Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Total synthesis and biological evaluation of phidianidines A and B uncovers unique pharmacological profiles at CNS targets.

ABSTRACT: The synthesis of phidianidines A and B, the first 1,2,4-oxadiazole-containing alkaloid, from the marine opisthobranch mollusk Phidiana militaris is reported. The synthesis proceeds in six steps from known indole acetic acids in 39.9% (phidianidine A) and 21% (phidianidine B) overall yields from commercially available materials. Biological characterization found that phidianidines A and B are selective inhibitors of DAT (versus SERT and NET) and a selective, potent ligand and partial agonist of the ? opioid receptor (versus ?- and ?-opioid receptors). Moreover, neither phidianidines A and B are cytotoxic, and thus represent an attractive starting point for chemical optimization; therefore, we piloted a number of chemistries and prepared a diverse series of unnatural analogs.

SUBMITTER: Brogan JT

PROVIDER: S-EPMC3447392 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Total synthesis and biological evaluation of phidianidines A and B uncovers unique pharmacological profiles at CNS targets.

Brogan John T JT Stoops Sydney L SL Lindsley Craig W CW

ACS chemical neuroscience 20120627 9

The synthesis of phidianidines A and B, the first 1,2,4-oxadiazole-containing alkaloid, from the marine opisthobranch mollusk Phidiana militaris is reported. The synthesis proceeds in six steps from known indole acetic acids in 39.9% (phidianidine A) and 21% (phidianidine B) overall yields from commercially available materials. Biological characterization found that phidianidines A and B are selective inhibitors of DAT (versus SERT and NET) and a selective, potent ligand and partial agonist of t ...[more]

PMID: 23019492

Similar Datasets

Total Synthesis (+)-7-Bromotrypargine and Unnatural Analogs: Biological Evaluation Uncovers Activity at CNS Targets of Therapeutic Relevance.

Project description:The first total synthesis of (+)-7-bromotrypargine, a β-carboline alkaloid from Ancornia sp. is reported. The synthesis proceeds in 9 steps, 8 steps longest linear sequence, in 36.9% overall yield. Biological characterization found that (+)-7-bromotrypargine is an H(3) antagonist, and a selective inhibitor of DAT and NET, without inhibiting SERT. Moreover, unlike electron rich congeners, (+)-7-bromotrypargine is not cytotoxic, and thus represents an attractive starting point for chemical optimization; therefore, we piloted a number of chemistries for the synthesis of unnatural analogs.

| S-EPMC3254090 | biostudies-literature

Total synthesis and biological evaluation of tyroscherin.

Project description:The efficient synthesis and biological evaluation of both the reported and revised structures of tyroscherin have been achieved. Central to our synthesis is a cross metathesis reaction that generated the trans-olefin regioselectively. This synthetic strategy enabled the facile manipulation of tyroscherin stereochemistry, facilitating the generation of all 16 tyroscherin diastereomers and a photoactivatable tyroscherin-based affinity probe for future mode of action studies.

| S-EPMC3175621 | biostudies-literature

Total synthesis, biosynthesis and biological profiles of clavine alkaloids.

Project description:This review highlights noteworthy synthetic and biological aspects of the clavine subfamily of ergot alkaloids. Recent biosynthetic insights have laid the groundwork for a better understanding of the diverse biological pathways leading to these indole derivatives. Ergot alkaloids were among the first fungal-derived natural products identified, inspiring pharmaceutical applications in CNS disorders, migraine, infective diseases, and cancer. Pergolide, for example, is a semi-synthetic clavine alkaloid that has been used to treat Parkinson's disease. Synthetic activities have been particularly valuable to facilitate access to rare members of the Clavine family and empower medicinal chemistry research. Improved molecular target identification tools and a better understanding of signaling pathways can now be deployed to further extend the biological and medical utility of Clavine alkaloids.

| S-EPMC4917493 | biostudies-literature

Total synthesis and biological evaluation of transvalencin Z.

Project description:The emerging global epidemic of drug-resistant tuberculosis has created an urgent need to identify novel therapeutic approaches for disease treatment. Transvalencin Z (1) is a natural product from Nocardia transvalensis with relatively potent and selective antimycobacterial activity against Mycobacterium smegmatis, making it an attractive target for structure-activity and mechanism of action studies. The total synthesis of the four possible diastereomers of transvalencin Z was completed (1a-d), and the absolute configurations were defined using chemical synthesis, HPLC retention times, and optical rotation measurements. Surprisingly, none of the transvalencin Z diastereomers exhibited any inhibitory activity against a panel of microbial pathogens, including several species of mycobacteria.

| S-EPMC3381897 | biostudies-literature

Total synthesis and biological evaluation of fluorinated cryptophycins.

