Rapp Maryse, Giraud Isabelle, Maurizis Jean Claude, Madelmont Jean Claude
INSERM UMR 484, Rue Montalembert, BP 184, 63005 Clermont-Ferrand, Cedex, France.
Bioorg Med Chem. 2003 Nov 17;11(23):5007-12. doi: 10.1016/j.bmc.2003.09.006.
As a part of our targeting program based on the affinity of the quaternary ammonium moiety for cartilage, our objective was to develop more selective anticancer drugs towards chondrosarcoma that would concentrate in this malignant cartilaginous tissue and so improve the therapeutic index through a reduction of side effects. For this purpose we have synthesized and labeled with 14C a quaternary ammonium (QA) derivative of chlorambucil. Biological studies performed in rats showed that [14C]-CQA and [14C]-chlorambucil exhibited different pharmacokinetic profiles. The blood elimination of [14C]-CQA was faster than that of parent compound. [14C]-CQA was principally excreted by the fecal way. However, until 15 min after administration, levels of radioactivity were measured in cartilaginous tissues of rats given [14C]-CQA which was not the case for the rats which had received [14C]-chlorambucil. Although rates of radioactivity were quantified only during 15 min, these results prove that the functionalization of chlorambucil by a quaternary ammonium group allows the molecule to be carried selectively to cartilaginous tissues.
作为我们基于季铵部分对软骨的亲和力的靶向计划的一部分，我们的目标是开发对软骨肉瘤更具选择性的抗癌药物，这种药物将集中在这种恶性软骨组织中，从而通过减少副作用来提高治疗指数。为此，我们合成了苯丁酸氮芥的季铵（QA）衍生物并用14C进行了标记。在大鼠中进行的生物学研究表明，[14C]-CQA和[14C]-苯丁酸氮芥表现出不同的药代动力学特征。[14C]-CQA的血液消除速度比母体化合物快。[14C]-CQA主要通过粪便途径排泄。然而，在给药后15分钟内，给予[14C]-CQA的大鼠的软骨组织中检测到放射性水平，而接受[14C]-苯丁酸氮芥的大鼠则没有这种情况。尽管仅在15分钟内对放射性速率进行了定量，但这些结果证明苯丁酸氮芥通过季铵基团的功能化使分子能够选择性地转运到软骨组织。
