Could LogP be a principal determinant of biological activity in 18-crown-6 ethers? Synthesis of biologically active adamantane-substituted diaza-crowns

Supek, Fran; Ramljak, Tatjana Šumanovac; Marjanović, Marko; Buljubašić, Maja; Kragol, Goran; Ilić, Nataša; Šmuc, Tomislav; Zahradka, Davor; Mlinarić‐Majerski, Kata; Kralj, Marijeta

doi:10.1016/j.ejmech.2011.05.009

Cited by 28 publications

(29 citation statements)

References 39 publications

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“…Furthermore, Gram-positive Bacillus subtilis has been demonstrated to be in general more susceptible to different crown ether derivatives than E. coli. 4,14 Interestingly, the activity of compound 1p, the most active compound in the antiproliferative experiments, was about 4-fold lower against S. aureus based on comparison between the GI 50 and MIC 50 values ( Table 1, Table 3). On the other hand, compound 1o with MIC 50 of 7.2 µM against S. aureus was only moderately active against the cancer cells (GI 50 values in the range of 17-21 µM, Table 1).…”

Section: A R T I C L E I N F O Abstract Antiproliferativementioning

confidence: 99%

“…The side-chain length affects significantly the hydrophobicity of the compound, and thus calculated logP values for 1f and 1g are markedly different (1.46 and 4.63, respectively, Table 1). According to Supek et al, 14 logP of the molecule is the most important molecular descriptor in determining the biological activity of 18-crown-6 ethers, and not generally affected by features such as the side chain length or molecular symmetry. For our compounds, the calculated logP values vary from -0.96 to 4.63 ( Table 1).…”

Section: A R T I C L E I N F O Abstract Antiproliferativementioning

confidence: 99%

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Synthesis and biological evaluation of crown ether acyl derivatives

Febles

Montalvão

Crespín

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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A set of crown ethyl acyl derivatives based on 18-crown-6 moiety was synthesized and evaluated for biological activity. In vitro antiproliferative profiling demonstrated significant activities against HBL-100, HeLa, SW1573 and WiDr human cell lines. The most active compound exhibited GI values in the range of 3.7-5.6μM. Antimicrobial evaluation showed that three polyaromatic compounds were active against Staphylococcus aureus (MIC values from 8.3μM to 50μM), whereas a (decyloxy)benzene substitution exhibited moderate activity against Candida albicans (MIC values 36μM). According to SAR evaluation, the size of the crown ether and the acyl side chain had a significant effect on the bioactivity. Aromatic moieties close to the acyl group led to improved bioactivity as exemplified by some of the tested compounds. These results provide further evidence on the potential of crown ethyl structure as a scaffold for developing new biological probes and lead candidates for drug development.

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Section: A R T I C L E I N F O Abstract Antiproliferativementioning

confidence: 99%

Section: A R T I C L E I N F O Abstract Antiproliferativementioning

confidence: 99%

Synthesis and biological evaluation of crown ether acyl derivatives

Febles

Montalvão

Crespín

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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“…In results of the two models of Ki and EC 50 , Alog P and ε lumo have strongly correlated with these activities (65%‐82% and 17%‐27%, respectively). In this set of compounds, Alog P seems to be a primary determinant of these two activities taking into account that the high logP for given molecules can hinder their biological effects . Ghose et al showed that in the methods of analysis and prediction of Alog P and Clog P, the method of the latter is better for small molecules between 1 and 20 atoms, and, on the other hand, for molecules of about 45 atoms, the method of Alog P is much more accurate; the two methods are also comparable in intervals of 21‐45 atoms, but there is a caveat on the accuracy of this logP estimate despite the different prediction methods.…”

Section: Resultsmentioning

confidence: 99%

Molecular docking and two‐dimensional quantitative structure‐activity relationship studies of synthetic flavonoids on horseradish peroxidase compounds (I, II, and III)

