Discovery of new human Sirtuin 5 inhibitors by mimicking glutaryl-lysine substrates

Fan, Yun; Su, Huilin; Deng, Jieying; Mou, Luohe; Wang, Huali; Li, Rong; Dai, Qi-Shan; Yan, Yu‐Hang; Qian, Shan; Wang, Zhouyu; Li, Guobo; Yang, Lingling

doi:10.1016/j.ejmech.2021.113803

Cited by 15 publications

(48 citation statements)

References 34 publications

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“…The 3-thioureidopropanoic acid derivative 13e is the most potent and selective, with an IC 50 value of 3.0 μM and no activity toward SIRT1–3 or SIRT6 at 600 μM. 169 This molecule has been obtained in the context of a medicinal chemistry campaign aimed at finding glutaryl-lysine mimicking molecules. Unfortunately, no biological data have been provided, hence it is unclear whether this class of molecules may have any cellular effect and in which context they may be useful.…”

Section: Discussionmentioning

confidence: 99%

“…Another study identified SIRT5 inhibitors by joining a heteroaromatic ring to a 3-thioureidopropanoic acid warhead through an aminoethyl linker to mimic the interactions of ε- N -glutaryllysine within the SIRT5 active site. 169 Among the synthesized molecules, compounds 13a and 13b bearing a pyridine scaffold and a 2-benzylamino substitution, respectively, were about threefold less potent than compound 13c (IC 50 (desuccinylation) = 9.6 μM), where pyridine was replaced by pyrimidine ( Table 5 ). Starting from 13c , various modifications were performed to gain SAR information.…”

Section: Pharmacological Modulation Of Sirt5mentioning

confidence: 99%

“…Moreover, 13j may react with the cosubstrate NAD + to form a more stable ADP-ribose-1′-thioimidate intermediate. 169 …”

Section: Pharmacological Modulation Of Sirt5mentioning

confidence: 99%

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Therapeutic Potential and Activity Modulation of the Protein Lysine Deacylase Sirtuin 5

et al. 2022

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Sirtiun 5 (SIRT5) is a NAD + -dependent protein lysine deacylase primarily located in mitochondria. SIRT5 displays an affinity for negatively charged acyl groups and mainly catalyzes lysine deglutarylation, desuccinylation, and demalonylation while possessing weak deacetylase activity. SIRT5 substrates play crucial roles in metabolism and reactive oxygen species (ROS) detoxification, and SIRT5 activity is protective in neuronal and cardiac physiology. Moreover, SIRT5 exhibits a dichotomous role in cancer, acting as context-dependent tumor promoter or suppressor. Given its multifaceted activity, SIRT5 is a promising target in the design of activators or inhibitors that might act as therapeutics in many pathologies, including cancer, cardiovascular disorders, and neurodegeneration. To date, few cellular-active peptide-based SIRT5 inhibitors (SIRT5i) have been described, and potent and selective small-molecule SIRT5i have yet to be discovered. In this perspective, we provide an outline of SIRT5’s roles in different biological settings and describe SIRT5 modulators in terms of their mode of action, pharmacological activity, and structure–activity relationships.

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Section: Discussionmentioning

confidence: 99%

Section: Pharmacological Modulation Of Sirt5mentioning

confidence: 99%

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Therapeutic Potential and Activity Modulation of the Protein Lysine Deacylase Sirtuin 5

et al. 2022

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Section: Sirt5 Modulatorsmentioning

confidence: 99%

“…The same research group also synthesized some cyclic derivatives of 30, which are reported in the next section [52]. Recently, Yang et al prepared a series of 3-thioureidopropanoic acid derivatives mimicking glutaryl-lysine substrates [53]; among them, 31 (Figure 7) showed promising inhibitory activity and selectivity for SIRT5 (IC50 = 3.0 μM, SIRT1-3,6 IC50 > 600 μM) [53]. Among a series of compounds bearing the thiourea warhead reported by Rajabi et al, 32 (Figure 8) exhibited the most potent and selective SIRT5-inhibitory activity (IC50 = 0.11 μM) [54].…”

Section: Synthetic Compoundsmentioning

confidence: 99%

Insights on the Modulation of SIRT5 Activity: A Challenging Balance

et al. 2022

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SIRT5 is a member of the Sirtuin family, a class of deacetylating enzymes consisting of seven isoforms, involved in the regulation of several processes, including gene expression, metabolism, stress response, and aging. Considering that the anomalous activity of SIRT5 is linked to many pathological conditions, we present herein an overview of the most interesting modulators, with the aim of contributing to further development in this field.

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Ruthenium‐Catalyzed Pyridyl‐Directed C−H Allylation of Arenes with 1‐Aryl‐2‐vinylpyrrolidines

Yu,

Wang

2023

Asian J Org Chem

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The [Ru(p‐cymene)Cl2]2‐catalyzed reaction of 2‐arylpyridines with 1‐aryl‐2‐vinylpyrrolidines is carried out in CF3CH2OH at 40 °C in the presence of KOAc, affording ortho‐C‐H allylation products of arenes in 29% to 99% yields and 1:0.7 to 1:5.4 Z/E ratio. The amino groups remain in the product molecules. The protocol suits for a wide scope of substrates and tolerates functional groups including alkyl, aryl, MeO, F, Cl, Br, OCF3, and CF3 groups.

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Discovery of new human Sirtuin 5 inhibitors by mimicking glutaryl-lysine substrates

Cited by 15 publications

References 34 publications

Therapeutic Potential and Activity Modulation of the Protein Lysine Deacylase Sirtuin 5

Therapeutic Potential and Activity Modulation of the Protein Lysine Deacylase Sirtuin 5

Insights on the Modulation of SIRT5 Activity: A Challenging Balance

Ruthenium‐Catalyzed Pyridyl‐Directed C−H Allylation of Arenes with 1‐Aryl‐2‐vinylpyrrolidines

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