Pérez-Rodríguez Santiago, Ortiz Maria A, Pereira Raquel, Rodríguez-Barrios Fátima, de Lera Angel R, Piedrafita F Javier
Departamento de Química Orgánica, Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain.
Eur J Med Chem. 2009 Jun;44(6):2434-46. doi: 10.1016/j.ejmech.2009.01.011. Epub 2009 Jan 20.
Retinoid-related molecules with an adamantyl group (adamantyl arotinoids) have been described with selective activities towards the retinoid receptors as agonists for NR1B2 and NR1B3 (RARbeta,gamma) (CD437, MX3350-1) or RAR antagonists (MX781) that induce growth arrest and apoptosis in cancer cells. Since these molecules induce apoptosis independently of RAR transactivation, we set up to synthesize novel analogs with impaired RAR binding. Here we describe adamantyl arotinoids with 2,2'-disubstituted biaryl rings prepared using the Suzuki coupling of the corresponding fragments. Those with cinnamic and naphthoic acid end groups showed significant antiproliferative activity in several cancer cell lines, and this effect correlated with the induction of apoptosis as measured by caspase activity. Strikingly, some of these compounds, whereas devoid of RAR binding capacity, were able to activate RXR.
具有金刚烷基的类视黄醇相关分子（金刚烷类视黄酸）已被描述为对类视黄醇受体具有选择性活性，作为NR1B2和NR1B3（RARβ、γ）的激动剂（CD437、MX3350-1）或诱导癌细胞生长停滞和凋亡的RAR拮抗剂（MX781）。由于这些分子独立于RAR反式激活诱导凋亡，我们着手合成RAR结合受损的新型类似物。在此，我们描述了使用相应片段的铃木偶联制备的具有2,2'-二取代联芳基环的金刚烷类视黄酸。具有肉桂酸和萘甲酸端基的那些在几种癌细胞系中显示出显著的抗增殖活性，并且这种效应与通过半胱天冬酶活性测量的凋亡诱导相关。引人注目的是，这些化合物中的一些虽然缺乏RAR结合能力，但能够激活RXR。
