Benzimidazole derivatives related to 2,3-acrylonitriles, benzimidazo[1,2-a]quinolines and fluorenes: synthesis, antitumor evaluation in vitro and crystal structure determination.
A synthesis and biological evaluation of new benzimidazole derivatives, related to 2,3-disubstituted acrylonitriles, benzimidazo[1,2-a]quinoline-6-carbonitriles and heteroaromatic fluorenes was described. The molecular and crystal structures of three compounds 4, 16 and 17 reveal that non-fused fluoro derivative, 4, deviates from planarity by 13.11(2) degrees, while fused methyl, 16, and fluoro, 17, derivatives are planar within 4 degrees exhibiting a planar aromatic surface capable to intercalate into double-stranded DNA. Compound 4 exists as E-isomer. The crystal structures confirmed that hydrogen bonding patterns are characterized dominantly by the weak C-H...N(F) bonds, except in the case of 4 where the presence of ethanol molecule of crystallization resulted in the N-H...O and O-H...N hydrogen bonds formation. In the crystal structures of 16 and 17 cyano group participates in hydrogen bonding formation, while in 4 this is not the case. All compounds, except 16 and 14 exerted pronounced antiproliferative activity on five tumor cell lines, whereby 2-benzimidazolyl-3-N-methylpyrolyl-acrylonitrile 13 and its fused analogue 23 exerted the highest activity on all cell lines (IC50=0.8-30 microM) and showed a special selectivity toward HeLa cells. There is no major difference in the biological activity between non-fused and fused analogues. Similarly, all compounds showed significant interaction with ct-DNA, supporting the fact that their antitumor activity could partially be the consequence of DNA-binding. The cyano moiety is important for the activity, but not the selectivity of tested compounds.
Hranjec
Marijana
M
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, P.O. Box 177, HR-10000 Zagreb, Croatia. mhranjec@fkit.hr
Pavlović
Gordana
G
Marjanović
Marko
M
Kralj
Marijeta
M
Karminski-Zamola
Grace
G
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D005449:Fluorenes / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D009570:Nitriles / Q000737:chemistry; D011804:Quinolines / Q000737:chemistry
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D005449:Fluorenes; D009570:Nitriles; D011804:Quinolines; C041509:fluorene; D004247:DNA; C427203:calf thymus DNA