Stereochemical 2D NMR Assignment of Thietane, Synthesis and Antiplatelet Activity of Novel Thietane-Containing 1-Isobutylpurine-2,6-dione Derivatives as Potential GPIIb/IIIa Inhibitors

Abstract

Abstract

1-Isobutylpurine-2,6-diones possess a broad spectrum of pharmacological activities, highlighting their relevance in the search for new biologically active agents. In this study, we report the synthesis of a series of novel thietane-containing 1-isobutylpurine-2,6-dione derivatives. A crucial aspect of this work is the detailed stereochemical and conformational analysis of the thietanyl substituent. For the first time, the unambiguous assignment of axial and equatorial protons within the thietane ring was achieved using 2D NMR spectroscopy, exemplified by a comprehensive study of the starting substance. Furthermore, the newly synthesized compounds were evalu-ated for their antiplatelet activity, revealing inhibition of platelet aggregation exceed-ing that of acetylsalicylic acid. Based on structural analogy to established antiplatelet agent, we hypothesize that the observed biological effect is mediated via the inhibition of the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor complex. These findings demonstrate that the incorporation of a thietane fragment into the 1-isobutylxanthine scaffold yields promising candidates for the development of novel GPIIb/IIIa-targeted an-tiplatelet therapeutics.