ABSTRACT
The heterocyclic alkaloids, ceratamines A and B, are isolates from a marine Pseudoceratina sp. sponge. They behave as antimitotic agents, with IC50 values in the low micromolar range. The mechanism of this activity involves the disruption of microtubule dynamics; therefore, the ceratamines are of great interest in cancer drug discovery. Studies of in vitro metabolism were performed using rat liver microsomes to begin to understand the pharmacokinetics of these unique natural products. A total of eight metabolites were identified using UV and LC-MS/MS techniques. The majority of metabolites were formed as a result of various demethylation reactions. The formation of two metabolites, M1 and M3, involved monooxygenation, most likely on the aromatic ring, however the exact structure has not been determined. UV absorbance revealed a hypsochromic shift as a result of monooxygenation, an observation that may suggest the loss of aromaticity; however, further investigation is required. The structures of two major metabolites of ceratamine B, M4 and M6, were confirmed by (1)H NMR spectroscopy. These metabolites formed as a result of demethylation at the methoxy and aminoimidazole, respectively.
Subject(s)
Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Azepines/isolation & purification , Azepines/pharmacology , Hydrocarbons, Brominated/isolation & purification , Hydrocarbons, Brominated/pharmacology , Imidazoles/isolation & purification , Imidazoles/pharmacology , Porifera/chemistry , Alkaloids/biosynthesis , Alkaloids/chemistry , Alkaloids/isolation & purification , Alzheimer Disease/drug therapy , Animals , Antineoplastic Agents/chemistry , Azepines/chemistry , Brain/drug effects , Hydrocarbons, Brominated/chemistry , Imidazoles/chemistry , Inhibitory Concentration 50 , Marine Biology , Microsomes, Liver/drug effects , Microtubules/drug effects , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , RatsABSTRACT
Neuronal nicotinic receptors have been implicated in several diseases and disorders such as autism, Alzheimer's disease, Parkinson's disease, epilepsy, and various forms of addiction. To understand the role of nicotinic receptors in these conditions, it would be beneficial to have selective molecules that target specific nicotinic receptors in vitro and in vivo. Our laboratory has previously identified novel negative allosteric modulators of human α4ß2 (Hα4ß2) and human α3ß4 (Hα3ß4) nicotinic receptors. The effects of novel sulfonylpiperazine analogues that act as negative allosteric modulators on both Hα4ß2 nAChRs and Hα3ß4 nAChRs were investigated. This work, through structure-activity relationship (SAR) studies, describes the chemical features of these molecules that are important for both potency and selectivity on Hα4ß2 nAChRs.
Subject(s)
Neurons/metabolism , Piperazines/chemical synthesis , Receptors, Nicotinic/metabolism , Sulfones/chemical synthesis , Allosteric Regulation , Calcium/metabolism , Cell Line , Humans , Piperazines/chemistry , Piperazines/pharmacology , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
The total synthesis of the tubulin-binding agents ceratamine A and B is reported, along with des-methyl analogs, via a synthetic route that is high-yielding and operationally efficient. The synthetic route involved a Beckmann rearrangement to form an azepine ring precursor, a Knoevenagel condensation to install the benzylic side chain, and an effective imidazole annulation onto an alpha-aminoketone precursor with a protected S-methylisothiourea. Final dehydrogenation proved remarkably facile using IBX.
Subject(s)
Azepines/chemical synthesis , Imidazoles/chemical synthesis , Iodobenzenes/chemistry , Tubulin Modulators/chemical synthesis , Animals , Azepines/chemistry , Azepines/pharmacology , Drug Design , Imidazoles/chemistry , Imidazoles/pharmacology , Molecular Structure , Porifera/chemistry , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
The design and synthesis of a detailed series of functional "top-half" substructures of azinomycin A and B is described.