Indoleamine 2,3-Dioxygenase Inhibitory Activity of Derivatives of Marine Alkaloid Tsitsikammamine A

Tsitsikammamines belonging to the pyrroloiminoquinone class of marine alkaloids were first isolated and characterized in 1996 from a Latrunculiidae sponge collected in the Tsitsikamma Marine Reserve of South Africa.[1] These and related compounds have attracted attention due to various interesting biological properties, including cytotoxicity, topoisomerase inhibition, antimicrobial and antifungal activity.[2] Recently, two novel regioisomeric series of tsitsikammamine A analogues were described.[3] The products were evaluated in an in vitro antiproliferative test against several cancer and normal (fibroblast) cell lines. This work allowed identifying a cytotoxic synthetic intermediate 1 with an unknown mechanism of action. Indoleamine 2,3-dioxygenase (IDO) was identified as an important factor in the tumor immune evasion mechanism. It was demonstrated that many human tumors express IDO in a constitutive manner.[4] Our groups recently published several articles on the development of new series of IDO inhibitors.[5] Here, we would like to report for the first time on an inhibitory activity of tsitsikammamine derivatives against IDO. Tsitsikammamine A analogue 2 displays submicromolar potency in an enzymatic test. A number of derivatives are also moderately active in a cellular test, establishing interest in this class of compounds as a potential source of leads for the development of new pharmaceutically useful IDO inhibitors.