- Seven new didemnins from the marine tunicate Trididemnum solidum
-
Seven new didemnins-didemnins M (1), N (2), X (3) and Y (4), nordidemnin N (5), epididemnin A1 (6), and acyclodidemnin A (7)-were isolated from an extract of the Caribbean tunicate Trididemnum solidum. The structures of these compounds were assigned, based on FABMS, high-field NMR data, and chemical degradation studies. Biological activities of these peptides are also described.
- Sakai, Ryuichi,Stroh, Justin G.,Sullins, David W.,Rinehart, Kenneth L.
-
-
Read Online
- Synthesis and absolute configuration of syringolide 2, an elicitor from Pseudomonas syringae pv. tomato
-
The enantioselective synthesis of syringolide 2, one of the two elicitors produced by Pseudomonas syringae pv. tomato, was accomplished in 11 steps from diethyl D-tartrate.
- Kuwahara, Shigefumi,Moriguchi, Masahiko,Miyagawa, Kazuhiro,Konno, Masako,Kodama, Osamu
-
-
Read Online
- Structure-Activity Relationship Study of Majusculamides A and B and Their Analogues on Osteogenic Activity
-
We discovered that majusculamide A (1) and majusculamide B (2), isolated from a marine cyanobacterium collected in Okinawa, induced osteoblast differentiation in MC3T3-E1 cells. Although majusculamide A (1) has a different configuration only at the C-19 stereocenter, bearing a methyl group, compared to majusculamide B (2), the effect of 1 was stronger than that of 2. We synthesized some analogues of the majusculamides (3-15) and evaluated osteogenic activities of these analogues. The structure-activity relationship study of majusculamide analogues suggested that the number of methyls and configuration at C-19 and the nature of the substituent at C-20 of majusculamide A (1) may be important for the osteoblast differentiation-inducing effect of 1.
- Nakajima, Daisuke,Natsume, Noriyuki,Ozaki, Kaori,Teruya, Toshiaki,Yokoshima, Satoshi
-
p. 2477 - 2482
(2020/10/02)
-
- MACROCYCLIC BROAD SPECTRUM ANTIBIOTICS
-
Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.
- -
-
Paragraph 00848
(2017/08/01)
-
- A Continuous, Fluorogenic Sirtuin 2 Deacylase Assay: Substrate Screening and Inhibitor Evaluation
-
Sirtuins are important regulators of lysine acylation, which is implicated in cellular metabolism and transcriptional control. This makes the sirtuin class of enzymes interesting targets for development of small molecule probes with pharmaceutical potential. To achieve detailed profiling and kinetic insight regarding sirtuin inhibitors, it is important to have access to efficient assays. In this work, we report readily synthesized fluorogenic substrates enabling enzyme-economical evaluation of SIRT2 inhibitors in a continuous assay format as well as evaluation of the properties of SIRT2 as a long chain deacylase enzyme. Novel enzymatic activities of SIRT2 were thus established in vitro, which warrant further investigation, and two known inhibitors, suramin and SirReal2, were profiled against substrates containing ε-N-acyllysine modifications of varying length.
- Galleano, Iacopo,Schiedel, Matthias,Jung, Manfred,Madsen, Andreas S.,Olsen, Christian A.
-
supporting information
p. 1021 - 1031
(2016/02/23)
-
- Design and Synthesis of 2-Alkylpyrimidine-4,6-diol and 6-Alkylpyridine-2,4-diol as Potent GPR84 Agonists
-
A series of alkylpyrimidine-4,6-diol derivatives were designed and synthesized as novel GRP84 agonists based on a high-throughput screening (HTS) hit 1. 6-Nonylpyridine-2,4-diol was identified as the most potent agonist of GPR84 reported so far, with an EC50 of 0.189 nM. These novel GPR84 agonists will provide valuable tools for the study of the physiological functions of GPR84.
