title: Could LogP be a principal determinant of biological activity in 18-crown-6 ethers? Synthesis of biologically active adamantane-substituted diaza-crowns.
abstract: 18-crown-6 ethers are known to exert their biological activity by transporting K(+) ions across cell membranes. Using non-linear Support Vector Machines regression, we searched for structural features that influence antiproliferative activity in a diverse set of 19 known oxa-, monoaza- and diaza-18-crown-6 ethers. Here, we show that the logP of the molecule is the most important molecular descriptor, among ∼1300 tested descriptors, in determining biological potency (R(2)(cv) = 0.704). The optimal logP was at 5.5 (Ghose-Crippen ALOGP estimate) while both higher and lower values were detrimental to biological potency. After controlling for logP, we found that the antiproliferative activity of the molecule was generally not affected by side chain length, molecular symmetry, or presence of side chain amide links. To validate this QSAR model, we synthesized six novel, highly lipophilic diaza-18-crown-6 derivatives with adamantane moieties attached to the side arms. These compounds have near-optimal logP values and consequently exhibit strong growth inhibition in various human cancer cell lines and a bacterial system. The bioactivities of different diaza-18-crown-6 analogs in Bacillus subtilis and cancer cells were correlated, suggesting conserved molecular features may be mediating the cytotoxic response. We conclude that relying primarily on the logP is a sensible strategy in preparing future 18-crown-6 analogs with optimized biological activity.
authors.affiliation: Division of Electronics, Ruđer Bošković Institute, Bijenička cesta 54, P.O. Box 180, HR-10002 Zagreb, Croatia.
authors.forename: Fran
authors.initials: F
authors.lastname: Supek
authors.forename: Tatjana Šumanovac
authors.initials: TŠ
authors.lastname: Ramljak
authors.forename: Marko
authors.initials: M
authors.lastname: Marjanović
authors.forename: Maja
authors.initials: M
authors.lastname: Buljubašić
authors.forename: Goran
authors.initials: G
authors.lastname: Kragol
authors.forename: Nataša
authors.initials: N
authors.lastname: Ilić
authors.forename: Tomislav
authors.initials: T
authors.lastname: Smuc
authors.forename: Davor
authors.initials: D
authors.lastname: Zahradka
authors.forename: Kata
authors.initials: K
authors.lastname: Mlinarić-Majerski
authors.forename: Marijeta
authors.initials: M
authors.lastname: Kralj
mesh_terms: D000218:Adamantane / Q000737:chemistry*; D000465:Algorithms; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects* / Q000254:growth & development; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D043844:Crown Ethers / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D004987:Ethers / Q000737:chemistry; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D021281:Quantitative Structure-Activity Relationship; D012984:Software; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D043844:Crown Ethers; D004987:Ethers; C015762:18-crown-6; D000218:Adamantane