The synthesis of indolo[2,3-b]quinoline derivatives with a guanidine group: highly selective cytotoxic agents.
The synthesis of indolo[2,3-b]quinoline derivatives containing guanidine, amino acid or guanylamino acid substituents as well as their in vitro evaluation for the cytotoxic and antifungal activity are reported. The influence of the guanidine group on the selective cytotoxic and hemolytic properties of indolo[2,3-b]quinoline was investigated. Most of the compounds displayed a high cytotoxic activity in vitro and two of the most promising compounds (3 and 12) exhibited a high selectivity between normal and cancer cell-lines. The cytotoxic activity of compound 3 was about 600-fold lower against normal fibroblasts than against A549 and MCF-7 cancer cell lines. Novel entities acted as the DNA-intercalators when tested using a DNA-methyl green assay but demonstrated zero or low hemolytic activity in comparison to their unsubstituted analogs. The mechanism of action was studied for guanidine derivatives 3 and 12 and both compounds were found to be very effective inducers of apoptosis.
Pharmaceutical Research Institute, 8 Rydygiera St., 01-793 Warsaw, Poland. Electronic address: k.sidoryk@ifarm.eu.
Katarzyna
K
Sidoryk
Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Weigla St., 53-114 Wroclaw, Poland.
Marta
M
Świtalska
Department of Lipids and Liposomes, Faculty of Biotechnology, University of Wroclaw, 14A Joliot-Curie St., 50-383 Wroclaw, Poland.
Anna
A
Jaromin
Pharmaceutical Research Institute, 8 Rydygiera St., 01-793 Warsaw, Poland; Institute of Organic Chemistry, Polish Academy of Sciences, 44/52 Kasprzaka St., 01-224 Warsaw, Poland.
Piotr
P
Cmoch
Pharmaceutical Research Institute, 8 Rydygiera St., 01-793 Warsaw, Poland.
Iwona
I
Bujak
Pharmaceutical Research Institute, 8 Rydygiera St., 01-793 Warsaw, Poland.
Monika
M
Kaczmarska
Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Weigla St., 53-114 Wroclaw, Poland; Institute of Chemistry Environmental Protection and Biotechnology, Jan Długosz University, 13/15 Armii Krajowej Ave., 42-200 Częstochowa, Poland.
Joanna
J
Wietrzyk
Department of Medicine, Section of Infectious Diseases, 4125 Microbial Sciences Building, 1550 Linden Dr., University of Wisconsin-Madison, Madison, WI 53706, USA.
Eddie G
EG
Dominguez
Department of Medicine, Section of Infectious Diseases, 4125 Microbial Sciences Building, 1550 Linden Dr., University of Wisconsin-Madison, Madison, WI 53706, USA.
Robert
R
Żarnowski
Department of Medicine, Section of Infectious Diseases, 4125 Microbial Sciences Building, 1550 Linden Dr., University of Wisconsin-Madison, Madison, WI 53706, USA.
David R
DR
Andes
Pharmaceutical Research Institute, 8 Rydygiera St., 01-793 Warsaw, Poland.
Krzysztof
K
Bańkowski
Pharmaceutical Research Institute, 8 Rydygiera St., 01-793 Warsaw, Poland.
Marcin
M
Cybulski
Pharmaceutical Research Institute, 8 Rydygiera St., 01-793 Warsaw, Poland.
Łukasz
Ł
Kaczmarek
D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018441:Biofilms / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019791:Guanidine / Q000737:chemistry / Q000494:pharmacology*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009336:Necrosis / Q000188:drug therapy; D009369:Neoplasms / Q000473:pathology*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D007211:Indoles; D011804:Quinolines; C000609949:indolo(2,3-b)quinoline; D020169:Caspases; D019791:Guanidine
Antifungal activity; Antiproliferative activity; Apoptosis; Biofilm; Guanidine group; Hemolytic activity; Mechanism of action; Neocryptolepine