Lead optimization : synthesis and biological evaluation of griseofulvin derivatives as novel SIRT6 activators

Zorko, Tilen (avtor), Kogovšek, Jan (avtor), Ciber, Luka (avtor), Ostojić, Ivana (avtor), Maraš, Nenad (avtor), Novinec, Marko (avtor), Štefane, Bogdan (avtor)

SIRT6, a crucial regulator of aging and cellular homeostasis, represents a promising target for small-molecule activation. In this study, we investigate griseofulvin and its derivatives as novel SIRT6 activators, focusing on the recently developed compound forvisirvat, which has progressed to Phase 2 clinical study. Biochemical evaluation revealed that griseofulvin itself possesses strong SIRT6-activating properties, achieving up to 10-fold activity at 100 μM. Modification of the griseofulvin scaffold generally led to reduced activity, prompting a focus on the oxadiazole moiety of forvisirvat. This strategy produced several analogues with higher potency, the most active at 100 μM being para-1,3,4-oxadiazolephenyl analog 21, which achieved 30-fold SIRT6 activation. Compounds bearing para-substituted phenyl rings exhibited excellent retention of activity at lower concentrations, with para-tolyl derivative 24 being the most potent at 10 μM. Retention of activity at pharmacologically relevant concentrations underscores their potential as potent SIRT6 activators and provides a rationale for continued development as drug candidates.

• Jezik: Angleški jezik
• Ključne besede: SIRT6, sirtuin activators, grisefulvin, forvisirvat, aging
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FKKT - Fakulteta za kemijo in kemijsko tehnologijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2026
• Št. strani: Str. 662-669
• Številčenje: Vol. 17, iss. 3
• PID: 20.500.12556/RUL-180760
• UDK: 547.7:577.24
• ISSN pri članku: 1948-5875
• DOI: 10.1021/acsmedchemlett.5c00690
• COBISS.SI-ID: 270595331
• Datum objave v RUL: 16.03.2026

Gradivo je del revije

• Naslov: ACS Medicinal Chemistry Letters
• Založnik: American Chemical Society
• ISSN: 1948-5875
• COBISS.SI-ID: 2959217

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: SIRT6, aktivatorji sirtuina, griseofulvin, forvisirvat, staranje