Synthesis and Structure Activity Relationships of Novel Dehydroepiandrosterone Derivatives as Potent Neuroprotective Agents and Nitric Oxide Production Inhibitors

Abstract

In this study, a series of dehydroepiandrosterone (DHEA) derivatives were synthesized by linking DHEA with active fragments such as carbamate, phthalimide and indoleacetic acid. In addition, the in vitro neuroprotective effects, via the oxidative stress mechanism, and nitric oxide (NO) production inhibitory activities of each compound were tested. The preliminary structure‐activity relationships of them indicated that DHEA with carbamate structure had a certain neuroprotective and anti‐inflammatory effect such as 3β‐(Cyclohexylamine‐1‐carboxylate)‐5‐androsten‐17‐one (A2) and 3β‐(3‐Chlorobenzylamine‐1‐carboxylate)‐5‐androsten‐17‐one (A6). And the ester derivatives with indoleacetic acid like 17β–(Heteroauxin‐1‐carboxylate)‐androst‐4‐en‐3‐one (A12) also exhibited both significant neuroprotective activity and NO inhibitory activity. According to these results, compound A6 is considered as a potential agent for the treatment of Alzheimer′s disease (AD) and deserve for further investigations.

Synthesis and Pharmacological Properties of Modified A- and D-Ring in Dehydroepiandrosterone (DHEA): A Review

“…Gan and group reported the synthesis of a series of DHEA derivatives synthesized by linking DHEA with active fragments such as carbamate, phthalimide, and indoleacetic acid (Scheme ) in 2019 . For the synthesis of DHEA-carbamate, DHEA and TEA were dissolved in dry DCM with p -nitrophenyl chloroformate at 0 °C to room temperature to give intermediate 156 , which is further treated with the corresponding amine and TEA in DCM to form the desired product 157a – f .…”

“…Gan and group reported the synthesis of a series of DHEA derivatives synthesized by linking DHEA with active fragments such as carbamate, phthalimide, and indoleacetic acid ( Scheme 23 ) in 2019. 31 For the synthesis of DHEA-carbamate, DHEA and TEA were dissolved in dry DCM with p -nitrophenyl chloroformate at 0 °C to room temperature to give intermediate 156 , which is further treated with the corresponding amine and TEA in DCM to form the desired product 157a – f . Subsequent, for the synthesis of DHEA-phthalimide, acetylation of DHEA using chloroacetyl chloride or 3-chloropropionyl chloride to give intermediate compounds 158 and 159 , which are further treated with phthalimide to afford the final products 160 and 161 , respectively.…”