Discovery of oxazolo[4,5-b]pyridines and related heterocyclic analogs as novel SIRT1 activators

Bemis, Jean E.; Vu, Chi B.; Xie, Roger L.; Nunes, Joseph J.; Ng, Pui Yee; Disch, Jeremy S.; Milne, Jill C.; Carney, David P.; Lynch, Amy V.; Jin, Lei; Smith, J. Joshua; Lavu, Siva; Iffland, André; Jirousek, Michael R.; Perni, Robert B.

doi:10.1016/j.bmcl.2008.11.106

Cited by 86 publications

(65 citation statements)

References 12 publications

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“…Therefore, modulating the SIRT1 activities by small mol-ecules might serve as an effective therapeutic strategy toward the aforementioned diseases, and there has been great interest in finding SIRT1-activating compounds (STACs) (Baur 2010;Sinclair and Guarente 2014). Largescale screenings have yielded a number of possible STACs, among which is a class of polyphenol compounds, notably represented by resveratrol, an ingredient of red wine (Howitz et al 2003;Sauve et al 2005;Milne et al 2007;Bemis et al 2009). However, several studies questioned the effectiveness of resveratrol and related compounds as direct SIRT1 activators, pointing out that the observed stimulatory effect depended on the presence of a fluorescent group in the substrates used in in vitro assays (Borra et al 2005;Kaeberlein et al 2005;Pacholec et al 2010).…”

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Structural basis for allosteric, substrate-dependent stimulation of SIRT1 activity by resveratrol

et al. 2015

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Sirtuins with an extended N-terminal domain (NTD), represented by yeast Sir2 and human SIRT1, harbor intrinsic mechanisms for regulation of their NAD-dependent deacetylase activities. Elucidation of the regulatory mechanisms is crucial for understanding the biological functions of sirtuins and development of potential therapeutics. In particular, SIRT1 has emerged as an attractive therapeutic target, and the search for SIRT1-activating compounds (STACs) has been actively pursued. However, the effectiveness of a class of reported STACs (represented by resveratrol) as direct SIRT1 activators is under debate due to the complication involving the use of fluorogenic substrates in in vitro assays. Future efforts of SIRT1-based therapeutics necessitate the dissection of the molecular mechanism of SIRT1 stimulation. We solved the structure of SIRT1 in complex with resveratrol and a 7-amino-4-methylcoumarin (AMC)-containing peptide. The structure reveals the presence of three resveratrol molecules, two of which mediate the interaction between the AMC peptide and the NTD of SIRT1. The two NTD-bound resveratrol molecules are principally responsible for promoting tighter binding between SIRT1 and the peptide and the stimulation of SIRT1 activity. The structural information provides valuable insights into regulation of SIRT1 activity and should benefit the development of authentic SIRT1 activators.

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confidence: 99%

Structural basis for allosteric, substrate-dependent stimulation of SIRT1 activity by resveratrol

et al. 2015

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“…These heterocycles have shown different pharmacological activities such as anti-inflammatory, anti-pyretic, analgesic [1][2][3], and antifungal properties [4]. They can also act as inhibitor of fatty acid amide hydrolaze (FAAH) [5,6], inhibitors of monoterpenoidindole alkaloid production in Catharanthus roseus cells [7], inhibitors of acetylcholinesterase/butyrylcholinesterase [8], and SIRT1 activators [9].…”

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confidence: 99%

Facile microwave-assisted synthesis of 2-aryloxazolo[4,5-b]pyridines using SBA-Pr-NH2

et al. 2014

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In this work, amino-functionalized SBA-15 (SBA-Pr-NH 2 ) has been used as a basic nano-catalyst in the one-pot synthesis of 2-aryloxazolo [4,5-b]pyridines by the condensation reaction of 2-amino-3-hydroxypyridine and benzoyl chlorides under microwave irradiation in solvent free conditions. Among the advantages of this work are short reaction times, high yields and simple work-up. SBAPr-NH 2 as an efficient heterogeneous nanoporous solid basic catalyst which was prepared by silica functionalization with 3-aminopropyltriethoxysilane, can be easily removed from the reaction mixture by simple filtration, and also recovered and reused without noticeable loss of reactivity. 2-Aryloxazolo[4,5-b]pyridines have different pharmacological activities (anti-inflammatory, anti-pyretic, analgesic, antifungal). In the current method for the synthesis of 2-aryloxazolo [4,5-b]pyridines, no hazardous organic solvent was used and simplicity of the procedure provides significant improvements over many of other existing methods. Furthermore, the SBA-15-Pr-NH 2 with pore size of 6 nm can act as nano-reactor.

