10 research outputs found
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
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 2âSelective 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
Synthesis and Evaluation of Substituted Chroman-4-one and Chromone Derivatives as Sirtuin 2âSelective 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 IC<sub>50</sub> of 1.5 ÎŒM. 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
Screen of Pseudopeptidic Inhibitors of Human Sirtuins 1â3: 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 1â3 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 G<sub>1</sub> phase
Slow-binding inhibitors of prolyl oligopeptidase with different functional groups at the P1 site
POP (prolyl oligopeptidase) specifically hydrolyses a number of small proline-containing peptides at the carboxy end of the proline residue and POP inhibitors have been shown to have cognition-enhancing properties. It has been noted that certain functional groups at the P1 site of the inhibitor, which correspond to the substrate residue on the N-terminal side of the bond to be cleaved, increase the inhibitory potency. However, detailed mechanistic and kinetic analysis of the inhibition has not been studied. In the present study, we examined the effect of different functional groups at the P1 site of the parent inhibitor isophthalic acid bis-(L-prolylpyrrolidine) amide on the binding kinetics to POP. Addition of CHO, CN or COCH(2)OH groups to the P1 site increased the inhibitory potency by two orders of magnitude (K(i)=11.8â0.1 nM) and caused a clear slow-binding inhibition. The inhibitor containing a CHO group had the lowest association rate constant, k(on)=(2.43±0.12)Ă10(5) M(â1)·s(â1), whereas the inhibitor with a CN group exhibited the fastest binding, k(on)=(12.0±0.08)Ă10(5) M(â1)·s(â1). In addition, the dissociation rate was found to be crucially dependent on the type of the functional group. Compounds with COCH(2)OH and CHO groups had much longer half-lives of dissociation (over 5 h) compared with the compound with the CN group (25 min), although the K(i) values of the compounds were relatively similar. A possibility to optimize the duration of inhibition by changing the functional group at the P1 site is important when planning therapeutically useful POP inhibitors
Chroman-4-one- and Chromone-Based Sirtuin 2 Inhibitors with Antiproliferative Properties in Cancer Cells
Peer reviewe