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

Abstract

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.

Sirtuin Inhibitors as Anticancer Agents

“…One N-thioacetyllysine-containing small molecule (Table 2, entry 3) showed selective SIRT1-inhibitory activity and caused a dose-dependent increase in p53 acetylation in human colon cancer HCT116 cells [107]. Structure-based computational design approach was performed in the design of N-thioacetyllysine containing pseudopeptidic inhibitors [108,109]. Three inhibitors (Table 2, entries 4–6) were picked out from a library of 30 thioacetyl pseudopeptides for further cellular studies.…”

The Discovery of a Highly Selective 5,6,7,8‐Tetrahydrobenzo[4,5]thieno[2,3‐d]pyrimidin‐4(3H)‐one SIRT2 Inhibitor that is Neuroprotective in an in vitro Parkinson’s Disease Model

“…[29] These include the physiological inhibitor nicotinamide (1), [30] the 2-hydroxy-naphthaldehyde derivatives sirtinol (2), [31] cambinol [32] and salermide (3), [33] AGK2 (4), [28,34] AK-7 (5) [35] and its analogous 3-(N-arylsulfamoyl)benzamide derivatives, [36] the natural dilactone tanikolide dimer (6), [37] splitomicin derivatives, [38,39] suramin, [40] NAD + derivatives, [41] 3'-phenethyloxy-2-anilinobenzamide analogues (7), [42] our previously identified 10,11-dihydro-5H-dibenz[b,f]azepine derivative 8, [43] thieno[3,2-d]pyrimidine-6-carboxamides (9), [44] thioacetylated pseudopeptides, [45] and a variety of recently discovered inhibitors. [46][47][48][49] There are still a number of significant challenges in the development of SIRT inhibitors however.…”

Quantitative insights for the design of substrate-based SIRT1 inhibitors

“…The purity of the compounds was determined by Elemental analysis obtained with Thermo Quest CE Instruments EA 1110 CHNS-O elemental analyzer and the analytical results are within ±0.40% of the theoretical values (see Supplementary Information). Compounds 1, 2, 3, 7, 8 and 19 were synthesized as previously reported by Huhtiniemi et al (2010Huhtiniemi et al ( , 2011 and Mellini et al (2013). The overview of synthetic procedures is shown in Scheme 1.…”

“…Later on, the mechanism of inhibition was revealed to be due to a formation of a stalled S-alkylamidate intermediate (Hawse et al, 2008). We have previously reported SIRT1 selective peptidic inhibitors, studied different lysine N e -modifications and developed many N e -thioacetylated inhibitors, some of them with antiproliferative properties in breast and lung cancer cell lines (Huhtiniemi et al, 2010(Huhtiniemi et al, , 2011Kiviranta et al, 2009;Mellini et al, 2013 The large number of developed substrate-based inhibitors prompted us to conduct a 3D quantitative structure-activity relationship (QSAR) study that can be used in the prediction of inhibitory activity of new inhibitors. 3D QSAR connects the activity with the properties of the whole molecule instead of individual substituents, which gives a better understanding of the chemical and structural features affecting the inhibitory activity.…”

“…1) and built a CoMFA model validating it with an external test set (Huhtiniemi et al, 2010(Huhtiniemi et al, , 2011Kiviranta et al, 2009;Mellini et al, 2013). The inhibitory activities of these compounds have been previously determined with the same procedure in our laboratory, which makes the comparison of the activities reliable.…”