Gastroprotective effects of new diterpenoid derivatives from Azorella cuatrecasasii Mathias & Constance obtained using a β-cyclodextrin complex with microbial and chemical transformations

• Published in: Bioorganic & medicinal chemistry letters 2016-07, Vol.26 (14), p.3220-3222
• Main Authors: Sepúlveda, Beatriz, Quispe, Cristina, Simirgiotis, Mario, García-Beltrán, Olimpo, Areche, Carlos
• Format: Article
• Language: English
• Subjects: Alcohols; Animals; Anti-Ulcer Agents - chemistry; Anti-Ulcer Agents - isolation & purification; Anti-Ulcer Agents - pharmacology; Apiaceae - chemistry; Azorella cuatrecasasii; beta-Cyclodextrins - chemistry; beta-Cyclodextrins - pharmacology; Biotransformation; Disease Models, Animal; Diterpenes - chemistry; Diterpenes - isolation & purification; Diterpenes - pharmacology; Dose-Response Relationship, Drug; Gastric Mucosa - drug effects; Gastric Mucosa - pathology; Gastric ulcer; Hydrochloric Acid; Mice; Microbial transformation; Molecular Conformation; Mucor plumbeus; Mulinane; Stomach Ulcer - chemically induced; Stomach Ulcer - drug therapy; Stomach Ulcer - pathology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.05.081

[Display omitted] Mulinane diterpenoids isolated from Azorella species have displayed gastroprotective effects in animal models. In this study we have transformed the main constituent, mulin-11,13-dien-20 oic acid from this plant using the filamentous fungus Mucor plumbeus and a β-cyclodextrin inclusion complex and we have obtained two main products with good yields (33% and 15% for compound 4 and 5, respectively) for further preparation of semisynthetic derivatives to evaluate their gastroprotective effects. In addition, one of the compounds isolated from Azorella cuatrecasasii was new (9-epi-13α-hydroxymulinene 1). Six new derivatives 4a–4c and 5a–5c were then prepared by simple chemical transformations. The structures of all compounds were elucidated by spectroscopic means based on 1D and 2D-NMR techniques. Some 8 diterpenes were evaluated for their gastroprotective effects in the ethanol/HCl-induced ulcer model in mice at 20mg/kg. The highest gastroprotective activity was shown by 7α,16-dihydroxymulin-11,13-dien-20-oic acid 5, which was higher than the reference drug lansoprazole, while 16-hydroxymulin-11,13-dien-20-oic acid 4 was as active as lansoprazole.