Benzofuranquinones as inhibitors of indoleamine 2,3-dioxygenase (IDO). Synthesis and biological evaluation

Abstract

A series of benzofuranquinones, analogues of the marine metabolite annulin A, has been synthesized and evaluated as inhibitors of human indoleamine 2,3-dioxygenase (IDO). The synthesis was carried out by copper(II)-mediated reaction of bromobenzoquinones with 1,3-dicarbonyl compounds followed by functional group interconversions. The most potent compounds were 5-methoxy-2-methylbenzofuranquinones containing a CH2OR group at position-3 with IC50 ~ 0.2 mM. The corresponding hydroquinones were inactive. Compounds based on the benzimidazolequinone framework are also active IDO inhibitors. The quinones do not generate significant levels of oxidative stress at concentrations that inhibit IDO.

Inhibition Mechanisms of Indoleamine 2,3-Dioxygenase 1 (IDO1)

“…There are numerous reports of quinones and amino-quinones as IDO1 inhibitors (e.g., refs ,,− and references therein). They usually show low micromolar to nanomolar potency in the enzymatic assay but less potency in cellular assays.…”

Inflammation in cancer and depression: a starring role for the kynurenine pathway

“…The 1-methyltryptophan, a competitive inhibitor of IDO1 (and IDO2) that exists as a mixture of chiral isoforms (i.e., 1-methyl-D-tryptophan (1-MDT) also known as indoximod and NLG8189), as well as second-generation IDO1 inhibitors (such as the orally available agent epacadostat (INCB024360) and NLG919), and IDO1-targeting vaccines, were studied clinically and preclinically in cancer patients. So far, other IDO1 inhibitors, including 1-methyl-L-tryptophan, methylthiohydantoin tryptophan, brassinin and derivatives, annulin B and derivatives, and exiguamine A and derivatives, as well as INCB023843, are in development (Vacchelli et al 2014); other drugs include benzofuranquinones and annulin A analogues (Carvalho et al 2014), just to name a few. 1-MDT is probably the most well studied and it is involved in some encouraging clinical trials (Godin-Ethier et al 2011).…”

Synthesis and Intracellular Redox Cycling of Natural Quinones and Their Analogues and Identification of Indoleamine‐2,3‐dioxygenase (IDO) as Potential Target for Anticancer Activity

“…[29] IDO catalyzes the first step in tryptophan catabolism, the oxidative cleavage of the indole 2,3 bond to give N-formylkynurenine,a nd is thought to play am ajor role in suppressing the immune response. [30][31][32][33][34][35][36] Inhibitors of IDO have potential as anticancer medicines, [29] and the first compounds in this class are now entering the clinic. [37,38] Therefore,itseemed logical to screen aulosirazole and its analogues as inhibitors of IDO.W ewere also mindful of the biological activity ascribed to pronqodine A, [12] in which the quinone reductase NAD(P)H quinone oxidoreductase 1( NQO1), formerly known as DT-diaphor- .…”