Mahfoudi

Tahri

Djeridane

et al. 2018

J Biochem & Molecular Tox

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For the first time, the enzymatic inhibition activity of 13 synthetic flavonoids was assessed by quantitative structure-activity relationship (QSAR) modeling and molecular docking with the three states of the enzyme horseradish peroxidase (HRP). The results show that apigenin, quercetin, kaempferol, fisetin, tricetin, and luteolin exerted a high competitive inhibition on HRP (Ki between 0.14 and 1.74 mM) compared with other flavonoids. The QSAR model of enzymatic activity (R = 0.95, RMSE = 5.48) showed that Ghose-Crippen octanol-water partition coefficient (Alog P) and lowest unoccupied molecular orbital's energy (ε ) correlated with 0.65 and 0.17, respectively, with Ki values. According to the docking results using Molegro Virtual Docker program, all the flavonoids have shown great binding affinity towards peroxidase. Apigenin has the largest MolDock score in the three states of HRP noting an increased affinity of these flavonoids between compound I and compound II by 2.26%. However, these affinities strongly decrease between compound II and compound III by 28.43% especially for luteolin whose MolDock score decreased by 74.7%. With the results of docking, the affinities of the flavonoids tested and translated by their Ki values are much more presentative of the inhibition of the first reaction states of HRP because their inhibitory effect is important.

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“…LogP is an estimate of a compound’s overall lipophilicity, which contributes to solubility and permeability through biological membranes; there are some reports that logP is a determinant factor in the anticancer effects of some compounds [ 37 , 38 ]. Supek et al reported that the optimum logP of crown ether compounds is approximately at 5.5 for anticancer effects [ 38 ]. In the present study, logP values of our 3-ring mesogenic compounds showing cytotoxicity (C1–C5 and compounds with 4- or 5-carbon alkyl chains) ranged from 4.84 to 6.38 in NSCLC cells.…”

Section: Discussionmentioning

confidence: 99%

p53-independent structure-activity relationships of 3-ring mesogenic compounds’ activity as cytotoxic effects against human non-small cell lung cancer lines

et al. 2016

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BackgroundWe recently demonstrated the cytotoxicity of liquid crystal precursors (hereafter referred to as “mesogenic compounds”) in the human non-small cell lung cancer (NSCLC) cell line A549 which carry wild-type p53. p53 mutations are observed in 50 % of NSCLC and contribute to their resistance to chemotherapy. To develop more effective and cancer-specific agents, in this study, we investigated the structure–activity relationships of mesogenic compounds with cytotoxic effects against multiple NSCLC cells.MethodsThe pharmacological effects of mesogenic compounds were examined in human NSCLC cells (A549, LU99, EBC-1, and H1299) and normal WI-38 human fibroblast. Analyses of the cell cycle, cell-death induction, and capsases expression were performed.ResultsThe 3-ring compounds possessing terminal alkyl and hydroxyl groups (compounds C1–C5) showed cytotoxicity in NSCLC cells regardless of the p53 status. The compounds C1 and C3, which possess a pyrimidine at the center of the core, induced G2/M arrest, while the compounds without a pyrimidine (C2, C4, and C5) caused G1 arrest; all compounds produced caspase-mediated cell death. These events occurred in a p53-independent manner. Furthermore, it was suggested that compounds induced cell death through p53-independent DNA damage-signaling pathway. Compounds C2, C4, and C5 did not show strong cytotoxicity in WI-38 cells, whereas C1 and C3 did. However, the cytotoxicity of compound C1 against WI-38 cells was improved by modulating the terminal alkyl chain lengths of the compound.ConclusionsWe showed the p53-indepdent structure–activity relationships of mesogenic compounds related to the cytotoxic effects. These structure–activity relationships will be helpful in the development of more effective and cancer-specific agents.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2585-6) contains supplementary material, which is available to authorized users.

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Could LogP be a principal determinant of biological activity in 18-crown-6 ethers? Synthesis of biologically active adamantane-substituted diaza-crowns

Cited by 28 publications

References 39 publications

Synthesis and biological evaluation of crown ether acyl derivatives

Synthesis and biological evaluation of crown ether acyl derivatives

Molecular docking and two‐dimensional quantitative structure‐activity relationship studies of synthetic flavonoids on horseradish peroxidase compounds (I, II, and III)

p53-independent structure-activity relationships of 3-ring mesogenic compounds’ activity as cytotoxic effects against human non-small cell lung cancer lines

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