Synthesis, evaluation and structure-activity relationship of new 3-carboxamide coumarins as FXIIa inhibitors.

Inhibitors of the coagulation factor XIIa (FXIIa) are attractive to detail the roles of this protease in hemostasis and thrombosis, to suppress artifact due to contact pathway activation in blood coagulation assays, and they are promising as antithrombotic therapy. The 3-carboxamide coumarins have been previously described as small-molecular-weight FXIIa inhibitors. In this study, we report a structure-activity relationship (SAR) study around this scaffold with the aim to discover new selective FXIIa inhibitors with an improved physico-chemical profile. To better understand these SAR, docking experiments were undertaken. For this purpose, we built an original hybrid model of FXIIa. This model has the advantage to gather the best features from the recently published crystal structure of FXIIa in its zymogen form and a more classical homology model. Results with the hybrid model are encouraging as they help understanding the activity and selectivity of our best compounds.

Indoleamine 2,3-dioxygenase inhibitors: a patent review (2008 - 2012).

INTRODUCTION: The inhibition of indoleamine 2,3-dioxygenase (IDO) has emerged as a key area in cancer immunotherapy in the past decade. Despite the large variety of potential inhibitors screened so far, the number of active scaffolds remains limited. AREAS COVERED: All relevant patent literature published between 2008 and 2012 is reviewed. Representative examples are given for each patent and/or class of compounds along with data (if available) on their inhibitory activity. The presentation is deepened by additional data published in peer-reviewed literature. EXPERT OPINION: Key events that stimulated the search of IDO inhibitors are presented. To date, however, the number of available scaffolds remains limited with only one confirmed inhibitor (from Incyte Corp.) in the clinic. Major challenges in the search for IDO inhibitors are discussed as well as the relevance of selectivity of IDO inhibition versus inhibition of tryptophan 2,3-dioxygenase.

Indoleamine 2,3-dioxygenase inhibitory activity of derivatives of marine alkaloid tsitsikammamine A.

Tsitsikammamines are marine alkaloids whose structure is based on the pyrroloiminoquinone scaffold. These and related compounds have attracted attention due to various interesting biological properties, including cytotoxicity, topoisomerase inhibition, antimicrobial, antifungal and antimalarial activity. Indoleamine 2,3-dioxygenase (IDO1) is a well-established therapeutic target as an important factor in the tumor immune evasion mechanism. In this preliminary communication, we report the inhibitory activity of tsitsikammamine derivatives against IDO1. Tsitsikammamine A analogue 11b displays submicromolar potency in an enzymatic assay. A number of derivatives are also active in a cellular assay while showing little or no activity towards tryptophan 2,3-dioxygenase (TDO), a functionally related enzyme. This IDO1 inhibitory activity is rationalized by molecular modeling studies. An interest is thus established in this class of compounds as a potential source of lead compounds for the development of new pharmaceutically useful IDO1 inhibitors.

Synthesis, crystal structures and electronic properties of isomers of chloro-pyridinylvinyl-1H-indoles.

Three isomers of chloro-3-(2-pyridin-3-ylvinyl)-1H-indole were synthesized and tested as inhibitors of human tryptophan 2,3-dioxygenase (hTDO). The crystal structures of two of them were solved by X-ray diffraction. The solubility of the molecules also was determined experimentally. The molecular electrostatic potentials and dipole moments of the three isomers were calculated by ab initio quantum mechanics (HF/6-311G). The single crystal X-ray analyses reveal non-planar structures. This non-coplanarity is retained during docking of the compounds into a model of hTDO, the molecular target of this series. The position of the Cl atom does not significantly affect the electronic delocalization. Nevertheless, the position of the Cl atom produces a local variation of bond lengths inducing different dipole moments for these isomers. Variations in dipole moments are consistent with the different melting points and crystal packings. Differences in aqueous solubilities are best explained by subtle changes in H-bonds resulting from different accessibilities of the indole NH's due to steric effects of the Cl substituent. The non-coplanarity plays an important role in the crystalline packing of the molecules in contrast to the position of the Cl. This study leads to a better understanding of the structural and electronic characteristics of this chemical series and can potentially help to better understand their inhibitory activity.

Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase.

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 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators.

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.

Discovery and preliminary SARs of keto-indoles as novel indoleamine 2,3-dioxygenase (IDO) inhibitors.

Indoleamine 2,3-dioxygenase (IDO) is an important new therapeutic target for the treatment of cancer. With the aim of discovering novel IDO inhibitors, a virtual screen was undertaken and led to the discovery of the keto-indole derivative 1a endowed with an inhibitory potency in the micromolar range. Detailed kinetics were performed and revealed an uncompetitive inhibition profile. Preliminary SARs were drawn in this series and corroborated the putative binding orientation as suggested by docking.

Indol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors.

Indoleamine 2,3-dioxygenase (IDO) is a heme dioxygenase which has been shown to be involved in the pathological immune escape of diseases such as cancer. The synthesis and structure-activity relationships (SAR) of a novel series of IDO inhibitors based on the indol-2-yl ethanone scaffold is described. In vitro and in vivo biological activities have been evaluated, leading to compounds with IC(50) values in the micromolar range in both tests. Introduction of small substituents in the 5- and 6-positions of the indole ring, indole N-methylation and variations of the aromatic side chain are all well tolerated. An iron coordinating group on the linker is a prerequisite for biological activity, thus corroborating the virtual screening results.

Gold electrode incorporating corrole as an ion-channel mimetic sensor for determination of dopamine.

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.