wakayin and pyrroloquinoline

Indoleamine 2,3-dioxygenase (IDO1) and tryptophane 2,3-dioxygenase (TDO) are two heme-containing 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 were synthesized using 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.

Topics: Alkaloids; Aquatic Organisms; Enzyme Inhibitors; HEK293 Cells; Humans; Indole Alkaloids; Indoleamine-Pyrrole 2,3,-Dioxygenase; Molecular Docking Simulation; Protein Binding; Protein Conformation; Pyrroles; Pyrroloiminoquinones; Quinolines; Small Molecule Libraries; Structure-Activity Relationship; Tryptophan Oxygenase

Two aza-analogues of the marine pyrroloquinoline alkaloids wakayin and tsitsikammamines A and B have been synthesized. The strategy used was based on a 1,3-dipolar cycloaddition reaction between indole 4,7-dione and a diazo-aminopropane derivative. One of the two analogues partially inhibits human topoisomerase I, whereas synthetic intermediates inhibit the enzyme DNA cleavage activity at a concentration comparable to that of the control drug camptothecin.

Topics: Animals; Aza Compounds; Cyclization; Humans; Indole Alkaloids; Molecular Structure; Pyrroles; Quinolines; Structure-Activity Relationship; Topoisomerase I Inhibitors

A series of aza analogues of the marine alkaloids wakayin and tsitsikammamines A and B have been synthesized. The strategy used was based on [3 + 2] cycloaddition reactions involving 3-ethylamine-indole-4,7-dione and different diazo reagents. All the compounds were evaluated in vitro for antiproliferative activity against five distinct cancer cell lines and for their inhibitory effect on topoisomerase isoenzymes I and II. Some of the compounds inhibited the topoisomerase I and/or II catalyzed relaxation of supercoiled DNA at a concentration comparable to the drugs camptothecin and etoposide. Only a few of them exhibited cytotoxic activity with IC50 values in the micromolar range.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Indole Alkaloids; Pyrazoles; Pyrroles; Quinolines; Structure-Activity Relationship; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors