Discovery and Optimization of Novel hDHODH Inhibitors for the Treatment of Inflammatory Bowel Disease.

As a key rate-limiting enzyme in the de novo synthesis of pyrimidine nucleotides, human dihydroorotate dehydrogenase (hDHODH) is considered a known target for the treatment of autoimmune diseases, including inflammatory bowel disease (IBD). Herein, BAY 41-2272 with a 1H-pyrazolo[3,4-b]pyridine scaffold was identified as an hDHODH inhibitor by screening an active compound library containing 5091 molecules. Further optimization led to 2-(1-(2-chloro-6-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-cyclopropylpyrimidin-4-amine (w2), which was found to be the most promising and drug-like compound with potent inhibitory activity against hDHODH (IC50 = 173.4 nM). Compound w2 demonstrated acceptable pharmacokinetic characteristics and alleviated the severity of acute ulcerative colitis induced by dextran sulfate sodium in a dose-dependent manner. Notably, w2 exerted better therapeutic effects on ulcerative colitis than hDHODH inhibitor vidofludimus and Janus kinase (JAK) inhibitor tofacitinib. Taken together, w2 is a promising hDHODH inhibitor for the treatment of IBD and deserves to be developed as a preclinical candidate.

Immobilization of 6-O-α-maltosyl-ß-cyclodextrin on the surface of black phosphorus nanosheets for selective chiral recognition of tyrosine enantiomers.

A novel chiral sensing platform, 6-O-α-maltosyl-ß-cyclodextrin (Mal-ßCD)-based film, is proposed for selective electrochemical recognition of tyrosine (Tyr) enantiomers. Black phosphorus nanosheets (BP NSs) and Mal-ßCD modified glassy carbon electrode (Mal-ßCD/BP NSs/GCE) were prepared by a layer-to-layer drop-casting method, and the platform was easy to fabricate and facile to operate. It is proposed that the amino and hydroxyl groups of the Tyr enantiomers and the chiral hydroxyl groups of Mal-ßCD selectively form intermolecular hydrogen bonds to dominate effective chiral recognition. Two linear equations of Ip (µA) = 11.40 CL-Tyr (mM) + 0.28 (R2 = 0.99147) and Ip (µA) = 7.96 CD-Tyr (mM) + 0.22 (R2 = 0.99583) in the concentration range 0.01-1.00 mM have been obtained. The limits of detection (S/N=3) for L-Tyr and D-Tyr were 4.81 and 6.89 µM, respectively. An interesting phenomenon was that the value of IL-Tyr/ID-Tyr (1.51) in this work was slightly higher than the value of IL-Trp/ID-Trp (1.49) reported in our previous study, where tryptophan (Trp) enantiomers were electrochemically recognized by Nafion (NF)-stabilized BPNSs-G2-ß-CD composite. The two similar sensors fabricated by different methods showed different recognition ability toward either Tyr or Trp enantiomers, and the underlying mechanism was discussed in detail. More importantly, the proposed chiral sensor enables prediction of the percentages of D-Tyr in racemic Tyr mixtures. The chiral sensor may provide a novel approach for the fabrication of novel chiral platforms in the practical detection of L- or D-enantiomer in racemic Tyr mixtures.Graphical abstract.

Nafion-stabilized black phosphorus nanosheets-maltosyl-ß-cyclodextrin as a chiral sensor for tryptophan enantiomers.

In this work, we have fabricated nafion (NF) stabilized black phosphorus nanosheets (BPNSs) and 6-O-α-maltosyl-ß-cyclodextrin (G2-ß-CD) composite (BPNSs-G2-ß-CD) as novel electrochemical sensoring platform for chiral recognition of tryptophan (Trp) enantiomers. BPNSs-G2-ß-CD composite modified glassy carbon electrode (BPNSs-G2-ß-CD/GCE) was further coated with NF which served as a protective film to immobilize BPNSs-G2-ß-CD on the electrode surface to achieve high stability. Under the optimum conditions, the oxidation peak current ratio of L-Trp to D-Trp (IL/ID) and the difference between the peak potential (ΔEp = ED - EL) were observed to be 1.49 and 20 mV at NF/BPNSs-G2-ß-CD/GCE by square wave voltammetry (SWV). In addition, a linear calibration curve could be obtained for peak current versus Trp enantiomers in the concentration range 0.01-1.00 mM with detection limits of 1.07 µM and 1.71 µM for L-Trp and D-Trp (signal-to-noise ratio of 3, S/N = 3), respectively. The chiral recognition mechanism was also proposed, and the intermolecular hydrogen bonding interactions as well as the hydrophobic-cavity-triggered embedding effect dominated the effective chiral recognition. Moreover, the proposed NF/BPNSs-G2-ß-CD/GCE showed excellent stability, good reproducibility and anti-interference capability. Therefore, the designed chiral sensor is expected to be practically applied for the sensitive recognition of Trp enantiomers in real samples.