General Synthesis of Unsymmetrical 3,3′-(Aza)diindolylmethane Derivatives

Diindolylmethane
(DIM) and its derivatives have recently been in
the focus of interest due to their significant biological activities,
specifically in cancer prevention and therapy. Molecular targets of
DIM have been identified, e.g., the immunostimulatory G protein-coupled
receptor GPR84. However, most of the reported and investigated DIM
derivatives are symmetrical because general methods for obtaining
unsymmetrical DIMs have been lacking. To optimize the interaction
of DIM derivatives with their protein targets, unsymmetrical substitution
is required. In the present study we developed a new, mild and efficient
access to unsymmetrically substituted 3,3′-DIMs by reaction
of (3-indolylmethyl)­trimethylammonium iodides with a wide range of
substituted indole derivatives. 7-Azaindole also led to the 3,3′-connected
DIM analogue, while 4- and 5-azaindoles reacted at the N1-nitrogen atom as confirmed by X-ray crystallography. The reactions
were performed in water without the requirement of a catalyst or other
additives. Wide substrate scope, operational simplicity, environmentally
benign workup, and high yields are further advantages of the new method.
The synthetic protocol proved to be suitable for upscaling to yield
gram amounts for pharmacological studies. This procedure will allow
the preparation of a broad range of novel, unsymmetrical DIM derivatives
to exploit their potential as novel drugs.