title: Unusual reactivity of β-hydroxy-serotonin, a forgotten serotonin derivative.
abstract: Serotonin (5-HT) is a well-known biogenic amine which regulates mood, sleep, and is involved in muscle contraction and blood coagulation. Based on an analogy to norepinephrine, a β-hydroxylated derivative of dopamine which has diverse physiological functions, beta-hydroxy-serotonin (β-OH-5-HT) originally encouraged interest as a potential pharmacological agent. Four decades ago, its organic synthesis was attempted. However, due to difficulties with the synthesis and the compound's instability, rigorous identification and characterization of β-OH-5-HT proved evasive. Here, we successfully synthesized β-OH-5-HT from 5-HT using a Pseudomonas enzyme, tryptophan side chain oxidase type I (TSOI), and we determined the structure by 2D-NMR and characterized β-OH-5-HT in detail. The CD spectra showed no optical activity, suggesting a racemic mixture. To separate DL-β-OH-5-HT, we synthesized L-Ala-5-HT and derivatized it into erythro- and threo-L-Ala-β-OH-5-HT with TSOI. Interestingly, both isolated fractions returned to a diastereoisomeric mixture within two hours at pH 5.0. Later, we found that, under acidic conditions, β-OH-5-HT readily reacted with nucleophiles like alcohols or thiols, yielding a variety of DL-β-substituted-5-HT. The unusual properties of β-OH-5-HT might be attributed to the unique nature of a β-hydroxyl group adjacent to an indole ring and amino group. The mechanism for the rapid racemization of β-OH-5-HT is discussed.
authors.affiliation: Department of Biomedical Chemistry, Institute of International Health, The University of Tokyo, Graduate School of Medicine, Tokyo, 113-0033, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kawashima
authors.forename: Jeremy
authors.initials: J
authors.lastname: Salinger
authors.forename: Koichi
authors.initials: K
authors.lastname: Hida
authors.forename: Katsuji
authors.initials: K
authors.lastname: Takai
authors.forename: Eiko
authors.initials: E
authors.lastname: Nakamaru-Ogiso
mesh_terms: D006900:Hydroxylation; D007536:Isomerism; D015394:Molecular Structure; D012701:Serotonin / Q000031:analogs & derivatives* / Q000138:chemical synthesis
chemical_list: D012701:Serotonin