title: Structure elucidation of phase I metabolites of the microtubule perturbagens: ceratamines A and B.
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.
authors: Department of Chemistry, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors: Sara E
authors: SE
authors: Smith
authors: Matthew C
authors: MC
authors: Dello Buono
authors: Daniel J
authors: DJ
authors: Carper
authors: Robert S
authors: RS
authors: Coleman
authors: Billy W
authors: BW
authors: Day
mesh_terms: D000470:Alkaloids / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001381:Azepines / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects; D006842:Hydrocarbons, Brominated / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008386:Marine Biology; D008862:Microsomes, Liver / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D011161:Porifera / Q000737:chemistry*; D051381:Rats
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D001381:Azepines; D006842:Hydrocarbons, Brominated; D007093:Imidazoles; C485389:ceratamine A; C485390:ceratamine B