Synthesis of calenduladiol derivatives of biological interest

Over the last decades triterpenoids have drawn attention because of their anti-inflammatory, anti-oedematous, antitumor, and anti-HIV activities. Abundant in many plants, these metabolites are valuable natural raw materials to perform chemicals modifications and obtain semisynthetic analogs for structure-activity relationship studies. Asteraceae family constitutes a rich source of several pentacyclic mono-alcohols, diols and triols terpenes such as calenduladiol, faradiol, heliantriol B2, taraxasterol, arnidiol, lupeol, etc. Acetylcholine serves as a neurotransmitter in the central and peripheral nervous system. Acetylcholinesterase (AChE) stops the function of acetylcholine by its hydrolytic destruction in the cholinergic synapses. Enhancement of acetylcholine level in the brain inhibiting AChE is considered one of the most promising approaches for treating Alzheimer\'s disease. In the course of our ongoing search of natural AChE inhibitors, we isolated calenduladiol (1), in good yields, from ethanolic extract of Chuquiraga erinacea D. don. subsp. erinacea (Asteraceae), collected in southwest of Buenos Aires province, Argentina. This triterpene elicited moderate AChE inhibition which encouraged us to synthesize five calenduladiol derivatives: 30-oxo-calenduladiol (2), 30-hydroxy-calenduladiol (3), calenduladiol diacetate (4), 30-oxo-calenduladiol diacetate (5) and 30-hydroxy-calenduladiol triacetate (6). Compounds 2 and 3 were obtained by oxidation with SeO₂ and, 4, 5 and 6 by esterification with Ac₂O and pyridine from compounds 1, 2 and 3 respectively. Compounds 2-6 which were obtained in good yields and characterized by ¹H and ¹³C NMR spectroscopy. The oxidized analogs, 2 and 3 resulted to be the most active ones with a 43 % and 40 % of AChE inhibition at 0.2 mM, respectively, in the Ellman\'s assay. Acetylated derivatives (4-6) elicited a weak activity compared with 1, at the same concentration. Our results indicate that calenduladiol analogues oxidized at C-30 could be a promising strategy for the enhancement of pharmacological properties of this type of triterpene alcohols.