Alkylation of phosphorothioated thrombin binding aptamers improves the selectivity of inhibition of tumor cell proliferation upon anticoagulation

• Published in: Biochimica et biophysica acta. General subjects Vol. 1861; no. 7; pp. 1864 - 1869
• Main Authors: Yang, Xiantao, Zhu, Yuejie, Wang, Chao, Guan, Zhu, Zhang, Lihe, Yang, Zhenjun
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2017
• Subjects: adverse effects; Alkylation; Anticoagulants - pharmacology; antineoplastic activity; antineoplastic agents; Antineoplastic Agents - pharmacology; Antitumor; Aptamers, Nucleotide - metabolism; Aptamers, Nucleotide - pharmacology; blood coagulation; Cell Line, Tumor; cell proliferation; Cell Proliferation - drug effects; Circular Dichroism; circular dichroism spectroscopy; DNA; Humans; neoplasm cells; oligonucleotides; Selectivity; Surface Plasmon Resonance; systematic evolution of ligands by exponential enrichment; therapeutics; thrombin; Thrombin - metabolism; Thrombin binding aptamer; Thrombin binding aptamer; Selectivity; Alkylation; Antitumor
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2017.04.002

Recently, aptamers have been extensively researched for therapy and diagnostic applications. Thrombin-binding aptamer is a 15nt deoxyribonucleic acid screened by SELEX, it can specifically bind to thrombin and inhibit blood coagulation. Since it is also endowed with excellent antitumor activity, the intrinsic anticoagulation advantage converted to a main potential side effect for its further application in antiproliferative therapy. Site-specific alkylation was conducted through nucleophilic reaction of phosphorothioated TBAs using bromide reagents. Circular dichroism (CD) spectroscopy and surface plasmon resonance (SPR) measurements were used to evaluate anticoagulation activity, and a CCK-8 assay was used to determine cell proliferation activity. The CD spectra of the modified TBAs were weakened, and their affinity for thrombin was dramatically reduced, as reflected by the KD values. On the other hand, their inhibition of A549 cells was retained. Incorporation of different alkyls apparently disrupted the binding of TBA to thrombin while maintaining the antitumor activity. A new modification strategy was established for the use of TBA as a more selective antitumor agent. [Display omitted] •Four kinds of alkylated TBAs were synthesized for the first time.•Incorporation of different alkyl groups apparently disturbed the binding to thrombin.•The antitumor activity of alkylated TBAs upon A549 cell was maintained.