Stereoselective Synthesis of 4'-Selenopurine Nucleosides as Potential A3 Adenosine Receptor Ligands

Abstract

Adenosine is a naturally occurring nucleoside involved in a wide variety of physiological processes. Specially, A3 adenosine receptors play an important role in brain ischemia, immunosuppression and etc. Thus highly selective A3 adenosine receptor agonists and antagonists can be candidates for potential drugs. Among many compounds that have been synthesized for binding to this receptor, 2-Chloro-N6-(3-iodobenzyl)-thioadenosine-5'-methylcarboxamide (Thio-Cl-IB-MECA, 3) has been found to be one of the most selective agonist for rat adenosine A3 receptor. On the other hand, selenonucleoside is in the spotlight as a next generation nucleoside and the unusual conformation of 4'-Selenouridine was reported. On the basis of a bioisosteric rationale with thio-Cl-IB-MECA 3, 2-Chloro-N6-(3-iodobenzyl)-selenoadenosine-5'-methylcarboxamide (Seleno-Cl-IB-MECA, 4) was designed and synthesized from D-ribose. The stereoselective synthesis of 4'-selenoxide 17 and its successful conversion to the corresponding 4'-selenoribosyl acetate 21, followed by condensation with silylated base under Lewis acidic conditions, afforded the desired 23. Finally, the Seleno-Cl-IB-MECA 4 was obtained by selective deprotection, oxidation and coupling reactions. Also, the first synthesis of 2-chloro-N6-substituted-4'-selenopurine nucleosides 5-8 was successfully achieved.;Adenosine은 다양한 생리학적 작용을 할 수 있는 체내에서 자연적으로 만들어진 nucleoside이다. 특히, A3 수용체는 허혈성 뇌질환이나 면역억제를 비롯한 여러 질병과 관련하여 중요한 역할을 한다. 따라서 높은 선택성을 갖는 A3 Adenosine 수용체의 agonist와 antagonist는 약으로 개발 될 수 있는 중요한 후보물질이 될 수 있다. 지금까지 합성된 많은 화합물 중에 2-Chloro-N6-(3-(iodobenzyl)-thioadenosine-5'-methylcarboxamide (thio-Cl-IB-MECA, 3)은 rat A3 Adenosine 수용체에서 가장 높은 선택성을 나타낸 agonist이다. 한편, selenonucleosides는 차세대 nucleoside로 개발 중에 있으며 특히 4'-selenouridine의 특이한 구조적 특징이 보고되어 새로운 nucleoside로 각광받고 있다. 따라서 이러한 thio-Cl-IB-MECA와의 bioisosteric rationale에 기초하여 D-ribose로부터 중요 중간체인 4'-selenoribosyl acetate 21을 거쳐서 2-Chloro-N6-(3-(iodobenzyl)-selenoadenosine-5'-methylcarboxamide (seleno-Cl-IB-MECA, 4)이 기획되고 합성되었다. 또한, 2-Chloro-N6-substituted-4'-selenopurine nucleosides 5-8도 처음으로 성공적으로 합성되었다.