IDO1 and TDO inhibitory evaluation of analogues of the marine pyrroloiminoquinone alkaloids: Wakayin and Tsitsikammamines

Abstract

Indoleamine 2,3-dioxygenase (IDO1) and tryptophane 2,3-dioxygenase (TDO) are two hemecontaining enzymes which catalyze the conversion of tryptophan to N-formylkynurenine.Both enzymes are well establish therapeutic targets as important factors in the tumor immune evasion mechanism. A number of analogues of the marine pyrroloquinoline alkaloids tsitsikammamines or wakayin have been synthesized, two of them being issued from an original method to build the bispyrroloquinone framework. All the derivatives were evaluated in a cellular assay for their capacity to inhibit the enzymes. Six compounds have shown a significant potency on HEK 293-EBNA cell lines expressing hIDO1 or hTDO.

Current Perspectives on Pyrroloiminoquinones: Distribution, Biosynthesis and Drug Discovery Potential

“…A multitude of other synthetic analogs have been evaluated for bioactivity, including synthetic makaluvamine analogs DHN-II-84 and DHN-III-14 (Figure 8) which de-creased c-KIT expression and elicited decreased neuroendocrine tumor markers myeloid cell leukemia-1 (MCL-1), X-chromosome linked inhibitor of apoptosis (XIAP), chromogranin A (CgA) and achaete-scute homolog 1 (ASCL1) [107]. Furthermore, a range of synthetic wakayin, tsitsikammamine and zyzzyanone analogs were tested in cellular assays of HEK 293-EBNA cell lines expressing hIDO1 or hTDO [108]. Interestingly, a zyzzyanone analog (Figure 8), which is not strictly speaking a pyrroloiminoquinone, showed the most promising inhibitory profile with ca.…”

“…Interestingly, a zyzzyanone analog (Figure 8), which is not strictly speaking a pyrroloiminoquinone, showed the most promising inhibitory profile with ca. 52% (IDO) and 15% (TDO) inhibition at 3.12 µM concentration, while exhibiting virtually no effect on cell viability [108]. In yet another study, a set of pyrroloiminoquinone analogs was synthesized to investigate their potential as anti-skin cancer drug leads [109].…”

Alashanines A–C, Three Quinone-Terpenoid Alkaloids from Syringa pinnatifolia with Cytotoxic Potential by Activation of ERK

“…Alkaloids are a large class of secondary metabolites and provide a crucial resource for drug discovery. Up to now, approximately 15 000 alkaloids have been divided into dozens of classes according to their carbon skeleton, which are known from plants and marine organisms. , Among them, quinone-containing alkaloids are characterized by unique structures containing quinone fragments and nitrogen atoms, such as carbazoloquinone, − pyrroloiminoquinone, − isoquinolinequinone, − bispyrroloquinone, and others. Quinone alkaloids have drawn great attention from organic chemists, pharmacologists, and (bio)­synthetic chemists because of their diverse structures, complex biosynthesis pathways, and fascinating antibacterial and cytotoxic activities. − Therefore, great efforts have been endeavored to synthesize and identify new quinone alkaloids.…”