Naturally Occurring Indolocarbazole Ligands

In the isolation process of glucobrassicin hydrolysis products, early observations led to file suggestion fiiat 227 was one of the major metabolites, and the most potent 

In a study by Stresser and co-workers, the effect on tumor modulation by 227 has been investigated. HPLC on liver extracts from Fisher 344 rats revealed two major compounds, 3,3 -bisindolylmefliane (133) and a linear trimer, together with a l(KX)-fold lower content of 4 in comparison with the two major substances. The HPLC isolate was derivatized with /V-methyl-/V-bis(trifluoroacetamide) that, upon MS detection, gave a compound identical to /V,W -ditrifluoroacetylindolo-[3,2-()]carbazole. The content of 4 in this system was estimated to be 0.(XKX)13% of the total dose of 227 given. Thus, it was concluded that the beneficial effect of oral distribution of 227 is due to the total content of derivatives formed (95MI5). 

Interestingly, Gassman and co-workers have demonstrated that the regulation of the induction of AHR by indolo[3,2-/)]carbazole (4) was reduced by prior activation of the hypoxia-inducible expression. As the hypoxia pathways are dependent on ARNT, prior activation may deplete the cell of available ARNT for AHR heterodimerization (97MI3). 

Recently, 202 and 203 were found to significantly reduce the mutation frequency induced by BaP in vivo as well (00UP3). Previously, flie same group had pointed out that some genotoxic effects could result from UV irradiation of tryptophan, but this had not been attributed to lipophilic substances like 202 and 203 (94MI5). 

Indications fliat endogenous AHR hgand(s) may be derived from tryptophan have been reported repeatedly (87JBC15422 91MI5 98MI6 OOMIl 1). This implies fliat the tryptophan photoproduct 202 and molecules with a similar sbuctural framework are the most likely candidates as endogenous ligands for the AHR. 

When N A/ -dimethyl-A X-difAenyl-p-phenylenediamine (231) underwent irradiation in the presence of oxygen, a remarkably regioselective reaction was observed, from which the /VX-dimefliylindolo[2,3-t ]carbazole (190) was obtained, without coformation of flie other possible isomeric product, indolo[3,2-fc]carbazole (4). The expected intermediate 232, where only one ring closure had taken place, could not be detected. The authors attributed this fact to a two-photon autosensitization mechanism in which the conversion of 231 into 190 is sensitized by 232, permitting accumulation of 232 only in extremely small concentrations (83JA6268). 

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