Truncated ring-A amaryllidaceae alkaloid modulates the host cell integrated stress response, exhibiting antiviral activity to HSV-1 and SARSCoV-2.

The total synthesis of four novel mono-methoxy and hydroxyl substituted ring-A dihydronarciclasine derivatives enabled identification of the 7-hydroxyl derivative as a potent and selective antiviral agent targeting SARSCoV-2 and HSV-1. The concentration of this small molecule that inhibited HSV-1 infection by 50% (IC50), determined by using induced pluripotent stem cells (iPCS)-derived brain organ organoids generated from two iPCS lines, was estimated to be 0.504 µM and 0.209 µM. No significant reduction in organoid viability was observed at concentrations up to 50 mM. Genomic expression analyses revealed a significant effect on host-cell innate immunity, revealing activation of the integrated stress response via PERK kinase upregulation, phosphorylation of eukaryotic initiation factor 2α (eIF2α) and type I IFN, as factors potentiating multiple host-defense mechanisms against viral infection. Following infection of mouse eyes with HSV-1, treatment with the compound dramatically reduced HSV-1 shedding in vivo.

Unnatural C-1 homologues of pancratistatin - Synthesis and promising biological activities.

Several C-1 homologues of pancratistatin and 7-deoxypancratistatin were synthesized by a phenanthrene-phenathridone oxidative recyclization strategy. The key steps involved the enzymatic dihydroxylation of bromobenzene, addition of an aryl alane to an epoxyaziridine, an intramolecular aziridine opening on silica gel in solid phase, and the above-mentioned recylization strategy. Experimental and spectral data are reported for all new compounds. All synthesized C-1 homologues of pancratistatin and 7-deoxypancratistatin were evaluated for antiproliferative activity in a panel of human cancer cell lines. As expected, the 7-hydroxy compounds were found to be more potent and the activity of the C-1 benzoxymethyl analogue exceeded that of narciclasine, which was used as a positive control.

On a réalisé la synthèse de plusieurs homologues en C-1 de la pancratistatine et de la 7-désoxypencratistatine en faisant appel à une stratégie de recyclisation oxydante phenantrène­phénathridone. Les étapes clés impliquent la dihydroxylation du bromobenzène, l'addition d'une arylalane à une époxyaziridine, une ouverture intramoléculaire d'aziridine sur gel de silice en phase solide et la stratégie de recyclisation mentionnée plus haut. Les données expérimentales et spectrales sont rapportées pour tous les nouveaux produits. Tous les homologues en C-1 de la pancratistatine et de la 7-désoxypencratistatine ont été évalués pour leur activité à contrer la prolifération dans un éventail de lignées de cellules cancéreuses humaines. Tel que prévu, les composés 7-hydroxy sont les plus puissants alors que l'activité de l'analogue C-1 benzoxyméthyle est supérieure à celle de la narciclasine qui a été utilisée comme contrôle positif.

Synthesis of C-1 homologues of pancratistatin and their preliminary biological evaluation.

The synthesis of two C-1 analogues of pancratistatin has been accomplished in 17 steps from bromobenzene. The key steps involved the enzymatic dihydroxylation, regioselective opening of epoxyaziridine 9 with the alane derived from 8, a solid-state silica-gel-catalyzed intramolecular opening of aziridine to produce phenanthrene 13 whose oxidative cleavage and recyclization provided the full skeleton of the Amaryllidaceae constituents. The new analogues 5 and 6 exhibited promising activity in several human cancer cell lines.