Antitumor effect of the integrin α4 signaling inhibitor JK273 in non-small cell lung cancer NCI-H460 cells.

Lung cancer accounts for the highest death rate among cancers worldwide, with most patients being diagnosed with non-small cell lung cancer (NSCLC), urging more effective therapies. We report that JK273, a pyrrolo[2,3-d]pyrimidine analog, which inhibits α4 integrin signaling, showed a selective cytotoxic effect against HCI-H460 NSCLC cells, with an IC50 of 0.98 ± 0.15 µM, but showed less sensitivity to fibroblasts with a selectivity index (SI) greater than 30. This effect was attributed to cell cycle arrest at S phase by JK273 treatment, resulting in the apoptosis of NCI-H460 cells, further confirmed by exposing phosphatidylserine and morphological changes. Taken together with the previous study of JK273 inhibiting cell migration, we propose that JK273 could serve as an antitumor compound to specifically target cancer cells but not non-cancerous cells by triggering programmed cell death, in addition to anti-metastatic effects in cancer therapy.

Synthesis and Structure Revision of Dimeric Tadalafil Analogue Adulterants in Dietary Supplements.

A number of phosphodiesterase 5 (PDE5) inhibitors approved by authorities have been used successfully in the treatment of erectile dysfunction. These medicines must be prescribed carefully due to their adverse effects, but they and their analogues are being illegally added to dietary supplements. These illegal dietary supplements pose a significant risk to public health. Several dimeric tadalafil analogues have been synthesized for use as reference standards in the inspection of functional foods that are mainly advertised as sexual enhancement products. During the course of this synthesis, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) was proven to be the reagent of choice for amide coupling to produce these dimeric tadalafil analogues. Moreover, the trans-isomer structures tentatively assigned for the isolated dimeric tadalafil analogues (bisprehomotadalafil and bisprecyclopentyltadalafil) found in dietary supplements are now revised to cis-isomer structures.

aza-Flavanones as potent cross-species microRNA inhibitors that arrest cell cycle.

aza-Flavanones have been identified as a new class of selective microRNA inhibitors. These compounds were found to arrest cell cycle via a novel cross species microRNA-dependent regulatory pathway interpreting an unexpected link between cell cycle arrest and microRNA mediated control in cancer.

Aza-Flavanone Diminishes Parkinsonism in the Drosophila melanogasterParkin Mutant.

Parkinson's disease is a chronic and progressive neurodegenerative disease, induced by slow and progressive death of the dopaminergic (DA) neurons from the midbrain region called substantia nigra (SNc) leading to difficulty in locomotion. At present, very few potential therapeutic drugs are available for treatment, necessitating an urgent need for development. In the current study, the parkin transgenic Drosophila melanogaster model that induces selective loss in dopaminergic neurons and impairment of locomotory functions has been used to see the effect of the aza-flavanone molecule. D. melanogaster serves as an amazing in vivo model making valuable contribution in the development of promising treatment strategies. Our in-silico study showed spontaneous binding of this molecule to the D2 receptor making it a potential dopamine agonist. PARKIN protein is well conserved, and it has been reported that Drosophila PARKIN is 42% identical to human PARKIN. Interestingly, this molecule enhances the motor coordination and survivability rate of the transgenic flies along with an increase in expression of the master regulator of Dopamine synthesis, that is, tyrosine hydroxylase (TH), in the substantia nigra region of the fly brain. Moreover, it plays a significant effect on mitochondrial health and biogenesis via modulation of a conserved mitochondrial protein PHB2. Therefore, this molecule could lead to the development of an effective therapeutic approach for the treatment of PD.

Isolation and structural elucidation of a new tadalafil analogue in health supplements: bisprenortadalafil.

A new tadalafil analogue was found, along with nortadalafil, using HPLC-DAD during the inspection of a health product sold without official approval. The analogue was separated using a semi-preparative HPLC system and its structure was determined by a combination of mass spectrometry and NMR spectroscopy. The compound was identified as a tadalafil analogue in which the N-methyl group of tadalafil was replaced with a tadalafil precursor moiety. Nuclear Overhauser effect spectroscopy experiments suggested a cis-relationship between the substituents on a piperidine ring in the tadalafil moiety.