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

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

Izvornik
European Journal of Medicinal Chemistry (0223-5234) 46 (2011), 8; 3444-3454

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
adamantane-substituted diaza-crowns; biological activity; Crown ethers; ionophores; Support Vector Machine

Sažetak
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 (R2cv=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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija, Temeljne medicinske znanosti

POVEZANOST RADA