Malassezia
furfur isolates from diseased skin
preferentially biosynthesize compounds which are among the most active
known aryl-hydrocarbon receptor (AhR) inducers, such as indirubin,
tryptanthrin, indolo[3,2-b]carbazole, and 6-formylindolo[3,2-b]carbazole. In our effort to study their production from Malassezia spp., we investigated the role of indole-3-carbaldehyde
(I3A), the most abundant metabolite of Malassezia when grown on tryptophan agar, as a possible starting material for
the biosynthesis of the alkaloids. Treatment of I3A with H2O2 and use of catalysts like diphenyldiselenide resulted
in the simultaneous one-step transformation of I3A to indirubin and
tryptanthrin in good yields. The same reaction was first applied on
simple indole and then on substituted indoles and indole-3-carbaldehydes,
leading to a series of mono- and bisubstituted indirubins and tryptanthrins
bearing halogens, alkyl, or carbomethoxy groups. Afterward, they were
evaluated for their AhR agonist activity in recombinant human and
mouse hepatoma cell lines containing a stably transfected AhR-response
luciferase reporter gene. Among them, 3,9-dibromotryptanthrin was
found to be equipotent to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as an AhR agonist, and 3-bromotryptanthrin was 10-times
more potent than TCDD in the human HG2L7.5c1 cell line. In contrast,
3,9-dibromotryptanthrin and 3-bromotryptanthrin were ∼4000
and >10,000 times less potent than TCDD in the mouse H1L7.5c3 cell
line, respectively, demonstrating that they are species-specific AhR
agonists. Involvement of the AhR in the action of 3-bromotryptanthrin
was confirmed by the ability of the AhR antagonists CH223191 and SR1
to inhibit 3-bromotryptanthrin-dependent reporter gene induction in
human HG2L7.5c1 cells. In conclusion, I3A can be the starting material
used by Malassezia for the production of both indirubin
and tryptanthrin through an oxidation mechanism, and modification
of these compounds can produce some highly potent, efficacious and
species-selective AhR agonists.
