Van Gelder J M, Breuer E, Ornoy A, Schlossman A, Patlas N, Golomb G
Department of Pharmacy, School of Pharmacy, Hebrew University of Jerusalem, Israel.
Bone. 1995 May;16(5):511-20. doi: 10.1016/8756-3282(95)00081-n.
Some geminal bisphosphonates are used clinically in a number of important bone and calcium-related diseases. This work reports the anticalcification and antiresorption effects of a series of bisacylphosphonates, nongeminal compounds with varying chain lengths having oxo groups in alpha positions relative to the phosphonic functions. We compared the activity of the novel compounds to clinically used geminal bisphosphonates, and to a bisphosphonate devoid of the oxo groups. The interaction of the compounds with calcium was studied by various in vitro and in vivo models. We found that keto groups in alpha positions to the phosphonic functions render activity. The bisacylphosphonates with a shorter chain [(CH2)n, = 4, 6] were found significantly to inhibit hydroxyapatite formation and dissolution in vitro, the calcification of bioprosthetic tissue implanted subdermally in rats, and bone resorption in the intact young animal model. The various in vitro results were found to be in good correlation with the in vivo results. Structure-activity relationship studies indicate that both bisacylphosphonates and geminal bisphosphonates are active only when at least three ionizable groups are present in the molecule. The role of the keto groups is related to their contribution to chelating calcium and/or to their electron-withdrawing influence on acidity.
一些偕二膦酸盐在临床上用于多种重要的骨骼和钙相关疾病。本研究报告了一系列双酰基膦酸盐（非偕二化合物，在相对于膦酸官能团的α位具有不同链长的羰基）的抗钙化和抗吸收作用。我们将这些新型化合物的活性与临床使用的偕二膦酸盐以及一种不含羰基的膦酸盐进行了比较。通过各种体外和体内模型研究了这些化合物与钙的相互作用。我们发现，相对于膦酸官能团处于α位的酮基赋予了活性。发现链较短的双酰基膦酸盐[（CH2）n，n = 4, 6]在体外能显著抑制羟基磷灰石的形成和溶解、大鼠皮下植入的生物假体组织的钙化以及完整幼龄动物模型中的骨吸收。各种体外结果与体内结果具有良好的相关性。构效关系研究表明，双酰基膦酸盐和偕二膦酸盐只有在分子中至少存在三个可电离基团时才具有活性。酮基的作用与其对螯合钙的贡献和/或其对酸度的吸电子影响有关。
