Antiproliferative Activity and Effect on GABA_A Receptors of the Abietane Diterpenoid Jiadifenoic Acid C and Other Callitrisic Acid (4-Epidehydroabietic Acid) Derivatives

At present, about fifty percent of commercial pharmaceutical drugs are derived from natural sources. The abietane-type and related diterpenoids are a class of naturally occurring terpenoids in the plant kingdom, which have demonstrated a wide range of biological activities against cancer, and a variety of infectious diseases (viral and bacterial). Several research groups have explored the potential as chemotherapeutic agents of abietanes by means of semisynthetic derivatives from abietic acid-derived materials such as dehydroabietic acid (DHA), and dehydroabietylamine, also called leelamine. For example, DHA displays not only antiulcer and antimicrobial properties, but also antitumor effects. Recently, DHA was reported as a positive GABAA receptor modulator (potentiation of I_GABA 682.3% at 100 mM).

 DHA displays an equatorial carboxylic group located at C18 while in other natural congeners the carboxylic group adopts the axial configuration (C19) as in 4-epidehydroabietic acid or callitrisic acid. Recently, a series of related acids having a C19 carboxylic group have been isolated. For example, the jiadifenoic acids A-I. These have shown antiviral properties against Coxsackie virus. We have developed the synthesis of jiadifenoic acid C from callitrisic acid isolated from Sandarac resin. The ready availability of these acids from our work and the absence of their biological and pharmacological studies as well as chemical manipulation prompted us to carry out this research. In this study, we carried out the synthesis of several derivatives of callitrisic acid, including jiadifenoic acid C, methyl callitrisate and callitrisinol together with evaluation of their antiproliferative and modulating GABAA receptor activities. Thus, we were able to compare with the DHA series.

 Biological results showed that the studied callitrisic derivatives (functionalization at C19) were less potent GABAA-modulating molecules (potentiation of I_GABA 269-311% at 100 mM) than DHA (carboxyl at C18), of which jiadifenoic acid C having an allylic alcohol instead of an isopropyl moiety was practically inactive. On the other hand, functional group manipulation at C19 led to more potent antiproliferative derivatives (GI₅₀= 3.4-61 mM) than their corresponding C18-functionalized congeners.