Quantum-chemical study of enantiomerization of oxazepam

Oksazepam je aktivni metabolit najpropisivanijeg anksiolitika diazepama. Pri fiziološkim uvjetima pokazuje značajnu stereokemijsku nestabilnost, zbog čega je poznavanje mehanizma enantiomerizacije oksazepama izrazito važno. U literaturi su predložena četiri mehanizma enantiomerizacije. U ovome radu je kvantno-kemijskim izračunima provjerena njihova relevantnost. Najjednostavniji mehanizam uključuje deprotoniranje kiralnog centra i nastanak karbaniona, međutim, malo je vjerojatan zbog niske kiselosti C3-H skupine. Također je predložen mehanizam keto-enolne tautomerije, ali kinetičkim i termodinamičkim izračunima je utvrđeno da nije relevantan za opis enantiomerizacije oksazepama. Treći mehanizam uključuje protoniranje C3-OH skupine, dehidrataciju uz nastanak karbokationa te reverzibilnu hidrataciju. S obzirom da je C3-OH skupina najmanje bazičan položaj, ovaj mehanizam se ne smatra odgovornim za enantiomerizaciju. Izračunati parametri za četvrti mehanizam prsten-lanac tautomerije sukladni su eksperimentalno izmjerenoj energijskoj barijeri od 91 kJ/mol, a uključuje prijenos protona s C3-OH na N4 atom. Stoga je zaključeno da je, između predloženih mehanizama, prsten-lanac tautomerija jedini mogući mehanizam enantiomerizacije oksazepama.Oxazepam is an active metabolite of diazepam, the most prescribed anxiolytic drug. Under physiological conditions oxazepam displays extreme chiral instability so examination of reaction mechanism underlying the enantiomerization of oxazepam is very important. Four different mechanisms, possibly involved in this epimerization, were proposed in the literature. In this work, quantum-chemical models were used to search for all feasible reaction pathways. The most simple enantiomerization process corresponds to a deprotonation pathway in which the proton at the chiral C3-atom is eliminated and the carbanion intermediate is formed. The computational results exclude the C3-H/H exchange as a possible mechanism because the C3-carbanion is calculated as the least stable species. Keto-enol tautomerization is also suggested as possible mechanism. But, thermodynamic and kinetic calculations confirm that enolization is not reaction mechanism underlying the enantiomerization of oxazepam. The third mechanism includes the protonation of the C3-OH group followed by the elimination of water. The resulting carbocation intermediate undergoes reversible hydration. The protonation of C3-OH group resulted in the least stable protonated species so this mechanism is not operative in stereochemical instability of oxazepam. The fourth mechanism which include the intramolecular proton transfer from the C3-OH to the imine N4 atom, fits within the targeted barrier limit (ΔG‡ < 91 kJ/mol) set by experiments. According to computational results, the enantiomerization of oxazepam follows the mechanism of the ring-chain tautomerism. No other mechanism, suggested earlier in the literature, matches the experimental data in terms of Gibbs free energy

The Effect of Deuteration on the H2 Receptor Histamine Binding Profile: A Computational Insight into Modified Hydrogen Bonding Interactions

We used a range of computational techniques to reveal an increased histamine affinity for its H2 receptor upon deuteration, which was interpreted through altered hydrogen bonding interactions within the receptor and the aqueous environment preceding the binding. Molecular docking identified the area between third and fifth transmembrane α-helices as the likely binding pocket for several histamine poses, with the most favorable binding energy of −7.4 kcal mol−1 closely matching the experimental value of −5.9 kcal mol−1. The subsequent molecular dynamics simulation and MM-GBSA analysis recognized Asp98 as the most dominant residue, accounting for 40% of the total binding energy, established through a persistent hydrogen bonding with the histamine −NH3+ group, the latter further held in place through the N–H∙∙∙O hydrogen bonding with Tyr250. Unlike earlier literature proposals, the important role of Thr190 is not evident in hydrogen bonds through its −OH group, but rather in the C–H∙∙∙π contacts with the imidazole ring, while its former moiety is constantly engaged in the hydrogen bonding with Asp186. Lastly, quantum-chemical calculations within the receptor cluster model and utilizing the empirical quantization of the ionizable X–H bonds (X = N, O, S), supported the deuteration- induced affinity increase, with the calculated difference in the binding free energy of −0.85 kcal mol−1, being in excellent agreement with an experimental value of −0.75 kcal mol−1, thus confirming the relevance of hydrogen bonding for the H2 receptor activation

