Cincinelli Raffaella, Musso Loana, Artali Roberto, Guglielmi Mario, Bianchino Erminia, Cardile Francesco, Colelli Fabiana, Pisano Claudio, Dallavalle Sabrina
Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università degli Studi di Milano, via Celoria 2, 20133 Milan, Italy.
Scientia Advice, di Roberto Artali, 20832 Desio, MB, Italy.
Eur J Med Chem. 2018 Jan 1;143:2005-2014. doi: 10.1016/j.ejmech.2017.11.021. Epub 2017 Nov 8.
Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of camptothecin derivatives and HDAC inhibitors. To exploit this synergy in a single active compound, we designed new dual-acting multivalent molecules simultaneously targeting topoisomerase I and HDAC. In particular, a selected compound containing a camptothecin and the psammaplin A scaffold showed a broad spectrum of antiproliferative activity, with IC values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability.
最近的研究表明，喜树碱衍生物与组蛋白去乙酰化酶（HDAC）抑制剂联合治疗具有增强的抗癌效果。为了在单一活性化合物中利用这种协同作用，我们设计了同时靶向拓扑异构酶I和HDAC的新型双功能多价分子。特别是，一种含有喜树碱和沙马普明A支架的选定化合物表现出广泛的抗增殖活性，IC值在纳摩尔范围内。初步体内实验结果表明，该化合物对原位移植于CD-1裸鼠的人恶性间皮瘤原代细胞系MM473具有很强的抗肿瘤活性，且耐受性非常高。
