Sirtuin functions and modulation: from chemistry to the clinic

Sirtuins are NAD+ -dependent histone deacetylases regulating important metabolic pathways in prokaryotes and eukaryotes and are involved in many biological processes such as cell survival, senescence, proliferation, apoptosis, DNA repair, cell metabolism, and caloric restriction. The seven members of this family of enzymes are considered potential targets for the treatment of human pathologies including neurodegenerative diseases, cardiovascular diseases, and cancer. Furthermore, recent interest focusing on sirtuin modulators as epigenetic players in the regulation of fundamental biological pathways has prompted increased efforts to discover new small molecules able to modify sirtuin activity. Here, we review the role, mechanism of action, and biological function of the seven sirtuins, as well as their inhibitors and activators

A scaffold replacement approach towards new sirtuin 2 inhibitors

Sirtuins (SIRT1-SIRT7) are an evolutionary conserved family of NAD(+)-dependent protein deacylases regulating the acylation state of epsilon-N-lysine residues of proteins thereby controlling key biological processes. Numerous studies have found association of the aberrant enzymatic activity of SIRTs with various diseases like diabetes, cancer and neurodegenerative disorders. Previously, we have shown that substituted 2-alkyl-chroman-4-one/chromone derivatives can serve as selective inhibitors of SIRT2 possessing an antiproliferative effect in two human cancer cell lines. In this study, we have explored the bioisosteric replacement of the chroman-4-one/chromone core structure with different less lipophilic bicyclic scaffolds to overcome problems associated to poor physiochemical properties due to a highly lipophilic substitution pattern required for achieve a good inhibitory effect. Various new derivatives based on the quinolin-4(1H)-one scaffold, bicyclic secondary sulfonamides or saccharins were synthesized and evaluated for their SIRT inhibitory effect. Among the evaluated scaffolds, the benzothiadiazine-1,1-dioxide-based compounds showed the highest SIRT2 inhibitory activity. Molecular modeling studies gave insight into the binding mode of the new scaffold-replacement analogues.Peer reviewe

The knowledge processes framework and multiliteracies in upper secondary school English textbooks ENA 3 Cultural phenomena (LOPS2016), Insights course 3 and On track 3

Tässä pro gradu -tutkielmassa tutkin, kuinka monilukutaito ja erityisesti tietoprosessit (knowledge processes) on otettu huomioon uuden opetussuunnitelman mukaisissa lukion englannin kielen oppikirjoissa. Tutkimuksessa myös selvitetään, miten tietoprosessien viitekehys (KP framework) toimii lukion englannin oppimateriaalien tutkimuksessa. Tutkimuksen materiaalina ovat lukion uuden opetussuunnitelman mukaiset englannin kielen kurssikirjat: ENA 3 Cultural Phenomena (LOPS2016), Insights Course 3 ja On Track 3. Uusi opetussuunnitelma tuli voimaan Suomen lukioissa syksyllä 2016. Lukion opetussuunnitelman (LOPS) mukaan monilukutaitoa tulisi käsitellä kaikissa oppiaineissa. Koska englannin kielellä on tärkeä asema maailmankielenä, voidaan myös monilukutaitoa, taitoa tulkita ja analysoida tietoa eri muodoissa, ja sen opettamista pitää erityisen merkittävänä taitona opintoja ja elämää ajatellen. Tietoprosessien viitekehys voi auttaa sekä opettajaa että opiskelijaa ymmärtämään ja käsittelemään erilaisia tekstejä eri tavoin. Tutkimuksen ensimmäisessä osassa esitellään teoreettinen viitekehys, eli mitä monilukutaito tarkoittaa sekä selvitetään eri tietoprosessit (knowledge processes): tunnetun ja uuden kokeminen (experiencing the known and the new), nimeämällä ja teorian avulla konseptualisointi (conceptualising by naming and with theory), funktionaalinen ja kriittinen analysointi (analysing functionally and critically) ja asianmukaisesti ja luovasti soveltaminen (applying appropriately and critically). Lisäksi käsitellään opetussuunnitelmaa ja englannin opetusta lukiossa. Tutkimuksen toisessa osassa esitellään materiaali ja sekä analyysi siitä, miten eri tietoprosessit esiintyvät materiaalissa. Analyysissa käytetään kvalitatiivisia ja kvantitatiivisia tutkimusmenetelmiä. Tutkimuksen tulokset osoittavat, että kaikki tietoprosessit on otettu huomioon kaikissa uuden opetussuunnitelman mukaisissa englannin kielen tekstikirjoissa. Yleisimmät kategoriat kaikissa kirjoissa olivat uuden kokeminen ja nimeämällä konseptualisointi. Harvinaisimmat kategoriat kaikissa kirjoissa olivat teorian avulla konseptualisointi, kriittinen analysointi ja luovasti soveltaminen. Tuloksissa todetaan myös, että tietoprosessien viitekehys soveltuu oppimateriaalitutkimukseen

Screen of pseudopeptidic inhibitors of human sirtuins 1-3: Two lead compounds with antiproliferative effects in cancer cells

