Synthesis and anti-cancer activities of the stereoisomers of cordyceamide A in a skin carcinoma cell line

Cordyceps (Ophiocordyceps sinensis) is a fungus reported with broad biological activities including cancer growth inhibition. Its extract contains several natural products such as cordycepin, cordyceamide A, and cordycepic acid. As a result, the identification and understanding of cellular mechanisms of inhibition are essential to further develop cordyceps as anti-cancer agents. This study aims to synthesize diastereomers of cordyceamide A and examine their anticancer activities, including proliferation, apoptosis, and migration on A431 skin cancer cells, and anti-inflammatory activity on macrophage cells. Firstly, two diastereomers of cordyceamide A (DD and LD) were synthesized via an amide coupling reaction between N-benzoyltyrosine and O-acetyl-phenylalaninol in the presence of dicyclohexyl carbodiimide (DCC) and a catalytic amount of hydroxybenzotriazole (HOBt) in 70-75% yields. The mixture of DD and LD isomers showed a suppression of A431 growth with IC50 values of 16.12 μM at 72 h. Furthermore, the diastereomers of cordyceamide A promoted DNA fragmentation, indicating apoptotic-mediated cell death. Additionally, the migration of A431 cells was drastically suppressed in the presence of the diastereomer mixture of cordyceamide A. Also, the role of the DD and LD mixture in inhibiting inflammation, considered as a cause of cancers, was investigated by determining nitric oxide production. The results revealed a promising but non-substantial reduction in the nitric oxide production in macrophage cells. Collectively, the chemically synthesized diastereoisomers of cordyceamide A possess anti-cancer activity over a skin cancer cell line and can potentially be developed for skin cancer treatment.