Design and Synthesis of New 9‐Substituted Norharmane Derivatives as Potential Sirt5 Inhibitors

Abstract

Sirt5 is a potential new drug target for the treatment of cancer, Alzheimer's disease, and Parkinson's disease. Given that norharmane is an important chemical synthon for some biologically important compounds and 9‐substituted norharmane derivatives containing a negatively charged carboxyl group may accord with the characteristic of potential Sirt5 inhibitors, a series of novel 9‐substituted norharmane derivatives were synthesized. The chemical structures and purities of all the target compounds were characterized by 1H NMR, 13C NMR, MS, and HPLC. By in vitro SIRT5 inhibitory assays, three compounds (1a, 3a, and 3b) show over 30% inhibition ratios at concentration of 100 µM, and the most active compound 3b has 35% and 52% inhibition ratios at 30 µM and 100 µM, respectively. Docking analysis showed that compound 3b is likely to fit very well on the substrate binding site of Sirt5, and hence, we believe that compound 3b can serve as a lead compound for further efforts to develop specific Sirt5 inhibitors.

Emerging Roles for SIRT5 in Metabolism and Cancer

“…com). BCL-XL, B cell lymphoma-XL; FOXO3A, forkhead box O3A; NRF2, nuclear factor erythroid-2-related factor 2. selectivity for SIRT5; the SIRT5 inhibitors, suramin, thiobarbiturates, NAM, cambinol, GW5074, and Ne-carboxyethylthiourea-lysine, have all demonstrated in vitro inhibition of other sirtuins at comparable potencies (21,30,32,62,87,90,97,109,114). By contrast, a SIRT5 target covalent inhibitor linked to a cyclic pentapeptide inhibited SIRT5 in vitro deacetylase activity at a 50% inhibitory concentration (IC50) of 7.5 lM and SIRT1/2/3/6 at IC 50 values between 200 and 1000 lM (52).…”

Insights on the Modulation of SIRT5 Activity: A Challenging Balance

“…Hence, the balance between its activation and inhibition should be carefully considered in the development of a SIRT5 modulator. Several new 9-substituted norharmane derivatives were studied by Yang and coworkers as SIRT5 inhibitors; the most active candidate, 58 (Figure 11), showed 35 and 52% inhibition at 30 µM and 100 µM, respectively [73]. This series was subsequently developed into a library of derivatives characterized by different linker bridges and phenyl substituents, which exhibited significant activities [74].…”

The deacylase SIRT5 supports melanoma viability by regulating chromatin dynamics

“…Since the phenotypes of Sirt5 null mice are quite mild, we propose that SIRT5 may represent an attractive new therapeutic target, in melanoma and specific other cancer types. In this regard, published studies (17, 91–94), including recent work focused on breast cancer (37) demonstrate that SIRT5 is in principle druggable with small molecules. SIRT5 dependency may be particularly translationally significant in uveal melanoma, where currently no effective therapeutic options exist for patients with metastatic disease.…”