Characterization of KRC-108 as a TrkA Kinase Inhibitor with Anti-Tumor Effects.

Tropomyosin receptor kinase A (TrkA) protein is a receptor tyrosine kinase encoded by the NTRK1 gene. TrkA signaling mediates the proliferation, differentiation, and survival of neurons and other cells following stimulation by its ligand, the nerve growth factor. Chromosomal rearrangements of the NTRK1 gene result in the generation of TrkA fusion protein, which is known to cause deregulation of TrkA signaling. Targeting TrkA activity represents a promising strategy for the treatment of cancers that harbor the TrkA fusion protein. In this study, we evaluated the TrkA-inhibitory activity of the benzoxazole compound KRC-108. KRC-108 inhibited TrkA activity in an in vitro kinase assay, and suppressed the growth of KM12C colon cancer cells harboring an NTRK1 gene fusion. KRC-108 treatment induced cell cycle arrest, apoptotic cell death, and autophagy. KRC-108 suppressed the phosphorylation of downstream signaling molecules of TrkA, including Akt, phospholipase Cγ, and ERK1/2. Furthermore, KRC-108 exhibited anti-tumor activity in vivo in a KM12C cell xenograft model. These results indicate that KRC-108 may be a promising therapeutic agent for Trk fusion-positive cancers.

Development and validation of liquid chromatography-tandem mass spectrometry method for screening six selective androgen receptor modulators in dietary supplements.

Selective androgen receptor modulators (SARMs) are compounds with specific androgenic properties that have been investigated for the treatment of conditions such as muscle wasting disease. The reported androgenic properties have resulted in their use by athletes, and consequently they have been on the World Anti-Doping Agency prohibited list for more than a decade. To minimise the chance of an unattended positive doping test and to avoid potential serious health problems, adequate screening methods for the detection of a wide range of SARMs in these supplements is necessary. In this study, a rapid and accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated simultaneously to screen and quantify six SARMs in dietary supplements, with confirmation by liquid chromatography-quadrupole-time of flight mass spectrometry (LC-Q-TOF/MS). The validated method was applied to 60 dietary supplements obtained by on-line and direct purchase from international vendors in 2020. Various SARMs were detected at high concentrations in 20 products which were advertised as having androgenic properties. For example, andarine was present at 7.2% in one product, and GW501516 was found at 3.49% in the another product. Furthermore, MK-677 and YK-11, not disclosed on the label, were detected in some products. YK-11 is easily hydrolysed in just a few hours. Although YK-11 is particularly unstable, such that the protonated ion [M + H]+ at m/z 431 for YK-11 was not detected, mass fragmentation, and a [M+ Na]+ ion at m/z 453.3 confirmed the presence of YK-11. Additionally, hydrolysed YK-11 under acidic conditions was confirmed by NMR spectral data, and 1H NMR and 13C NMR spectral data for YK-11 were in good agreement with literature data. This rapid and accurate LC-MS/MS method can therefore be successfully applied to screen and identify SARMs for the continuous control and supervision of dietary supplements.

Cross-Metathesis of Methallyl Halides: Concise Enantioselective Formal Total Synthesis of (-)-Presphaerene.

The cross-metathesis (CM) of methallyl halides catalyzed using four different ruthenium-based complexes-Grubbs catalyst, Grubbs second-generation catalyst, Hoveyda-Grubbs second-generation catalyst, and Stewart-Grubbs catalyst-was investigated. When methallyl chloride or bromide was reacted with a model substrate containing a benzyl ether group, the Grubbs catalyst, and Grubbs second-generation catalyst did not promote the reaction well. However, the Hoveyda-Grubbs second-generation catalyst and Stewart-Grubbs catalyst afforded the corresponding products in moderate to good yield with moderate E/Z selectivity. Accordingly, several functionalized methallyl halides were prepared by CM. Various functional groups were well-tolerated in this system when the Stewart-Grubbs catalyst was used. To demonstrate the practical utility of our method, methallyl halide CM was successfully employed for the formal total synthesis of a natural product (-)-presphaerene, in which the precursor of the key cyclopentanecarboxylate intermediate was efficiently prepared in three steps.