerimicins as antibacterials has been challenging due their complex structures. In this study, we construct characteristic skeleton...

It is urgent to develop novel anti-Pseudomonas agents that should also be active against multidrug resistant P. aeruginosa. Expanding the antibacterial spectrum of muraymycins toward aeruginosa was investigated by systematic structure-activity relationship study. revealed two functional groups, a lipophilic side chain and guanidino group, at accessory moiety were important for activity, analogue 29 exhibited activity range strains with minimum inhibitory concentration values 4-8 μg/mL.

The total synthesis of tunicamycin V is described. This strategy based on the initial construction tunicaminyluracil, which regarded to play an important role in observed biological activities. key was a Mukaiyama aldol reaction followed by furan-oxidation construct undecose skeleton, [3,3] sigmatropic rearrangement cyanate, and highly selective trehalose-type glycosylation.