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

Abstract

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 beta-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-13 alpha-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 20 mg/kg. The highest gastroprotective activity was shown by 7 alpha,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.