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

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• 作者：Ljubica Glavaš ; -Obrovac ; Ivo Piantanida ; Saš ; ka Marczi ; Lozika Maš ; ić ; Iliana I. Timcheva ; Todor G. Deligeorgiev
• 关键词：Monomethine cyanines ; DNA/RNA binding ; Cytotoxicity ; Human normal and tumour cells ; Cellular uptake
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2009
• 出版时间：1 July 2009
• 年：2009
• 卷：17
• 期：13
• 页码：4747-4755
• 全文大小：658 K

文摘

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 (IC₅₀ = 0.001–6.6 μM), whereby normal human aortic endothelial cells (HAEC) were significantly less affected (IC₅₀ = 1–200 μM). The cells of chronic myeloid leukaemia in blast crisis (K562) were especially sensitive to all tested compounds (IC₅₀ = 0.001–0.6 μM), while normal lymphocytes were more resistant (IC₅₀ = 0.01–1 μM). 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.