2-(3-Indolyl)acetamides and their oxazoline analogues: Anticancer SAR study.

We previously studied 2-aryl-2-(3-indolyl)acetohydroxamates as potential agents against melanoma. These compounds were ineffective in a mouse melanoma xenograft model, most likely due to unfavorable metabolic properties, specifically due to glucuronidation of the N-hydroxyl of the hydoxamic moiety. In the present work, we prepared a series of analogues, 2-aryl-2-(3-indolyl)acetamides and their oxazoline derivatives, which do not contain the N-hydroxyl group. We investigated the structure-activity relationship in both series of compounds and found that the 2-naphthyl is a preferred group at C-2 of the indole in the amide series, whereas the tetralin moiety is favorable in the same location in the oxazoline series. Overall, three compounds in the amide series have GI50 values as low as 0.2-0.3 µM and the results clearly indicate that the N-hydroxyl group is not necessary for high potency in vitro.

Oxidative Cyclization of 4-(2-Aminophenyl)-4-oxo-2-phenylbutanenitriles into 2-(3-Oxoindolin-2-ylidene)acetonitriles.

A facile and highly efficient method for the preparation of 2-(3-oxoindolin-2-ylidene)acetonitriles from 4-(2-aminophenyl)-4-oxo-2-phenylbutanenitriles is described. The featured transformation operates via nucleophilic intramolecular cyclization and involves oxidation of the aniline moiety. Overall, this modification allowed for the improvement of yields and expansion of the reaction scope.

Preparation of 3,5-diarylsubstituted 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones via base-assisted cyclization of 3-cyanoketones.

A convenient preparative method is developed allowing for expeditious assembly of 3,5-diarylsubstituted 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones from routinely available inexpensive synthetic precursors. These compounds could not be prepared via the previously known protocols, as 2-aminofuran derivatives were produced instead.

Synthesis of 2-(1H-Indol-2-yl)acetamides via Brønsted Acid-Assisted Cyclization Cascade.

An efficient and straightforward Brønsted-acid mediated cascade process was developed, involving cyclization of readily available ß-ketonitriles into 2-aminofurans, and their subsequent recyclization into 2-(1H-indol-2-yl)acetamides is developed. This synthetic route opens a new avenue for an expeditious assembly of various isotryptamine derivatives for medicinal chemistry.