Project description:Cryptophycins are cytotoxic natural products that exhibit considerable activities even against multi-drug-resistant tumor cell lines. As fluorinated pharmaceuticals have become more and more important during the past decades, fluorine-functionalized cryptophycins were synthesized and evaluated in cell-based cytotoxicity assays. The unit A trifluoromethyl-modified cryptophycin proved to be highly active against KB-3-1 cells and exhibited an IC(50) value in the low picomolar range. However, the replacement of the 3-chloro-4-methoxyphenyl-substituent in unit B by a pentafluorophenyl moiety resulted in a significant loss of activity.

| S-EPMC3511040 | biostudies-literature

Total synthesis and biological evaluation of 22-hydroxyacuminatine.

Project description:A total synthesis of 22-hydroxyacuminatine, a cytotoxic alkaloid isolated from Camptotheca acuminata, is reported. The key step in the synthesis involves the reaction of 2,3-dihydro-1H-pyrrolo[3,4-b]quinoline with a brominated phthalide to generate a substituted pentacyclic 12H-5,11a-diazadibenzo[b,h]fluoren-11-one intermediate. Despite its structural resemblance to camptothecin and luotonin A, a biological evaluation of 22-hydroxyacuminatine in a topoisomerase I-deficient cell line P388/CPT45 has confirmed that the observed cytotoxicity is not due to topoisomerase I inhibition, even though 22-hydroxyacuminatine has a hydroxyl group that can theoretically hydrogen bond to Asp533. This result is consistent with the hypothesis that pi-pi stacking is more important than hydrogen-bonding interactions in determining topoisomerase I inhibitor binding in the ternary cleavage complex.

| S-EPMC2532531 | biostudies-literature

Total Synthesis and Biological Evaluation of Clavatadines C–E

Project description:We described herein

| S-EPMC9260760 | biostudies-literature

Amphidinolide B: total synthesis, structural investigation, and biological evaluation.

Project description:The total syntheses of amphidinolide B1 and the proposed structure of amphidinolide B2 have been accomplished. Key aspects of this work include the development of a practical, non-transition-metal-mediated method for the construction of the C13-C15 diene, the identification of α-chelation and dipole minimization models for diastereoselective methyl ketone aldol reactions, the discovery of a spontaneous Horner-Wadsworth-Emmons macrocyclization strategy, and the development of a novel late stage method for construction of an allylic epoxide moiety. The originally proposed structure for amphidinolide B2 and diastereomers thereof display potent antitumor activities with IC50 values ranging from 3.3 to 94.5 nM against human solid and blood tumor cells. Of the different stereoisomers, the proposed structure of amphidinolide B2 is over 12-fold more potent than the C8,9-epimer and C18-epimer in human DU145 prostate cancer cells. These data suggest that the epoxide stereochemistry is a significant factor for anticancer activity.

| S-EPMC3631602 | biostudies-literature

Total Synthesis and Biological Evaluation of Modified Ilamycin Derivatives.

Project description:Ilamycins/rufomycins are marine cycloheptapeptides containing unusual amino acids. Produced by Streptomyces sp., these compounds show potent activity against a range of mycobacteria, including multidrug-resistant strains of Mycobacterium tuberculosis. The cyclic peptides target the AAA+ protein ClpC1 that, together with the peptidases ClpP1/ClpP2, forms an essential ATP-driven protease. Derivatives of the ilamycins with a simplified tryptophane unit are synthesized in a straightforward manner. The ilamycin derivative 26 with a cyclic hemiaminal structure is active in the nM-range against several mycobacterial strains and shows no significant cytotoxicity. In contrast, derivative 27, with a glutamic acid at this position, is significantly less active, with MICs in the mid µM-range. Detailed investigations of the mode of action of 26 indicate that 26 deregulates ClpC1 activity and strongly enhances ClpC1-WT ATPase activity. The consequences of 26 on ClpC1 proteolytic activities were substrate-specific, suggesting dual effects of 26 on ClpC1-WT function. The positive effect relates to ClpC1-WT ATPase activation, and the negative to competition with substrates for binding to the ClpC1 NTD.

| S-EPMC9605216 | biostudies-literature

Total synthesis, biological evaluation and biosynthetic re-evaluation of Illicium-derived neolignans.

Project description:We report the first total syntheses of simonsol F (3), simonsinol (5), fargenin (4), and macranthol (6) in addition to syntheses of simonsol C (2), simonsol G (1), and honokiol (14). The syntheses are based upon a phosphonium ylide-mediated cascade reaction and upon natural product isomerization reactions which proceed through Cope rearrangements of putative biosynthetic dienone intermediates. As a corollary of the natural product isomerization reactions, we propose an alternative biosynthesis of honokiol (14), simonsinol (5), and macranthol (6) which unites the natural products in this family under a single common precursor, chavicol (7). Finally, we demonstrate that simonsol C (2) and simonsol F (3) promote axonal growth in primary mouse cortical neurons.

| S-EPMC11290413 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data