Eduard Dolušić

Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO1) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance, and IDO1 inhibition is an active area of drug development. Tryptophan 2,3-dioxygenase (TDO) is an unrelated hepatic enzyme that also degrades tryptophan along the kynurenine pathway. Here, we show that enzymatically active TDO is expressed in a significant proportion of human tumors. In a preclinical model, TDO expression by tumors prevented their rejection by immunized mice. We developed a TDO inhibitor, which, upon systemic treatment, restored the ability of mice to reject TDO-expressing tumors. Our results describe a mechanism of tumoral immune resistance based on TDO expression and establish proof-of-concept for the use of TDO inhibitors in cancer therapy.

Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an active area of research in drug development. Recently, our group has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. Herein, we report a structure-activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure-activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His(55) and Thr(254) residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (K(i) = 5.5 μM), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.

In this paper, we describe the efficient and selective synthesis of aryldipyrromethanes in aqueous medium by acid-catalyzed (HCl) condensations of aromatic aldehydes with 3 equivalents of pyrrole at room temperature. The precipitated aryldipyrromethanes can be isolated directly from the reaction mixture in an essentially pure state by simple filtration. Time control seems to be essential to avoid significant formation of the tripyrromethane analogue and the reaction time is strongly dependent on the nature of the aromatic aldehyde. A one-pot synthesis of several aryldipyrromethenes and various novel meso-aryl-substituted trans-A 2 B-corroles was also achieved starting from the obtained aryldipyrromethanes. Trichloroacetic acid was the preferred acid catalyst for the preparation of meso-triarylcorroles from the condensation of 5-(2,6dichlorophenyl)dipyrromethane with more reactive aldehydes, while trifluoroacetic acid was preferred for less reactive substrates.

Here, we report on an ion-channel mimetic sensor using self-assembly monolayers deposited onto gold electrodes for electrochemical determination of dopamine. The different compositions of the modification solution consist of corrole-SH and other thiol derivatives used as the "background compounds" such as 1-dodecanethiol (DDT), 6-mercapto-1-hexanol (HS(CH(2))(6)OH), or 11-mercapto-1-undecanol (HS(CH(2))(11)OH) were explored to find the best self-assembled monolayer (SAM) suitable for dopamine determination. Among them, the mixed SAM consisting of corroles with the -SH group and 6-mercapto-1-hexanol (HS(CH(2))(6)OH) in the molar ratio 1:10 was the most sensitive. The signals generated by the formation of a complex between the corrole host and the dopamine guest were measured by Osteryoung square-wave voltammetry (OSWV) and electrochemical impedance spectroscopy (EIS) with [Ru(NH(3))(6)](3+) as an electroactive marker. The developed sensor was free of interferences of components of human plasma such as ascorbic acid, creatinine, creatine, and uric acid. The detection limits observed by EIS in buffer solution and in the presence of centrifuged human plasma 80 times diluted with a 0.9% NaCl containing 0.01 M borate buffer solution of pH 7.0 were 3.3 x 10(-12) and 5.3 x 10(-12) M, respectively.