Abstract：
The most effective anticancer drugs currently entail substantial and formidable side effects, and resistance of tumors to chemotherapeutic agents is a further challenge. Thus, the search for new anticancer drugs as well as novel therapeutic methods is still extremely important. Non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit COX (cyclooxygenase), overexpressed in some tumors. Carboranes are emerging as promising pharmacophores. We have therefore combined both moieties in a single molecule to design drugs with a dual mode of action and enhanced effectiveness. The NSAIDs ibuprofen, flurbiprofen, and fenoprofen were connected with 1,2-dicarba-closo-dodecaborane(12) via methylene, ethylene or propylene spacers. Three sets of carborane-NSAID conjugates were synthesized and analyzed through multinuclear (1H, 11B, and 13C) NMR spectroscopy. Conjugates with methylene spacers exhibited the most potent COX inhibition potential, particularly conjugates with flurbiprofen and fenoprofen, displaying higher selectivity towards COX-1. Furthermore, conjugates with methylene and ethylene spacers were more efficient in suppressing the growth of human cancer cell lines than their propylene counterparts. The carborane-flurbiprofen conjugate with an ethylene spacer was the most efficient and selective toward the COX-2-negative cell line HCT116. Its mode of action was basically cytostatic with minor contribution of apoptotic cell death and dominance of cells trapped in the division process.
摘要：
目前最有效的抗癌药物会带来巨大的副作用，而肿瘤对化疗剂的抗性是另一个挑战。因此，寻找新的抗癌药物和新的治疗方法仍然非常重要。非甾体抗炎药（NSAIDs）可以抑制COX（环氧合酶），在一些肿瘤中过度表达。碳硼烷正在成为有希望的药效团。因此,我们将两个部分组合在单个分子中以设计具有双重作用模式和增强的有效性的药物。NSAIDs布洛芬，氟比洛芬,和非诺洛芬通过亚甲基与1,2-二溴氯十二硼烷（12）连接，乙烯或丙烯垫片。通过多核（1H，11B,和13C)NMR光谱。带有亚甲基间隔区的缀合物表现出最有效的COX抑制潜力，特别是与氟比洛芬和非诺洛芬的结合物，对COX-1显示更高的选择性。此外，与亚甲基和亚乙基间隔子的缀合物比它们的丙烯对应物更有效地抑制人类癌细胞系的生长。具有乙烯间隔物的碳硼烷-氟比洛芬缀合物对COX-2阴性细胞系HCT116是最有效和选择性的。它的作用方式基本上是细胞抑制的，对凋亡细胞死亡和分裂过程中捕获的细胞占主导地位的贡献很小。
