Binding properties and DNA sequence-specific recognition of two bithiazole-linked netropsin hybrid molecules

Abstract

We report the DNA binding properties of two hybrid molecules which result from the combination of the DNA sequence-specific minor groove ligand netropsin with the bithiazole moiety of the antitumor drug bleomycin. The drug-DNA interaction has been investigated by means of electric linear dichroism (ELD) spectroscopy and DNase I footprinting. In compound 1 the two moieties are linked by a flexible aliphatic tether while in compound 2 the two aromatic ring systems are directly coupled by a rigid peptide bond. The results are consistent with a model in which the netropsin moiety of compound 1 resides in the minor groove of DNA and where the appended bithiazole moiety is projected away from the DNA groove. This monocationic hybrid compound has a weak affinity for DNA and shows a strict preference for A and T stretches. ELD measurements indicate that in the presence of DNA compound 2 has an orientation typical of a minor groove binder. Similar orientation angles were measured for netropsin and compound 2. This ligand which has a biscationic nature tightly binds to DNA (Ka = 6.3 x 10(5) M-1) and is mainly an AT-specific groove binder. But, depending on the nature of the sequence flanking the AT site first targeted by its netropsin moiety, the bithiazole moiety of 2 can accommodate various types of nucleotide motifs with the exception of homooligomeric sequences. As evidenced by footprinting data, the bithiazole group of bleomycin acts as a DNA recognition element, offering opportunities to recognize GC bp-containing DNA sequences with apparently a preference (although not absolute) for a pyrimidine-G-pyrimidine motif. Thus, the bithiazole unit of bleomycin provides an additional anchor for DNA binding and is also capable of specifically recognizing particular DNA sequences when it is appended to a strongly sequence selective groove binding entity. Finally, a model which schematizes the binding of compound 2 to the sequence 5'-TATGC is proposed. This model readily explains the experimentally observed specificity of this netropsin-bithiazole conjugate.

DNA Minor Groove Binders: an Overview on Molecular Modeling and QSAR Approaches

“…In 1992 a paper was published which deals with studies on two hybrid molecules which posses the skeleton of the DNA sequencespecific minor groove ligand NTR linked to the bithiazole moiety of the antitumour drug bleomycin [51]. In 1992 a paper was published which deals with studies on two hybrid molecules which posses the skeleton of the DNA sequencespecific minor groove ligand NTR linked to the bithiazole moiety of the antitumour drug bleomycin [51].…”

Sequence-Specific DNA Minor Groove Binders. Design and Synthesis of Netropsin and Distamycin Analogues

“…The bithiazole moiety of the antitumor drug bleomycin has offered opportunities for binding to GC sites. The netropsin moiety of the conjugate 15 drives the drug to AT sites and allows the appended bithiazole unit to contact a pyrimidine-G-pyrimidine motif (94).…”

Structural basis of DNA duplex distortion induced by thiazole-containing hairpin polyamides

“…Expanding the heterocyclic repertoire of current hairpin polyamide designs offers a powerful alternative for broadening the dsDNA binding lexicon currently available and provides a means to optimize cell uptake by tuning their physicochemical parameters ( 44 – 51 ). Thiazole-4-carboxylic acids (Nt) ( 46 ) are attractive analogues of Im ( 52 ) building blocks in this regard as they contain endocyclic heteroatoms (S1 and N3), which are potential hydrogen-bond acceptors for the exocyclic N2 amine of G ( 50 , 51 , 53 – 55 ). Moreover, facile synthetic routes are available to prepare Nt analogues containing alkyl substituents in the 5-position, thereby allowing the hydrophobicity of these building blocks to be tuned accordingly ( 56 – 58 ).…”