Design, synthesis and evaluation of biological activities of novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitor/sirtuin-1 (SIRT-1) activator hybride molecules

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Thesis Type: Doctorate

Institution Of The Thesis: Gazi University, Sağlık Bilimleri Enstitüsü, -, Turkey

Approval Date: 2025

Thesis Language: Turkish

Student: Fikriye ÖZGENCİL

Supervisor: Gökçen Eren

Open Archive Collection: AVESIS Open Access Collection

Abstract:

In cancer cells, enhanced metabolism, growth, and activity of NAD⁺-consuming enzymes lead to a more rapid depletion of NAD⁺ compared to normal cells, resulting in cancer cells being more sensitive to NAD⁺ deficiency. Therefore, NAMPT, the rate-limiting enzyme in the main NAD⁺ biosynthesis pathway, has emerged as a significant target in cancer therapy. SIRT1, on the other hand, uses NAD⁺ as a cofactor to regulate various cellular processes, including DNA repair, gene expression, and cell death. In our research, we aimed to achieve a stronger antiproliferative effect in cancer cells sensitive to NAD⁺ depletion by simultaneously inhibiting NAMPT and activating SIRT1, thereby more effectively reducing cellular NAD⁺ levels. For this purpose, a sequential virtual screening study was carried out using pharmacophore models designed for both targets to identify hybrid compounds that could both inhibit NAMPT and activate SIRT1. As a result of the screening, nine compounds (F1-F9) that met the desired criteria for both targets were purchased and evaluated for their in vitro NAMPT and SIRT1 activities. Compounds F1, F2, F3, and F5 were found to possess both NAMPT inhibitory and SIRT1 activating effects. Among these, F1 was selected as the lead compound due to its potent NAMPT inhibition (IC50=0,89 µM) and selective SIRT1 activation (EC1,5=16,45 µM). Subsequently, twelve 3-[N-(arylmethyl)sulfamoyl]-N-(aryl)benzamide derivatives (STF1-STF12) were designed through an optimization study. Among these, STF2 (NAMPT IC50=11,24 µM; SIRT1 EC1,5=16,98 µM) and STF6 (NAMPT IC50=19,15 µM; SIRT1 EC1,5=0,59 µM) were identified as dual NAMPT inhibitors and SIRT1 activators. The effects of the dual-acting compounds F1, F2, STF2, and STF6 were investigated on human Caki-1 renal, HCT116 colorectal, and Hep3B liver cancer cell lines, as well as on non-cancerous human HEK293T embryonic kidney cells, and the findings were correlated with their effects on NAMPT and SIRT1.