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“…Through high throughput screening of a large selection of small molecules, Milne et al identified three imidazothiazole derivatives as potent SIRT1 activators, which are structurally unrelated to but 1,000-fold more active than resveratrol. 7 Recently, in order to improve the potency as well as the solubility of the imidazothiazole derivatives, two different libraries of analogues, imidazo [1,2-b]thiazole 8 and oxazolo [4,5-b]pyridine, 9 were constructed and extensively investigated. The aim of the present study is to derive a predictive method for designing novel potent SIRT1 activators through construction of 3D QSAR models.…”

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confidence: 99%

“…For this purpose, from the literature, 8,9 SIRT1 activation data of 33 imidazothiazole and oxazolopyridine derivatives were obtained (Fig. 1).…”

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confidence: 99%

“…The reported EC 1.5 values (concentration of a compound required to increase the enzyme activity by 50%) of the training set as well as test set molecules 8,9 were converted into logEC1.5 to describe the potency. CoMFA and CoMSIA were set at standard values (with default grid spacing of 2.0 Å), with a sp 3 carbon atom with one positive charge used to probe steric and electrostatic fields.…”

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3D-QSAR of SIRT1 Activators Targeting Against Diet-Induced Metabolic Syndrome

Park

Choo³

et al. 2009

Bulletin of the Korean Chemical Society

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The prevalence of metabolic syndrome associated with increased risk for cardiovascular disease, type 2 diabetes, or cancer has been increasing over the past decade.1,2 While traditional drug discovery efforts have been tackling these diseases by aiming at individual targets, recent studies in humans have suggested the possibility that the collection of the metabolic degenerative processes can be approached as a whole by controlling diet, especially calorie restriction. Studies of calorie restriction in a broad range of animals including primates, mice, worms, and yeast have suggested that a reduction in calorie intake lengthens lifespan and protects against cancer and other age-related diseases.3-5 There has therefore been much interest in developing pharmacological agents that mimic the effects of calorie restriction. Resveratrol, a natural product derived from grapes, is the first reported mimetic of calorie restriction.6 Ever since the mode of action of resveratrol was elucidated to activate SIRT1 [sirtuin (silent mating type information regulation 2 homolog) 1] which, in turn, deacetylates p53 and promotes cell survival in a NAD + -dependent manner, 6 numerous efforts have been devoted to discover novel activators of SIRT1. Through high throughput screening of a large selection of small molecules, Milne et al. identified three imidazothiazole derivatives as potent SIRT1 activators, which are structurally unrelated to but 1,000-fold more active than resveratrol. 7 Recently, in order to improve the potency as well as the solubility of the imidazothiazole derivatives, two different libraries of analogues, imidazo[1,2-b]thiazole 8 and oxazolo [4,5-b]pyridine, 9 were constructed and extensively investigated. The aim of the present study is to derive a predictive method for designing novel potent SIRT1 activators through construction of 3D QSAR models.For this purpose, from the literature, 8,9 SIRT1 activation data of 33 imidazothiazole and oxazolopyridine derivatives were obtained (Fig. 1). At first, the 33 compounds were divided into two groups: 27 compounds as a training set and the other 6 compounds as a test set. The CoMFA 10,11 (comparative molecular force analysis) and CoMSIA 12,13 (comparative molecular similarity indices analysis) methods were employed for deriving 3D-QSAR models consisting for a training set of 27 imidazothiazole and oxazolopyridine derivatives, keeping in vitro activity as a dependent variable. The 3D-QSAR models were then validated using a test set of 6 compounds, which were not included in the development of the models. Finally, the contour plots of the 3D-QSAR model were analyzed to a These two authors contributed equally to this work provide helpful information on how to improve the potency of imidazothiazole as well as oxazolopyridine derivatives by structural modifications.Tripos standard CoMFA field was used for construction of a CoMFA model, whereas a CoMSIA model was built by using combinations of steric, electrostatic, hydrogen bond donor, hydrogen bond acceptor, and hydrophob...

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Discovery of oxazolo[4,5-b]pyridines and related heterocyclic analogs as novel SIRT1 activators

Cited by 86 publications

References 12 publications

Structural basis for allosteric, substrate-dependent stimulation of SIRT1 activity by resveratrol

Structural basis for allosteric, substrate-dependent stimulation of SIRT1 activity by resveratrol

Facile microwave-assisted synthesis of 2-aryloxazolo[4,5-b]pyridines using SBA-Pr-NH2

3D-QSAR of SIRT1 Activators Targeting Against Diet-Induced Metabolic Syndrome

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