Sodji Quaovi H, Kornacki James R, McDonald John F, Mrksich Milan, Oyelere Adegboyega K
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA.
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA; Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.
Eur J Med Chem. 2015;96:340-59. doi: 10.1016/j.ejmech.2015.04.014. Epub 2015 Apr 8.
Histone deacetylase (HDAC) inhibition has recently emerged as a novel therapeutic approach for the treatment of various pathological conditions including cancer. Currently, two HDAC inhibitors (HDACi) – Vorinostat and Romidepsin – have been approved for the treatment of cutaneous T-cell lymphoma. However, HDACi remain ineffective against solid tumors and are associated with adverse events including cardiotoxicity. Targeted delivery may enhance the therapeutic indices of HDACi and enable them to be efficacious against solid tumors. We showed herein that morphing of folic and pteroic acids into the surface recognition group of HDACi results in hydroxamate and benzamide HDACi which derived tumor homing by targeting folate receptor (FR), a receptor commonly overexpressed in solid tumors. We observed a correlation between the potency of HDAC1 inhibition and cytotoxicity as only the potent pteroate hydroxamates, 11d and 11e, displayed antiproliferative activity against two representative FR-expression cancer cells. Our observation further supports the previous results which suggest that for a drug to be successfully targeted using the FR, it must be extremely potent against its primary target as the FR has a low delivery efficiency.
组蛋白去乙酰化酶（HDAC）抑制作用最近已成为治疗包括癌症在内的各种病理状况的一种新型治疗方法。目前，两种HDAC抑制剂（HDACi）——伏立诺他和罗米地辛——已被批准用于治疗皮肤T细胞淋巴瘤。然而，HDACi对实体瘤仍然无效，并且与包括心脏毒性在内的不良事件相关。靶向递送可能会提高HDACi的治疗指数，并使其对实体瘤有效。我们在此表明，将叶酸和蝶酸转化为HDACi的表面识别基团会产生异羟肟酸酯和苯甲酰胺HDACi，它们通过靶向叶酸受体（FR）实现肿瘤归巢，叶酸受体是实体瘤中通常过度表达的一种受体。我们观察到HDAC1抑制效力与细胞毒性之间存在相关性，因为只有强效的蝶酸异羟肟酸酯11d和11e对两种代表性的FR表达癌细胞显示出抗增殖活性。我们的观察结果进一步支持了先前的结果，这些结果表明，要使用FR成功靶向一种药物，它必须对其主要靶点具有极强的效力，因为FR的递送效率较低。
