ABSTRACT
DFT calculations probing potential (4 + 2) and (4 + 3) cycloaddition pathways leading to the polycyclic ring systems found in the coral secondary metabolites plumarellide, mandapamate and rameswaralide are described. Formation of plumarellide and mandapamate via stepwise intramolecular cycloaddition of a furanoxonium ion onto a 1,3-diene is shown to be viable. The calculations also predict the outcome of related cyclisations involving model systems.
Subject(s)
Anthozoa/chemistry , Furans/chemistry , Heterocyclic Compounds, 4 or More Rings/isolation & purification , Onium Compounds/chemistry , Polycyclic Compounds/isolation & purification , Quantum Theory , Animals , Anthozoa/metabolism , Cycloaddition Reaction , Furans/metabolism , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/metabolism , Ions/chemistry , Ions/metabolism , Molecular Conformation , Onium Compounds/metabolism , Polycyclic Compounds/chemistry , Polycyclic Compounds/metabolismABSTRACT
Several marine macrolide toxins act as potent and specific actin-severing molecules. Recent elucidation of their stereochemistries and modes of interaction with actin has allowed the syntheses of bioactive analogues. Here we used synthetic analogues in a structure-function analysis of ulapualide A, a trisoxazole-based macrolide. Ulapualide A harboured potent actin-depolymerising activity both in cells and in vitro. Its synthetic diastereoisomer was three orders of magnitude less active than the natural toxin and synthetic macrolide fragments lacked actin-capping/ severing activity altogether. Modulation of serum response factor (SRF)-dependent gene expression, as described for other actin-binding toxins, was also examined. Specific changes in response to ulapualide A were not observed, primarily due to its profound effects on cytoskeletal integrity and cell adhesion. Several synthetic fragments of ulapualide A also had no effect on SRF-dependent gene expression. However, inhibition was observed with a molecule corresponding to the extended aliphatic side chain of halichondramide, a structurally related macrolide. These findings indicate that side-chain derivatives of trisoxazole-based macrolides may serve to uncouple gene-regulatory events from actin dynamics.
Subject(s)
Actins/metabolism , Gene Expression Regulation/drug effects , Macrolides/pharmacology , Oxazoles/pharmacology , Actins/genetics , Animals , Cell Adhesion/drug effects , Cytoskeleton/drug effects , HeLa Cells , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Mice , Models, Molecular , NIH 3T3 Cells , Oxazoles/chemistry , Protein Binding/drug effects , Structure-Activity RelationshipABSTRACT
Ab initio calculations at the RHF/6-31G* and MP2/6-31G*//RHF/6-31G* levels of theory are performed for 2-methyl-4-carboxamido-oxazoles and -thiazoles, including rotational profiles for the ring-carboxamide bond, which showed the expected conjugation and hydrogen bonding effects. On the basis of these data, newly optimised stretch, bend and torsional parameters for the AMBER* force field are derived, along with CHELPG-fitted partial atomic charges.
Subject(s)
Oxazoles/chemistry , Peptides, Cyclic/chemistry , Thiazoles/chemistry , Models, Molecular , Protein Conformation , Software , ThermodynamicsABSTRACT
A molecular mechanics study of the marine metabolite ulapualide A, which is suggested to have ionophoric properties, has been carried out on various metal chelated complexes in order to predict the stereochemistry of the natural product. The results suggest a stereochemistry for ulapualide A which is closely similar to structurally related marine metabolites, whose stereochemistries have been established by X-ray crystallography and by partial synthesis.
Subject(s)
Ionophores/chemistry , Mollusca/chemistry , Oxazoles/chemistry , Animals , Computer Simulation , Models, Molecular , Molecular Conformation , Molecular Structure , Stereoisomerism , ThermodynamicsABSTRACT
Tissue cultures ofChrysanthemum cinerariaefolium were established, and then used to study the production of pyrethrin insecticides, and their precursor chrysanthemic acid. Callus cultures and root-differentiated cultures did not contain pyrethrins whereas shoot differentiated callus was found to produce the pyrethrins. Chrysanthemic acid was isolated by extraction from callus cultures, and feeding(14)C-labelled chrysanthemic acid to a cell suspension ofC. cinerariaefolium established that the acid accumulates largely as a glucoside ester.
