Bruchelt Gernot, Klose Chihab, Lischka Matthias, Brandes Marietta, Handgretinger Rupert, Brueckner Reinhard
Children's University Hospital, Hoppe-Seyler-Str. 1, D-72076 Tuebingen, Germany.
Institute of Organic Chemistry, Albert-Ludwigs-University, Albertstr. 21, D-79104 Freiburg, Germany.
J Clin Med. 2023 Jul 3;12(13):4469. doi: 10.3390/jcm12134469.
The therapy of neuroblastoma relies, amongst other things, on administering chemotherapeutics and radioactive compounds, e.g., the (-iodobenzyl)guanidine [I]mIBG. For special applications (conditioning before stem cell transplantation), busulfan and melphalan (M) proved to be effective. However, both drugs are not used for normal chemotherapy in neuroblastoma because of their side effects. The alkylating drug melphalan contains a (Cl-CH-CH-)N- group in the -position of the phenyl moiety of the essential amino acid phenylalanine (Phe) and can, therefore, be taken up by virtually all kinds of cells by amino acid transporters. In contrast, mIBG isotopologs are taken up more selectively by neuroblastoma cells via the noradrenaline transporter (NAT). The present study aimed at synthesising and studying hybrid molecules of benzylguanidine (BG) and the alkylating motif of M. Such hybrids should combine the preferential uptake of BGs into neuroblastoma cells with the cytotoxicity of M. Besides the hybrid of BG with the dialkylating group (Cl-CH-CH-)N- bound in the -position as in M (pMBG), we also synthesised mMBG, which is BG -substituted by a (Cl-CH-CH-)N- group. Furthermore, two monoalkylating hybrid molecules were synthesised: the BG -substituted by a (Cl-CH-CH-)NH- group (pMBG) and the BG -substituted by a (Cl-CH-CH-)NH- group (mMBG). The effects of the four new compounds were studied with human neuroblastoma cell lines (SK-N-SH, Kelly, and LS) with regard to uptake, viability, and proliferation by standard test systems. The dialkylating hybrid molecules pMBG and mMBG were at least as effective as M, whereas the monoalkylating hybrid molecules pMBG and mMBG were more effective than M. Considering the preferred uptake via the noradrenaline transporter by neuroblastoma cells, we conclude that they might be well suited for therapy.
神经母细胞瘤的治疗方法包括使用化疗药物和放射性化合物，例如（-碘苄基）胍[I]mIBG。在特殊应用（干细胞移植前预处理）中，白消安和美法仑（M）已被证明是有效的。然而，由于这两种药物的副作用，它们并不用于神经母细胞瘤的常规化疗。烷基化药物美法仑在必需氨基酸苯丙氨酸（Phe）的苯基部分的α-位含有一个（Cl-CH-CH-）N-基团，因此几乎可以被所有类型的细胞通过氨基酸转运体摄取。相比之下，mIBG同位素类似物通过去甲肾上腺素转运体（NAT）被神经母细胞瘤细胞更有选择性地摄取。本研究旨在合成并研究苄基胍（BG）与M的烷基化基序的杂合分子。此类杂合体应将BG优先摄取到神经母细胞瘤细胞的特性与M的细胞毒性结合起来。除了BG与如M中那样在α-位结合的二烷基化基团（Cl-CH-CH-）N-的杂合体（pMBG）外，我们还合成了mMBG，它是被一个（Cl-CH-CH-）N-基团取代的BG。此外，还合成了两种单烷基化杂合分子：被一个（Cl-CH-CH-）NH-基团取代的BG（pMBG）和被一个（Cl-CH-CH-）NH-基团取代的BG（mMBG）。通过标准测试系统，研究了这四种新化合物对人神经母细胞瘤细胞系（SK-N-SH、Kelly和LS）在摄取、活力和增殖方面的影响。二烷基化杂合分子pMBG和mMBG至少与M一样有效，而单烷基化杂合分子pMBG和mMBG比M更有效。考虑到神经母细胞瘤细胞通过去甲肾上腺素转运体的优先摄取，我们得出结论，它们可能非常适合治疗。