- Liu, Yang,Zhang, Qing,Chen, Lin-Hai,Yang, Hui,Lu, Wei,Xie, Xin,Nan, Fa-Jun
-
supporting information
p. 579 - 583
(2016/07/06)
-
- Synthesis of tritium labelled and photoactivatable N-acyl-L-homoserine lactones: Inter-kingdom signalling molecules
-
N-Acyl-L-homoserine lactones (AHLs) are signal molecules that are synthesized in nature by Gram-negative bacteria. They allow communication between bacteria (quorum sensing) and between microorganisms and their eukaryotic host cells (inter-kingdom signalling). However, very little is known about the mechanisms of the latter system. Therefore, tritium labelled photoactivatable AHLs were synthesized to identify specific receptors in immune cells (e.g., human polymorphonuclear neutrophils, PMN) that bind to AHL. A photoaffinity label - a diazirine group - was chosen as the smallest possible photoactivatable group that can be activated by light irradiation. The resulting highly active carbene will bind covalently to the closest chemical structure in the pocket of the receptor. The diazirine label was introduced into the AHL molecule according to a literature method. To isolate the labelled receptor from the cellular protein moiety, the AHL was additionally labelled with tritium. During the development of an effective isotopic labelling method, a simple route to hydrogen isotope incorporation into the AHLs was proposed and explored in detail. According to the new protocol, the photoactivatable diazirine-AHL was labelled with deuterium and tritium by a postsynthetic catalytic exchange of the hydrogen with its isotopes, using deuterium or tritium labelled water along with catalytic amounts of metal salts under mild basic conditions. The N-(3-oxo-5-diazirinedodecanoyl-[2-3H2])-L-homoserine lactone was successfully synthesized in five steps. Due to a photoactivatable diazirine group and easily tracked radioactive label, the product could be applied in research on the mechanism of inter-kingdom signalling. Importantly, incorporation of the tritium label takes place in the last step of the synthesis. Copyright
- Jakubczyk, Dorota,Brenner-Weiss, Gerald,Braese, Stefan
-
p. 592 - 597
(2014/02/14)
-
- Synthesis of Tritium Labelled and Photoactivatable N-Acyl- L -homoserine Lactones: Inter-Kingdom Signalling Molecules
-
N-Acyl-L-homoserine lactones (AHLs) are signal molecules that are synthesized in nature by Gram-negative bacteria. They allow communication between bacteria (quorum sensing) and between microorganisms and their eukaryotic host cells (inter-kingdom signalling). However, very little is known about the mechanisms of the latter system. Therefore, tritium labelled photoactivatable AHLs were synthesized to identify specific receptors in immune cells (e.g., human polymorphonuclear neutrophils, PMN) that bind to AHL. A photoaffinity label - a diazirine group - was chosen as the smallest possible photoactivatable group that can be activated by light irradiation. The resulting highly active carbene will bind covalently to the closest chemical structure in the pocket of the receptor. The diazirine label was introduced into the AHL molecule according to a literature method. To isolate the labelled receptor from the cellular protein moiety, the AHL was additionally labelled with tritium. During the development of an effective isotopic labelling method, a simple route to hydrogen isotope incorporation into the AHLs was proposed and explored in detail. According to the new protocol, the photoactivatable diazirine-AHL was labelled with deuterium and tritium by a postsynthetic catalytic exchange of the hydrogen with its isotopes, using deuterium or tritium labelled water along with catalytic amounts of metal salts under mild basic conditions.
- Jakubczyk, Dorota,Brenner-Weiss, Gerald,Br?se, Stefan
-
p. 592 - 597
(2015/10/05)
-
- From in vitro to in cellulo: Structure-activity relationship of (2-nitrophenyl)methanol derivatives as inhibitors of PqsD in Pseudomonas aeruginosa
-
Recent studies have shown that compounds based on a (2-nitrophenyl)methanol scaffold are promising inhibitors of PqsD, a key enzyme of signal molecule biosynthesis in the cell-to-cell communication of Pseudomonas aeruginosa. The most promising molecule displayed anti-biofilm activity and a tight-binding mode of action. Herein, we report on the convenient synthesis and biochemical evaluation of a comprehensive series of (2-nitrophenyl)methanol derivatives. The in vitro potency of these inhibitors against recombinant PqsD as well as the effect of selected compounds on the production of the signal molecules HHQ and PQS in P. aeruginosa were examined. The gathered data allowed the establishment of a structure-activity relationship, which was used to design fluorescent inhibitors, and finally, led to the discovery of (2-nitrophenyl)methanol derivatives with improved in cellulo efficacy providing new perspectives towards the application of PqsD inhibitors as anti-infectives. This journal is the Partner Organisations 2014.
- Storz, Michael P.,Allegretta, Giuseppe,Kirsch, Benjamin,Empting, Martin,Hartmann, Rolf W.
-
supporting information
p. 6094 - 6104
(2014/08/05)
-
- Validation of PqsD as an anti-biofilm target in pseudomonas aeruginosa by development of small-molecule inhibitors
-
2-Heptyl-4-hydroxyquinoline (HHQ) and Pseudomonas quinolone signal (PQS) are involved in the regulation of virulence factor production and biofilm formation in Pseudomonas aeruginosa. PqsD is a key enzyme in the biosynthesis of these signal molecules. Using a ligand-based approach, we have identified the first class of PqsD inhibitors. Simplification and rigidization led to fragments with high ligand efficiencies. These small molecules repress HHQ and PQS production and biofilm formation in P. aeruginosa. This validates PqsD as a target for the development of anti-infectives.
- Storz, Michael P.,Maurer, Christine K.,Zimmer, Christina,Wagner, Nathalie,Brengel, Christian,De Jong, Johannes C.,Lucas, Simon,Muesken, Mathias,Haeussler, Susanne,Steinbach, Anke,Hartmann, Rolf W.