From Hydrogen Peroxide-Responsive Boronated Nucleosides Towards Antisense Therapeutics – A Computational Mechanistic Study

We used a combination of MD simulations and DFT calculations to reveal the precise chemical mechanism underlying the conversion of boronated nucleosides to natural nucleosides in the presence of hydrogen peroxide, which was recently experimentally demonstrated by Morihiro and Obika et al. (Chem. Sci. 2018, 9, 1112). Our results show that this process is initiated by the H2O2 deprotonation to a base concerted with the nucleophilic attack of the resulting OOH– anion onto the boron atom as the rate-limiting step of the overall transformation. This liberates a free base, followed by the 1,2-rearrangement to the C–OOH– adduct. Lastly, breaking of the O–O bond within the peroxide moiety cleaves the boron–carbon bond, giving boronic acid ester and the matching ketone as the final products. The obtained reaction profiles successfully interpret a much higher conversion rate of the thymine derivative over its guanine analogue, and rationalize why t-Bu-hydroperoxide is hindering the conversion, thus placing both aspects in firm agreement with experiments. The offered insight represents a promising tool for the future synthetic approaches of stimuli-responsive biomolecules, especially chemically caged prodrug-type nucleic acid therapeutics, bearing significant importance due to their application potential in diagnostics and therapy of various genetic disorders. This work is licensed under a Creative Commons Attribution 4.0 International License

Farmaceutski značaj procesa stereoizomerizacije

Proučavanje procesa stereoizomerizacije od iznimne je važnosti u farmaceutskoj kemiji i biomedicini. Različiti izomeri mogu pokazivati značajne razlike u interakciji s biološkim makromolekulama, što može dovesti do razlika i u njihovim farmakokinetičkim i farmakodinamičkim svojstvima te, u konačnici, u terapijskim i neželjenim učincima. Iako postoji velik broj primjera koji svjedoče o važnosti stereokemije, u ovome radu dan je pregled nekoliko najznačajnijih i najreprezentativnijih slučajeva u farmaciji

Synthesis, Computational Analysis, and Antiproliferative Activity of Novel Benzimidazole Acrylonitriles as Tubulin Polymerization Inhibitors: Part 2

We used classical linear and microwave-assisted synthesis methods to prepare novel Nsubstituted, benzimidazole-derived acrylonitriles with antiproliferative activity against several cancer cells in vitro. The most potent systems showed pronounced activity against all tested hematological cancer cell lines, with favorable selectivity towards normal cells. The selection of lead compounds was also tested in vitro for tubulin polymerization inhibition as a possible mechanism of biological action. A combination of docking and molecular dynamics simulations confirmed the suitability of the employed organic skeleton for the design of antitumor drugs and demonstrated that their biological activity relies on binding to the colchicine binding site in tubulin. In addition, it also underlined that higher tubulin affinities are linked with (i) bulkier alkyl and aryl moieties on the benzimidazole nitrogen and (ii) electron-donating substituents on the phenyl group that allow deeper entrance into the hydrophobic pocket within the tubulin’s -subunit, consisting of Leu255, Leu248, Met259, Ala354, and Ile378 residues

Experimental and Computational Study of the Antioxidative Potential of Novel Nitro and Amino Substituted Benzimidazole/Benzothiazole-2- Carboxamides with Antiproliferative Activity

We present the synthesis of a range of benzimidazole/benzothiazole-2-carboxamides with a variable number of methoxy and hydroxy groups, substituted with nitro, amino, or amino protonated moieties, which were evaluated for their antiproliferative activity in vitro and the antioxidant capacity. Antiproliferative features were tested on three human cancer cells, while the antioxidative activity was measured using 1, 1- diphenyl-picrylhydrazyl (DPPH) free radical scavenging and ferric reducing/antioxidant power (FRAP) assays . Trimethoxy substituted benzimidazole-2-carboxamide 8 showed the most promising antiproliferative activity (IC50 = 0.6– 2.0 µM), while trihydroxy substituted benzothiazole-2-carboxamide 29 was identified as the most promising antioxidant, being significantly more potent than the reference butylated hydroxytoluene BHT in both assays. Moreover, the latter also displays antioxidative activity in tumor cells. The measured antioxidative capacities were rationalized through density functional theory (DFT) calculations, showing that 29 owes its activity to the formation of two [O•∙∙∙H–O] hydrogen bonds in the formed radical. Systems 8 and 29 were both chosen as lead compounds for further optimization of the benzazole-2-carboxamide scaffold in order to develop more efficient antioxidants and/or systems with the antiproliferative activit