Minor structural differences of monomethine cyanine derivatives yield strong variation in their interactions with DNA, RNA as well as on their in vitro antiproliferative activity.
Comparison of binding properties of a series of monomethine cyanine derivatives to ds-DNA and ds-RNA revealed significant impact of the properties of substituent attached to the longer axis of aromatic core. Namely, it seems that only compounds 7, 8 characterised by length of longer axis not exceeding the length of longer axis of basepairs could intercalate into ds-DNA and ds-RNA, while the increased substituent length and additional possibility of hydrogen bonds formation directed binding of 1-6 into ds-DNA minor groove. Consequent ds-RNA over ds-DNA selectivity of 7 and 8 is the most appealing and rather rare property among small molecules. The interactions of 1-8 with ss-RNA were strongly dependent on both, structure of compound and base composition of RNA. The cytotoxicity screening of compounds 1-8 by MTT test revealed considerable antiproliferative activity against solid tumours and especially toward haematological malignancies (IC(50)=0.001-6.6 microM), whereby normal human aortic endothelial cells (HAEC) were significantly less affected (IC(50)=1-200 microM). The cells of chronic myeloid leukaemia in blast crisis (K562) were especially sensitive to all tested compounds (IC(50)=0.001-0.6 microM), while normal lymphocytes were more resistant (IC(50)=0.01-1 microM). Results of uptake and intracellular distribution of compounds 1 and 2 in the living cells showed that they do not bind primarily to nuclear DNA but their fluorescence is scattered through the whole cells. A detailed mechanism of antitumor activity of tested molecules remains to be investigated.
Glavas-Obrovac
Ljubica
L
Department of Medical Chemistry and Biochemistry, School of Medicine, JJ Strossmayer University of Osijek, Osijek, Croatia. glavas-obrovac.ljubica@kbo.hr
Piantanida
Ivo
I
Marczi
Saska
S
Masić
Lozika
L
Timcheva
Iliana I
II
Deligeorgiev
Todor G
TG
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D052160:Benzothiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012313:RNA / Q000737:chemistry / Q000378:metabolism*; D012330:RNA, Double-Stranded / Q000737:chemistry / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D013696:Temperature; D017186:Titrimetry
D000970:Antineoplastic Agents; D052160:Benzothiazoles; D011743:Pyrimidines; D012330:RNA, Double-Stranded; D012313:RNA; D004247:DNA