15 research outputs found
Bergsons intuitives Erkennen
Grete HoffmannInnsbruck, Univ., phil. Diss., 1923(VLID)5735
Short and Protecting-Group-Free Approach to the (â)âÎ<sup>8</sup>âTHC-Motif: Synthesis of THC-Analogues, (â)-Machaeriol B and (â)-Machaeriol D
FriedelâCrafts
alkylation of resorcinols with (<i>S</i>)-<i>cis</i>-verbenol and subsequent cyclization allows
the construction of the tetrahydroÂdibenzopyran core of (â)-Î<sup>8</sup>-THC which is also found in other natural products in one
step. Using a benzofuryl substituted resorcinol, followed by diastereoselective
hydroboration and oxidative or reductive workup, directly provides
(â)-machaeriol B and D in 42% and 43% overall yields. Bromoresorcinol
as a coupling partner delivers BrâTHC that can be applied for
late-stage diversification by SuzukiâMiyaura cross-coupling
to readily access (â)-Î<sup>8</sup>-THC analogues
Investigation of phase II metabolism of 11-hydroxy-Î-9-tetrahydrocannabinol and metabolite verification by chemical synthesis of 11-hydroxy-Î-9-tetrahydrocannabinol-glucuronide
(-)-Î-9-tetrahydrocannabinol ((-)-Î-9-THC) is the main psychoactive constituent in cannabis. During phase I metabolism, it is metabolized to (-)-11-hydroxy-Î-9-tetrahydrocannabinol ((-)-11-OH-Î-9-THC), which is psychoactive, and to (-)-11-nor-9-carboxy-Î-9-tetrahydrocannabinol ((-)-Î-9-THC-COOH), which is psychoinactive. It is glucuronidated during phase II metabolism. The biotransformation of (-)-Î-9-tetrahydrocannabinol-glucuronide ((-)-Î-9-THC-Glc) and (-)-11-nor-9-carboxy-Î-9-tetrahydrocannabinol-glucuronide ((-)-Î-9-THC-COOH-Glc) is well understood, which is mainly due to the availability of commercial reference standards. Since such a standardized reference is not yet available for (-)-11-hydroxy-Î-9-tetrahydrocannabinol-glucuronide ((-)-11-OH-Î-9-THC-Glc), its biotransformation is harder to study and the nature of the glucuronide bonding-alcoholic and/or phenolic-remains unclear. Consequently, the aim of this study was to investigate the biotransformation of (-)-11-OH-Î-9-THC-Glc in vitro as well as in vivo and to identify the glucuronide by chemically synthesis of a reference standard. For in vitro analysis, pooled human S9 liver fraction was incubated with (-)-Î-9-THC. Resulting metabolites were detected by high-performance liquid chromatography system coupled to a high-resolution mass spectrometer (HPLC-HRMS) with heated electrospray ionization (HESI) in positive and negative full scan mode. Five different chromatographic peaks of OH-Î-9-THC-Glc have been detected in HESI positive and negative mode, respectively. The experiment set up according to Wen et al. indicates the two main metabolites being an alcoholic and a phenolic glucuronide metabolite. In vivo analysis of urine (nâ=â10) and serum (nâ=â10) samples from cannabis users confirmed these two main metabolites. Thus, OH-Î-9-THC is glucuronidated at either the phenolic or the alcoholic hydroxy group. A double glucuronidation was not observed. The alcoholic (-)-11-OH-Î-9-THC-Glc was successfully chemically synthesized and identified the main alcoholic glucuronide in vitro and in vivo. (-)-11-OH-Î-9-THC-Glc is the first reference standard for direct identification and quantification. This enables future research to answer the question whether phenolic or alcoholic glucuronidation forms the predominant way of metabolism