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Interactions of 21 fentanyl derivatives with μ-opioid receptor (μOR) were studied using experimental and theoretical methods. Their binding to μOR was assessed with radioligand competitive binding assay. A uniform set of binding affinity data contains values for two novel and one previously uncharacterized derivative. The data confirms trends known so far and thanks to their uniformity, they facilitate further comparisons. In order to provide structural hypotheses explaining the experimental affinities, the complexes of the studied derivatives with μOR were modeled and subject to molecular dynamics simulations. Five common General Features (GFs) of fentanyls’ binding modes stemmed from these simulations. They include: GF1) the ionic interaction between D147 and the ligands’ piperidine NH+ moiety; GF2) the N-chain orientation towards the μOR interior; GF3) the other pole of ligands is directed towards the receptor outlet; GF4) the aromatic anilide ring penetrates the subpocket formed by TM3, TM4, ECL1 and ECL2; GF5) the 4-axial substituent (if present) is directed towards W318. Except for the ionic interaction with D147, the majority of fentanyl-μOR contacts is hydrophobic. Interestingly, it was possible to find nonlinear relationships between the binding affinity and the volume of the N-chain and/or anilide’s aromatic ring. This kind of relationships is consistent with the apolar character of interactions involved in ligand–receptor binding. The affinity reaches the optimum for medium size while it decreases for both large and small substituents. Additionally, a linear correlation between the volumes and the average dihedral angles of W293 and W133 was revealed by the molecular dynamics study. This seems particularly important, as the W293 residue is involved in the activation processes. Further, the Y326 (OH) and D147 (Cγ) distance found in the simulations also depends on the ligands’ size. In contrast, neither RMSF measures nor D114/Y336 hydrations show significant structure-based correlations. They also do not differentiate studied fentanyl derivatives. Eventually, none of 14 popular scoring functions yielded a significant correlation between the predicted and observed affinity data (R < 0.30, n = 28).

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Suzuki reaction of tribromo‐2,6‐lutidine with (2‐methoxyphenyl)boronic acid gave 3,4,5‐tris(2‐methoxyphenyl)‐2,6‐lutidine in the form of a mixture of three atropisomers that were stable at room temperature. Each isomer was isolated and fully characterized, including by X‐ray structure determination. One of the isomers, being a racemic mixture, was separated into individual enantiomers by using semipreparative chiral HPLC. Their absolute stereochemistry was initially assigned on the basis of computational calculation of the CD spectra and finally confirmed by X‐ray analysis.

We have developed a strategy for the stereoselective synthesis of cyclolignans related to podophyllotoxin and its derivatives. The crucial step of the synthesis is the photocyclization of a chiral atropoisomeric 1,2-bisbenzylidenesuccinate amide ester, which can be prepared from suitable aromatic aldehydes, diethyl succinate and l-prolinol. The photocyclization was found to be more efficient when irradiation was performed in a home-built continuous flow photochemical reactor. The in-flow irradiation also allowed us to perform the reaction on a multigram scale. The chiral auxiliary was removed by reductive cleavage with the Schwartz's reagent to give the cytotoxic 1R,2R-cis-podophyllic aldehyde, which in turn could be easily reduced to the corresponding alcohol, completing the formal synthesis of (-)-podophyllotoxin.

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Doxorubicin (DOX) is a leading cytostatic drug with many adverse effects in use. We are still looking for methods that will allow us to preserve the therapeutic effect against the tumor cells and reduce the toxicity to the normal cells. In our work, we obtained amide derivatives of DOX by reaction of the amino group with α-linolenic (LNA) and docosahexaenoic (DHA) acids (2, 3), as well as double-substituted derivatives via amide and ester linkages (4, 5). The structures of the compounds were confirmed by Proton Nuclear Magnetic Resonance (1H NMR), Carbon-13 Nuclear Magnetic Resonance (13C NMR), and High Resolution Mass Spectrometry (HRMS) analyses. For all compounds 3-(4,5-dimethylthiazolyl-2)-2,5diphenyltetrazolium bromide (MTT) assay was used to determine the cytotoxic effect on human cancer cell lines (SW480, SW620, and PC3) and Chinese hamster lung fibroblasts (V79) that were used as a control. The cytotoxic activity was established by calculation of the inhibitory concentration IC 50. In addition, a cytotoxic capacity against tumor cells for tested compounds was expressed as a selectivity factor (selectivity index, SI). Lactate dehydrogenase (LDH) assay was performed for all compounds to assess the level of cell damage. To explain the basic mechanism of cell death induction the Annexin V-FITC/IP flow cytometry analysis was investigated. We found that all studied conjugates exhibit lower cytotoxicity but higher selectivity than DOX. Among the all derivatives, the conjugates formed by the amide and ester linkages (4, 5) were found to be more promising compared with conjugates (2, 3) formed only by the amide linkage. They show high cytotoxicity toward the tumor cell lines and moderate cytotoxicity towards the normal cell line. Keywords Doxorubicin derivatives • Unsaturated fatty acids • Cytotoxicity • Apoptosis