title: Membrane perturbations induced by new analogs of neocryptolepine.
abstract: Indoloquinoline alkaloids represent an important class of antimalarial, antibacterial and antiviral compounds. Indolo[2,3-b]quinolines are a family of DNA intercalators and inhibitors of topoisomerase II, synthetic analogs of neocryptolepine, an alkaloid traditionally used in African folk medicine. These cytotoxic substances are promising anticancer agents. Active representatives of indolo[2,3-b]quinolines affect model and natural membranes. The distinct structure and hydrophobicity of the compounds leads to marked differences in the disturbing effects on membrane organization and function. Our results also indicated a strong relationship between the presence of the chain and the Poct of the molecule as well as the capacity for incorporation into carboxyfluorescein-trapped liposomes in the 0.02-0.06 mM range. Moreover, a correlation between binding to neutral dimyristoylphosphatidylcholine (DMPC) or negative charged dimyristoylphosphatidylcholine:dimyristoylphosphatidylglycerol (DMPC:DMPG, 9:1 w/w) liposomes, as well as to erythrocyte ghosts and pKa, was also found. All the compounds cause hemolysis in isotonic conditions with concentration causing 50% hemolysis (HC50) in the 0.12-0.88 mM range. The concentration-dependent inhibitory effect of the tested agents on erythrocyte ghosts' acetylcholinesterase activity was also studied.
authors.affiliation: Department of Lipids and Liposomes, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland. ajaromin@ibmb.uni.wroc.pl
authors.forename: Anna
authors.initials: A
authors.lastname: Jaromin
authors.forename: Mariola
authors.initials: M
authors.lastname: Korycińska
authors.forename: Magdalena
authors.initials: M
authors.lastname: Piętka-Ottlik
authors.forename: Witold
authors.initials: W
authors.lastname: Musiał
authors.forename: Wanda
authors.initials: W
authors.lastname: Peczyńska-Czoch
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Kaczmarek
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Kozubek
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D031106:Cryptolepis / Q000737:chemistry*; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects*; D057927:Hydrophobic and Hydrophilic Interactions; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology; D008081:Liposomes; D016488:Medicine, African Traditional; D010715:Phosphatidylglycerols / Q000737:chemistry; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D012756:Sheep; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D007364:Intercalating Agents; D008081:Liposomes; D010715:Phosphatidylglycerols; D010936:Plant Extracts; D011804:Quinolines; D059005:Topoisomerase II Inhibitors; C414982:neocryptolepine; C002773:dimyristoylphosphatidylglycerol; D000110:Acetylcholinesterase; D004134:Dimyristoylphosphatidylcholine