In the past few years sirtuins have gained growing attention for their involvement in many biological processes such as cellular metabolism, apoptosis, aging and inflammation. In this contribution, we report the synthesis of a library of thioacetylated pseudopeptides that were screened against human sirtuins 1-3 to reveal their in vitro inhibition activities. Molecular modeling studies were performed to acquire data about the binding modes of the inhibitors. Three sirtuin inhibitors were subjected to cellular studies, and all of them showed an increase in acetylation of Lys382 of p53 after DNA damage. Furthermore, two of the compounds were able to inhibit both A549 lung carcinoma and MCF-7 breast carcinoma cell growth in micromolar concentration with the ability to arrest cancer cell cycle in the G1 phase

Identification of the Binding Site of Chroman-4-one-Based Sirtuin 2‑Selective Inhibitors using Photoaffinity Labeling in Combination with Tandem Mass Spectrometry

Photoaffinity labeling (PAL) was used to identify the binding site of chroman-4-one-based SIRT2-selective inhibitors. The photoactive diazirine <b>4</b>, a potent SIRT2 inhibitor, was subjected to detailed photochemical characterization. In PAL experiments with SIRT2, a tryptic peptide originating from the covalent attachment of photoactivated <b>4</b> was identified. The peptide covers both the active site of SIRT2 and the proposed binding site of chroman-4-one-based inhibitors. A high-power LED was used as source for the monochromatic UV light enabling rapid photoactivation

Natural polyphenols as sirtuin 6 modulators

Abstract Flavonoids are polyphenolic secondary metabolites synthesized by plants and fungus with various pharmacological effects. Due to their plethora of biological activities, they have been studied extensively in drug development. They have been shown to modulate the activity of a NAD+-dependent histone deacetylase, SIRT6. Because SIRT6 has been implicated in longevity, metabolism, DNA-repair, and inflammatory response reduction, it is an interesting target in inflammatory and metabolic diseases as well as in cancer. Here we show, that flavonoids can alter SIRT6 activity in a structure dependent manner. Catechin derivatives with galloyl moiety displayed significant inhibition potency against SIRT6 at 10 µM concentration. The most potent SIRT6 activator, cyanidin, belonged to anthocyanidins, and produced a 55-fold increase in SIRT6 activity compared to the 3–10 fold increase for the others. Cyanidin also significantly increased SIRT6 expression in Caco-2 cells. Results from the docking studies indicated possible binding sites for the inhibitors and activators. Inhibitors likely bind in a manner that could disturb NAD+ binding. The putative activator binding site was found next to a loop near the acetylated peptide substrate binding site. In some cases, the activators changed the conformation of this loop suggesting that it may play a role in SIRT6 activation

Screen of Pseudopeptidic Inhibitors of Human Sirtuins 1–3: Two Lead Compounds with Antiproliferative Effects in Cancer Cells

In the past few years sirtuins have gained growing attention for their involvement in many biological processes such as cellular metabolism, apoptosis, aging and inflammation. In this contribution, we report the synthesis of a library of thioacetylated pseudopeptides that were screened against human sirtuins 1–3 to reveal their in vitro inhibition activities. Molecular modeling studies were performed to acquire data about the binding modes of the inhibitors. Three sirtuin inhibitors were subjected to cellular studies, and all of them showed an increase in acetylation of Lys382 of p53 after DNA damage. Furthermore, two of the compounds were able to inhibit both A549 lung carcinoma and MCF-7 breast carcinoma cell growth in micromolar concentration with the ability to arrest cancer cell cycle in the G₁ phase

Synthesis and Evaluation of Substituted Chroman-4-one and Chromone Derivatives as Sirtuin 2‑Selective Inhibitors

A series of substituted chromone/chroman-4-one derivatives has been synthesized and evaluated as novel inhibitors of SIRT2, an enzyme involved in aging-related diseases, e.g., neurodegenerative disorders. The analogues were efficiently synthesized in a one-step procedure including a base-mediated aldol condensation using microwave irradiation. The most potent compounds, with inhibitory concentrations in the low micromolar range, were substituted in the 2-, 6-, and 8-positions. Larger, electron-withdrawing substituents in the 6- and 8-positions were favorable. The most potent inhibitor of SIRT2 was 6,8-dibromo-2-pentylchroman-4-one with an IC₅₀ of 1.5 μM. The synthesized compounds show high selectivity toward SIRT2 over SIRT1 and SIRT3 and represent an important starting point for the development of novel SIRT2 inhibitors

Peptides and Pseudopeptides as SIRT6 Deacetylation Inhibitors

SIRT6 belongs to the family of histone deacetylases (class III), but it also has mono-ADP-ribosyltransferase activity. SIRT6 is a nuclear sirtuin that has been associated with aging, cellular protection, and sugar metabolism. Despite these important roles for SIRT6, thus far, there are only a few weak SIRT6 inhibitors available, and no structure–activity relationship (SAR) studies have been published. This is the first study concerning peptides and pseudopeptides as SIRT6 deacetylation inhibitors and the first SAR data concerning SIRT6. We also investigated the molecular interactions using a homology model. We report three compounds exhibiting 62–91% SIRT6 inhibition at 200 μM concentration. These compounds can serve as starting points for systematic SAR studies and SIRT6 inhibitor design