Discovery of TCP-(MP)-caffeic acid analogs as a new class of agents for treatment of osteoclastic bone loss.

Inhibition of LSD1 was proposed as promising and attractive therapies for treating osteoporosis. Here, we synthesized a series of novel TCP-(MP)-Caffeic acid analogs as potential LSD1 inhibitors to assess their inhibitory effects on osteoclastogenesis by using TRAP-staining assay and try to explore the preliminary SAR. Among them, TCP-MP-CA (11a) demonstrated osteoclastic bone loss both in vitro and in vivo, showing a significant improvement in the in vivo effects compared to the LSD1 inhibitor GSK-LSD1. Additionally, we elucidated a mechanism that 11a and its precursor that 11e directly bind to LSD1/CoREST complex through FAD to inhibit LSD1 demethylation activity and influence its downstream IκB/NF-κB signaling pathway, and thus regulate osteoclastic bone loss. These findings suggested 11a or 11e as potential novel candidates for treating osteoclastic bone loss, and a concept for further development of TCP-(MP)-Caffeic acid analogs for therapeutic use in osteoporosis clinics.

Direct Synthesis of Aryloxy Phosphonamidate Nucleotide Prodrugs Using the Cross Metathesis Assisted by Ultrasonic Irradiation.

A direct synthetic strategy of aryloxy phosphonamidate nucleotide prodrugs (A, G, C, and U) was developed with the CM reaction assisted by ultrasonic irradiation and partitioned addition of 12 mol % of Hoveyda-Grubbs (H-G) II catalyst in 61-82% yields as a mixture of E-/Z-isomers (∼2:1) from aryloxy vinylphosponamidate and 5'-vinyl nucleoside moieties.

Synthesis and biological evaluation of new ß-D-N4-hydroxycytidine analogs against SARS-CoV-2, influenza viruses and DENV-2.

Drug repurposing approach was applied to find a potent antiviral agent against RNA viruses such as SARS-CoV-2, influenza viruses and dengue virus with a concise strategy of small change in parent molecular structure. For this purpose, ß-D-N4-hydroxycytidine (NHC, 1) with a broad spectrum of antiviral activity was chosen as the parent molecule. Among the prepared NHC analogs (8a-g, and 9) from uridine, ß-D-N4-O-isobutyrylcytidine (8a) showed potent activity against SARS-CoV-2 (EC50 3.50 µM), Flu A (H1N1) (EC50 5.80 µM), Flu A (H3N2) (EC50 7.30 µM), Flu B (EC50 3.40 µM) and DENV-2 (EC50 3.95 µM) in vitro. Furthermore, its potency against SARS-CoV-2 was >5-fold, 3.4-fold, and 3-fold compared to that of NHC (1), MK-4482 (2), and remdesivir (RDV) in vitro, respectively. Ultimately, compound 8a was expected to be a potent inhibitor toward RNA viruses as a viral mutagenic agent like MK-4482.