Department of Chemistry and Institute of Chemical Biology & Drug Discovery, State University of New York at Stony Brook, Stony Brook, New York 11794-3400, USA.
J Nat Prod. 2009 Mar 27;72(3):554-65. doi: 10.1021/np8006556.
Among the numerous chemotherapeutic drugs, paclitaxel and docetaxel are among the most widely used against various types of cancer. However, these drugs cause undesirable side effects as well as drug resistance. Therefore, it is essential to develop "taxane" anticancer agents with better pharmacological properties and improved activity especially against drug-resistant cancers. Several laboratories have performed extensive SAR studies on paclitaxel. Our SAR studies have led to the development of numerous highly potent novel second- and third-generation taxoids with systematic modifications at the C-2, C-10, and C-3' positions. The third-generation taxoids showed virtually no difference in potency against drug-resistant and drug-sensitive cell lines. Some of the new generation taxoids also exhibited excellent cytotoxicity against pancreatic cell lines expressing multidrug-resistant genes. We have also designed taxoids with strategic fluorine incorporation to investigate their effects on the cytotoxicity and the blockage of known metabolic pathways. Furthermore, we have successfully employed computational biology analysis to design novel macrocyclic taxoids to mimic the bioactive conformation of paclitaxel. This account describes our work on the design, synthesis, and biological evaluation of these novel taxoids, which has led to the discovery of very promising candidates for further preclinical studies.
在众多的化疗药物中，紫杉醇和多西紫杉醇是最广泛用于治疗各种类型癌症的药物之一。然而，这些药物会引起不良的副作用和耐药性。因此，开发具有更好药理性质和更高活性的“紫杉烷”抗癌药物，特别是针对耐药性癌症，是非常重要的。许多实验室对紫杉醇进行了广泛的 SAR 研究。我们的 SAR 研究导致了许多具有系统修饰的 C-2、C-10 和 C-3'位的高活性新型第二代和第三代紫杉烷的开发。第三代紫杉烷对耐药性和敏感性细胞系的活性几乎没有差异。一些新一代紫杉烷对表达多药耐药基因的胰腺细胞系也表现出优异的细胞毒性。我们还设计了具有战略氟化物掺入的紫杉烷，以研究它们对细胞毒性和已知代谢途径阻断的影响。此外，我们还成功地运用计算生物学分析来设计新型的大环紫杉烷，以模拟紫杉醇的生物活性构象。本报告描述了我们在这些新型紫杉烷的设计、合成和生物学评价方面的工作，这些工作发现了非常有前途的候选药物，可进一步进行临床前研究。
