Indoleamine 2,3-Dioxygenase Inhibitors from the Northeastern Pacific Marine Hydroid Garveia annulata

Abstract

Crude extracts of the marine hydroid Garveia annulata show potent inhibition of indoleamine 2,3-dioxygenase (IDO). Fractionation of the extract led to the identification of the new polyketides annulin C (1), 2-hydroxygarveatin E (4), garveatin E (5), and garvin C (9). Annulins A (2), B (3), and C (1) were found to be submicromolar inhibitors of IDO.

Natural Product-Inspired Pyranonaphthoquinone Inhibitors of Indoleamine 2,3-Dioxygenase-1 (IDO-1)

“…Examples include brassinin, [21,41] exiguamine A, [42][43][44] plectosphaeroic acids A and B, [45] and annulin B [22,46,47] (Fig. 1).…”

“…The pyranonaphthoquinones, annulin A and B, were first isolated in 1986 from the marine hydroid Garveia annulata, [47] with annulin C discovered from the same source sometime later [46] (Fig. 2).…”

“…2). Annulin B was subsequently shown to be a potent inhibitor of IDO-1 (K i ¼ 0.12 mM), [46] inspiring the synthesis of a series of pyranonaphthoquinone inhibitors based on the annulin pyranonaphthoquinone core structure. [22] The synthetic pyranonaphthoquinones tested were amongst the most potent IDO-1 inhibitors recorded to date using an isolated enzyme assay (K i ¼ 61-70 nM), with a select few also causing minimal impact on cell viability at 100 mM after 24 h. [22] It is well established that various naphthoquinones display potent activity as IDO-1 inhibitors, [22,[42][43][44]46,47] suggesting this moiety to be a key pharmacophore and a likely indole mimetic.…”

“…Annulin B was subsequently shown to be a potent inhibitor of IDO-1 (K i ¼ 0.12 mM), [46] inspiring the synthesis of a series of pyranonaphthoquinone inhibitors based on the annulin pyranonaphthoquinone core structure. [22] The synthetic pyranonaphthoquinones tested were amongst the most potent IDO-1 inhibitors recorded to date using an isolated enzyme assay (K i ¼ 61-70 nM), with a select few also causing minimal impact on cell viability at 100 mM after 24 h. [22] It is well established that various naphthoquinones display potent activity as IDO-1 inhibitors, [22,[42][43][44]46,47] suggesting this moiety to be a key pharmacophore and a likely indole mimetic. [22] As the pyran containing natural products annulin B [46,47] and exiguamine A [42,43] are both potent IDO-1 inhibitors, we planned on testing a series of pyranonaphthoquinone derivatives possessing both the pyran and naphthoquinone structural features of these natural products, thus extending the naphthoquinone series of novel IDO-1 inhibitors based on lead compounds from nature (Scheme 1).…”

Indol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors

“…The best inhibitor of the brassinin class has a K i of 12 lM but is not Lipinski-compliant due to high hydrophobicity. 22 In 2006, potent IDO inhibitors were isolated from marine invertebrate extracts, 23,24 leading to two new series of uncompetitive nanomolar inhibitors. 26,27 However, some of the most active compounds of the original series revealed to be inactive in a 0968-0896/$ -see front matter Ó 2010 Elsevier Ltd. All rights reserved.…”