-
supporting information
p. 16143 - 16146
(2012/11/07)
-
- Syntheses and studies of amamistatin B analogs reveals that anticancer activity is relatively independent of stereochemistry, ester or amide linkage and select replacement of one of the metal chelating groups
-
A series of analogs of the amamistatin natural products was designed and synthesized to facilitate additional anticancer structure-activity relationships. The results indicate that the anticancer activity is relatively independent of stereochemistry, ester or amide linkage and replacement of the oxazoline/oxazole based iron-binding group with a catechol.
- Wu, Chunrui,Miller, Patricia A.,Miller, Marvin J.
-
scheme or table
p. 2611 - 2615
(2011/06/20)
-
- Natural product inhibitors of fatty acid biosynthesis: synthesis of the marine microbial metabolites pseudopyronines A and B and evaluation of their anti-infective activities
-
Total syntheses of the title natural products, pseudopyronines A (1) and B (2), have been achieved using methyl β-oxo carboxylic ester starting materials. The natural products and a small set of structurally related compounds were evaluated for growth inh
- Giddens, Anna C.,Nielsen, Lone,Boshoff, Helena I.,Tasdemir, Deniz,Perozzo, Remo,Kaiser, Marcel,Wang, Feng,Sacchettini, James C.,Copp, Brent R.
-
p. 1242 - 1249
(2008/09/18)
-
- Synthesis of Pseudomonas quorum-sensing autoinducer analogs and structural entities required for induction of apoptosis in macrophages
-
The synthesis of the analogs of N-3-oxododecanoyl-l-homoserine lactone (1) and their structure-activity relationship for the apoptotic induction in macrophages, P388D1 cells, are described. It was revealed that the position of the oxo group in the acyl si
- Horikawa, Manabu,Tateda, Kazuhiro,Tuzuki, Etsu,Ishii, Yoshikazu,Ueda, Chihiro,Takabatake, Tohru,Miyairi, Shinichi,Yamaguchi, Keizou,Ishiguro, Masaji
-
p. 2130 - 2133
(2007/10/03)
-
- Small molecule inhibitors of bacterial quorum sensing and biofilm formation
-
Bacteria monitor their local population densities using small molecules (or autoinducers) in a process known as quorum sensing. Here, we report a new and efficient synthetic route to naturally occurring bacterial autoinducers [N-acyl L-homoserine lactones (AHLs)] that is readily amenable to the synthesis of analogues. This route has been applied in the first synthesis of a library of non-native AHLs. Evaluation of these compounds in bacterial reporter gene and biofilm assays has revealed a potent set of quorum sensing antagonists. These ligands will serve as valuable new tools to explore the role of quorum sensing in bacterial pathogenesis. Copyright
- Geske, Grant D.,Wezeman, Rachel J.,Siegel, Adam P.,Blackwell, Helen E.
-
p. 12762 - 12763
(2007/10/03)
-
- A new approach to the synthesis of 3,6- and 5,6-dialkyl derivatives of 4-hydroxy-2-pyrone. Synthesis of rac-germicidin
-
A new approach to the synthesis of 3,6- and 5,6-dialkyl-4-hydroxy-2- pyrones has been developed. The method includes the formation of acylated Meldrum's acids (5-(2-alkyl-3-oxoacyl)-2,2-dimethyl-1,3-dioxane-4,6-diones) followed by their thermal transformation. Introduction of 3-alkyl substituents was accomplished by acylation of 4-hydroxy-2-pyrones and ionic hydrogenation of the 3-acyl derivatives obtained. The effectiveness of this new approach has been demonstrated in the synthesis of rac-germicidin, an autoregulative germination inhibitor of Streptomyces viridochromogenes NRRL B-1551.
- Lokot, Igor P.,Pashkovsky, Felix S.,Lakhvich, Fedor A.
-
p. 4783 - 4792
(2007/10/03)
-
- Synthesis of (-)-Syringolides 1 and 2
-
The enatioselective synthesis of (-)-syringolides 1 and 2 which were isolated as specific elicitors produced by Pseudomonas syringae pv. tomato was accomplished in 11 steps from diethyl D-tartrate.The specific rotations of synthetic samples were in good accord with those of the natural syringolides, and synthetic syringolide 2 showed almost the same biological activity as that of natural syringolide 2.
- Kuwahara, Shigefumi,Moriguchi, Masahiko,Miyagawa, Kazuhiro,Konno, Masako,Kodama, Osamu
-
p. 8809 - 8814
(2007/10/02)
-
- SYNTHESIS OF β-KETO ACIDS AND METHYL KETONES USING BIS(TRIMETHYLSILYL)MALONATE AND TRIETHYLAMINE IN THE PRESENCE OF LITHIUM OR MAGNESIUM HALIDES
-
Bis(trimethylsilyl) malonate is acylated in good yields with acid chlorides and acyl carbonates using triethylamine and magnesium or lithium salts to give β-keto acids or methyl ketones.Compared to other procedures, which use strong bases, this method is inexpensive, safe and convenient; especially for large scale reactions.
- Rathke, Michael W.,Nowak, Michael A.
-
p. 1039 - 1050
(2007/10/02)
-