title: Synthesis and biological evaluation of new amino acid and dipeptide derivatives of neocryptolepine as anticancer agents.
abstract: The syntheses of neocryptolepine derivatives containing an amino acid or a dipeptide at the C-9 position and their evaluation for antitumor activity in vitro and in vivo are reported. To establish the influence of an amino acid or a peptide on the physicochemical properties of 5H-indolo[2,3-b]quinoline (DiMIQ), lipophilic and hemolytic properties were investigated. Most of the compounds displayed a high antiproliferative activity in vitro and strongly inhibited growth of tumor in mice compared to cyclophosphamide. The attachment of the hydrophilic amino acid or the peptide to the hydrophobic DiMIQ increased its hydrophilic properties and decreased its hemolytic activity. The glycylglycine conjugate (7a) was the most promising derivative. It strongly inhibited the growth of the tumor in mice (at dose 50 mg kg(-1) day(-1) it inhibited the tumor growth by 46-63% on days 11-16 and by 29-43% on days 18-23) and significantly decreased hemolytic activity and lowered the in vivo toxicity compared to DiMIQ.
authors.affiliation: Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warszawa, Poland. k.sidoryk@ifarm.eu
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Sidoryk
authors.forename: Marta
authors.initials: M
authors.lastname: Switalska
authors.forename: Joanna
authors.initials: J
authors.lastname: Wietrzyk
authors.forename: Anna
authors.initials: A
authors.lastname: Jaromin
authors.forename: Magdalena
authors.initials: M
authors.lastname: Piętka-Ottlik
authors.forename: Piotr
authors.initials: P
authors.lastname: Cmoch
authors.forename: Joanna
authors.initials: J
authors.lastname: Zagrodzka
authors.forename: Wojciech
authors.initials: W
authors.lastname: Szczepek
authors.forename: Lukasz
authors.initials: L
authors.lastname: Kaczmarek
authors.forename: Wanda
authors.initials: W
authors.lastname: Peczyńska-Czoch
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006461:Hemolysis; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D000596:Amino Acids; D000970:Antineoplastic Agents; D002243:Carbolines; D004151:Dipeptides; D011804:Quinolines; C414982:neocryptolepine; C055575:5,11-dimethyl-5H-indolo(2,3-b)quinoline