Antoszczak Michal, Maj Ewa, Kleczewska Natalia, Wietrzyk Joanna, Celewicz Lech, Huczynski Adam
Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland.
Med Chem. 2017;13(2):127-136. doi: 10.2174/1573406412666160823165522.
Pharmacophore hybridization by bioconjugation, in which two bioactive moieties are covalently linked, is one of the current strategies in drug discovery for the development of new compounds with improved affinity and efficacy relative to those of the parent molecules. Prompted by the idea that cancer cells may be effectively killed by 3'-azido-3'-deoxythymidine (AZT) and salinomycin (SAL) individually, we synthesized hybrids of these compounds. The development of this type of derivatives, which can easily penetrate the lipid-rich cell membranes and then undergo hydrolysis inside the cancer cells, is an important research area.
Efficient methods for the synthesis of two new conjugates are presented. The first method is based on the 'click' chemistry and involves the copper(I) catalysed 1,3-dipolar Huisgen cycloaddition reaction. In the second method AZT as well as SAL are connected by the ester bond under mild reaction conditions. The in vitro anti-proliferative activity of both conjugates against several drugsensitive and drug-resistant cancer cell lines as well as toxicity against normal murine embryonic fibroblasts are also determined.
Our studies clearly showed that the hybrid obtained via esterification reaction (SAL-OAZT) seems to be attractive in the fight against neoplastic diseases because it helps to overcome a strong drug-resistance of the cancer cell lines examined at low micromolar concentrations. The anticancer activity of this hybrid is also connected with high selectivity indexes (low toxicity) against normal cells.On the other hand, the 'click' conjugate (SAL-AZT) is practically inactive against the drug-resistant cancer cell lines tested and weakly active against the drug-sensitive ones. Also no synergistic effect has been found between SAL and AZT against eight cancer cell lines studied.
All of our findings support a strategy to decrease the doxorubicin concentration in combination with SAL-O-AZT hybrid in order to reduce the toxicity of this drug, as recently demonstrated for SAL. The advantages of the SAL-O-AZT conjugate over SAL are better RI and SI parameters at similar IC50values.
通过生物共轭进行药效团杂交，即将两个生物活性部分共价连接，是药物研发中当前的策略之一，用于开发相对于母体分子具有更高亲和力和疗效的新化合物。受3'-叠氮基-3'-脱氧胸苷（AZT）和沙利霉素（SAL）可分别有效杀死癌细胞这一想法的启发，我们合成了这些化合物的杂交体。这类能够轻松穿透富含脂质的细胞膜并随后在癌细胞内发生水解的衍生物的开发是一个重要的研究领域。
介绍了两种新共轭物的高效合成方法。第一种方法基于“点击”化学，涉及铜（I）催化的1,3 - 偶极胡伊斯根环加成反应。第二种方法是在温和反应条件下通过酯键连接AZT和SAL。还测定了两种共轭物对几种药敏和耐药癌细胞系的体外抗增殖活性以及对正常小鼠胚胎成纤维细胞的毒性。
我们的研究清楚地表明，通过酯化反应获得的杂交体（SAL - OAZT）在对抗肿瘤疾病方面似乎很有吸引力，因为它有助于在低微摩尔浓度下克服所检测癌细胞系的强大耐药性。这种杂交体的抗癌活性还与对正常细胞的高选择性指数（低毒性）相关。另一方面，“点击”共轭物（SAL - AZT）对所测试的耐药癌细胞系实际上无活性，对药敏细胞系活性较弱。在针对所研究的八种癌细胞系的实验中，SAL和AZT之间也未发现协同效应。
我们所有的研究结果都支持一种策略，即与SAL - O - AZT杂交体联合使用以降低阿霉素浓度，从而降低该药物的毒性，正如最近对SAL所证明的那样。在相似的IC50值下，SAL - O - AZT共轭物相对于SAL的优势在于更好的RI和SI参数。
