Interactions with polynucleotides and antitumor activity of amidino and imidazolinyl substituted 2-phenylbenzothiazole mesylates

• Improved water solubility of disubstituted 2-phenylbenzothiazole mesylate salts compared to hydrochloride salts.
• Binding mode: ds-RNA intercalation, ds-AT-DNA minor groove binding.
• Only amino-imidazolinyl 2-phenylbenzothiazole, 4b displayed dominant binding mode with polypurine sequences (ss-RNA).
• Moderate to high antiproliferative activity, in some cases dependent on a type of amidino group attached to aromatic moieties.
• Lower acute oral toxicities of disubstituted 2-phenylbenzothiazole mesylate salts compared to hydrochloride salts.

Based on previously reported antiproliferative activity screening, four most promising disubstituted 2-phenylbenzothiazole hydrochlorides were chosen for detailed study. Water solubility, as well as liphophilicity/hydrophilicity balance of organic core were modified by conversion to mesylate salts. For purpose of structure/activity studies their structures were determined by X-ray structure analysis. Detailed analysis of interactions of new compounds with double stranded (ds-) DNA/RNA by UV/Vis and CD titrations, thermal melting and viscometry experiments revealed that most of studied compounds intercalate into ds-RNA but bind into minor groove of AT-DNA, and agglomerate along GC-DNA. Furthermore, compounds also interact with ss-RNA, but only amino-imidazolinyl 2-phenylbenzothiazole, 4b displayed well defined orientation and dominant binding mode (by induced CD signals) with poly A and poly G. Besides, in vitro investigations revealed moderate to high antiproliferative activity of benzothiazoles against seven human cancer cell lines, while in some cases (HTC 116, SW620, MIA PaCa-2) high correlation between the type of the amidino group and cytotoxic activity was observed.

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