Dobrydneva Yuliya, Abelt Christopher J, Dovel Beth, Thadigiri Celina M, Williams Roy L, Blackmore Peter F
Department of Physiological Sciences, Eastern Virginia Medical School, P.O. Box 1980, Norfolk, VA 23501, USA.
Mol Pharmacol. 2006 Jan;69(1):247-56. doi: 10.1124/mol.105.015701. Epub 2005 Oct 7.
We have synthesized a series of 2-aminoethoxydiphenyl borate (2-APB, 2,2-diphenyl-1,3,2-oxazaborolidine) analogs and tested their ability to inhibit thrombin-induced Ca(2+) influx in human platelets. The analogs were either synthesized by adding various substituents to the oxazaborolidine ring (methyl, dimethyl, tert-butyl, phenyl, methyl phenyl, and pyridyl) or increasing the size of the oxazaborolidine ring to seven- and nine-membered rings. NMR analysis of the boron-containing analogs suggests that each of them exist as a ring structure through the formation of an N-->B coordinate bond (except for the hexyl analog). The possibility that these boron-containing compounds formed dimers was also considered. All compounds dose-dependently inhibited thrombin-induced Ca(2+) influx in human platelets, with the 2,2-diphenyl-1,3,2-oxazaborolidine-5-one derivative having the weakest activity at 100 microM, whereas the (S)-4-benzyl and (R)-4-benzyl derivatives of 2-APB were approximately 10 times more potent than the parent 2-APB. Two nonboron analogs (3-methyl and 3-tert-butyl 2,2-diphenyl-1,3-oxazolidine) were synthesized; they had approximately the same activity as 2-APB, and this implies that the presence of boron was not necessary for inhibitory activity. All of the compounds tested were also able to inhibit thrombin-induced calcium release. We concluded that extensive modifications of the oxazaborolidine ring in 2-APB can be made, and Ca(2+)-blocking activity was maintained.
我们合成了一系列2-氨基乙氧基二苯基硼酸酯（2-APB，2,2-二苯基-1,3,2-氧杂硼杂环戊烷）类似物，并测试了它们抑制凝血酶诱导的人血小板Ca(2+)内流的能力。这些类似物要么是通过在氧杂硼杂环戊烷环上添加各种取代基（甲基、二甲基、叔丁基、苯基、甲基苯基和吡啶基）合成的，要么是将氧杂硼杂环戊烷环扩大为七元环和九元环。对含硼类似物的核磁共振分析表明，除己基类似物外，它们均通过形成N→B配位键以环状结构存在。还考虑了这些含硼化合物形成二聚体的可能性。所有化合物均剂量依赖性地抑制凝血酶诱导的人血小板Ca(2+)内流，其中2,2-二苯基-1,3,2-氧杂硼杂环戊烷-5-酮衍生物在100 microM时活性最弱，而2-APB的(S)-4-苄基和(R)-4-苄基衍生物的活性比母体2-APB强约10倍。合成了两种非硼类似物（3-甲基和3-叔丁基2,2-二苯基-1,3-恶唑烷）；它们的活性与2-APB大致相同，这意味着硼的存在对于抑制活性并非必需。所有测试的化合物也都能够抑制凝血酶诱导的钙释放。我们得出结论，2-APB中的氧杂硼杂环戊烷环可以进行广泛修饰，并且Ca(2+)阻断活性得以维持。
