Person: ERDEM, SAFİYE
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ERDEM
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SAFİYE
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Publication Metadata only New horizon in phospha-michael reaction: Ultrafast double addition of P-H bond-bearing nucleophiles to alectron-deficient triple bonds and its use for functional monomer synthesis and polymer modification(2023-01-01) ÇAKMAKÇI, EMRAH; FINDIK, VOLKAN; ERDEM, SAFİYE; Sagdic G., Daglar O., ÇAKMAKÇI E., FINDIK V., ERDEM S., Tunca Ü., Günay U. S., Durmaz H.In this work, a novel, straightforward, robust, fast, and organocatalyst-mediated phospha-Michael reaction (OCPMR) was developed for the addition of phosphorus nucleophiles to electron-deficient alkynes. Several P-H bond-bearing compounds with either fully aliphatic or aromatic units were utilized for this newly developed reaction, and it was found that phosphorous species containing only aromatic groups reacted with activated alkynes within 5 min at room temperature. The reaction led to a fast double-addition of the phosphorous compounds to the triple bond of the alkynes. An in-depth analysis of the reaction mechanism and selectivity of this OCPMR was performed using computational methods. Using the developed method, double-phosphorylated allyl-functional monomers were synthesized and subsequently used for the synthesis of linear and crosslinked polymers via thiol-ene photopolymerization. The thermoset materials exhibited LOI values as high as 26.4%. We also showed that polyesters having electron-deficient triple bonds could be easily functionalized with the P-H bond-bearing compounds. The synthetic method proposed herein promises easy and fast P-C bond formation under mild reaction conditions, and it is a straightforward method for the synthesis of phosphorus-containing monomers, linear or crosslinked polymers, and for polymer post-functionalization. We believe this feature will be of great interest not only to material chemists and polymer scientists but also to organic chemists, pharmaceutical researchers, etc.Publication Metadata only Mechanistic Investigation of Lysine-Targeted Covalent Inhibition of PI3K delta via ONIOM QM:QM Computations(2022-08-01) ERDEM, SAFİYE; FINDIK, VOLKAN; FINDIK V., Gercik B. T. V. , Sinek O., ERDEM S., Ruiz-Lopez M. F.Phosphoinositide 3-kinase (PI3K) enzymes are important drug targets, especially in oncology, and several inhibitors are currently under investigation in clinical trials for the treatment of lymphocytic leukemia, follicular lymphoma, breast, thyroid, colorectal, and lung cancer. Targeted covalent inhibitors hold significant promise for drug discovery research especially for kinases. Targeting the lysine residues attracts attention as a new strategy in designing targeted covalent inhibitors, since the lysine residue provides several advantages over the traditional cysteine residue. Recently, new highly selective covalent inhibitors of PI3K delta with activated ester warheads, targeting the conserved Lys779 residue, were reported. Based on the observed kinetics, a covalent inhibition mechanism was proposed, but the atomistic details of the reaction are still not understood. Therefore, in the present work, we have conducted quantum chemical ONIOM M06-2X/6-31+G(d,p):PM6 calculations on the active site cluster structure of PI3K delta to elucidate the microscopic details of the mechanism of the aminolysis reaction between Lys779 and the ester inhibitors. Our calculations clearly discriminate the noncovalent methyl ester inhibitor and the covalent inhibitors with activated phenolic esters. For the representative p-NO2, p-F, p-H, and p-OCH3 phenolic esters, the Gibbs free energy profiles of alternative mechanistic paths through either Asp782 or Asp911 demonstrate the modulatory role of active site aspartate residues. The most plausible path alters depending on the electron-withdrawing/donating nature of the psubstituted phenolate leaving group. Inhibitors with sufficiently strong electron-withdrawing group prefer direct dissociation of the leaving group from the tetrahedral zwitterion intermediate, while the ones with electron-donating group favor the formation of a neutral tetrahedral intermediate prior to the dissociation. The relative Gibbs free energy barriers of p-NO2 < p- F < p-H < p-OCH3 substituted phenyl esters display the same qualitative trend as the experimentally measured k(inact)/K-1 values. Our results provide in depth insight into the mechanism, which can pave the way for optimizing the inhibitor efficiency.Publication Metadata only Advanced atomistic simulations on amine acetylation reaction in aqueous medium(2020-09-07) FINDIK, VOLKAN; ERDEM, SAFİYE; Fındık V., Erdem S., F. Ruiz-Lopez M.Publication Metadata only Theoretical study on lysine-targeting covalent inhibition mechanism in water and pi3kd enzyme(2022-06-21) ERDEM, SAFİYE; FINDIK, VOLKAN; Fındık V., Erdem S., F. Ruiz-Lopez M.