Cincinelli Raffaella, Dallavalle Sabrina, Nannei Raffaella, Merlini Lucio, Penco Sergio, Giannini Giuseppe, Pisano Claudio, Vesci Loredana, Ferrara Fabiana Fosca, Zuco Valentina, Zanchi Chiara, Zunino Franco
Dipartimento di Scienze Molecolari Agroalimentari, Università di Milano, Via Celoria 2, 20133 Milano, Italy.
Bioorg Med Chem. 2007 Jul 15;15(14):4863-75. doi: 10.1016/j.bmc.2007.04.057. Epub 2007 May 3.
Atypical retinoids, or retinoid-related molecules (RRMs), represent a class of proapoptotic agents with a promising potential in the treatment of neoplastic diseases. In the present work, the synthesis and structure-activity relationship of a series of 3'-adamantan-1-yl-biphenyl-4-yl-acrylic acids substituted in ring A were studied. The synthesized compounds were evaluated for their antiproliferative activity in a human promyelocitic leukemia cell line (NB4), and in an ovarian carcinoma cell system including IGROV-1, carrying a functional wild-type p53, and a cisplatin-resistant subline, IGROV-1/Pt-1. The presence of at least one oxygenated substituent in positions 4' or 5' appears determinant for the antiproliferative activity. With two substituents of this kind the activity increases, particularly in the case of alkylenedioxy compounds. The activation of DNA damage response as indicated by phosphorylation of H2AX histone, RPA-2 protein, and p53 at serine 15 by the most apoptotic compounds provides additional support to the hypothesis that the genotoxic stress is a critical event mediating apoptosis induction by compounds of this group.
非典型类视黄醇或类视黄醇相关分子（RRMs）是一类促凋亡剂，在肿瘤疾病治疗方面具有广阔的应用前景。在本研究中，我们对一系列A环上有取代基的3'-金刚烷-1-基-联苯-4-基丙烯酸的合成及其构效关系进行了研究。对合成的化合物在人早幼粒细胞白血病细胞系（NB4）以及卵巢癌细胞系（包括携带功能性野生型p53的IGROV-1和顺铂耐药亚系IGROV-1/Pt-1）中进行了抗增殖活性评估。4'或5'位至少存在一个含氧取代基似乎是抗增殖活性的决定因素。有两个此类取代基时活性增强，尤其是在亚烷基二氧基化合物的情况下。最具凋亡活性的化合物使H2AX组蛋白、RPA-2蛋白和丝氨酸15位点的p53磷酸化，表明DNA损伤反应被激活，这为遗传毒性应激是介导该类化合物诱导凋亡的关键事件这一假说提供了额外支持。
