Nicolaou K C, Riemer C, Kerr M A, Rideout D, Wrasidlo W
Department of Chemistry, Scripps Research Institute, La Jolla, California 92037.
Nature. 1993 Jul 29;364(6436):464-6. doi: 10.1038/364464a0.
Taxol is a product isolated from the Pacific yew tree (Taxus brevifolia) and is a potent microtubule-stabilizing agent which has recently been approved for treatment of otherwise intractable ovarian cancer. Despite taxol's therapeutic promise, its aqueous insolubility (< 0.004 mg ml-1) hampers its clinical application. Here we report the design, synthesis and biological activity of a series of taxol-releasing compounds (protaxols) with improved pharmacological properties. These prodrugs were designed to increase their aqueous solubility and allow for taxol release under basic or physiological conditions. We demonstrate the stability of these prodrugs at pH < or = 7 and their ability to release taxol in a basic medium. Taxol-like microtubule-stabilizing activity appears after the release of taxol. In vitro these prodrugs have cytotoxic properties against tumour cell lines comparable to those of taxol; moreover, human plasma catalyses the release of active taxol. These protaxols have greater potential as anticancer agents than the parent compounds taxol and taxotere (Fig. 1a).
紫杉醇是从太平洋紫杉树（短叶红豆杉）中分离得到的一种产物，是一种强效的微管稳定剂，最近已被批准用于治疗其他方法难以治愈的卵巢癌。尽管紫杉醇具有治疗前景，但其水不溶性（<0.004 mg/ml）阻碍了其临床应用。在此，我们报道了一系列具有改善药理性质的紫杉醇释放化合物（前体紫杉醇）的设计、合成及生物活性。这些前体药物旨在提高其水溶性，并使其在碱性或生理条件下释放紫杉醇。我们证明了这些前体药物在pH≤7时的稳定性以及它们在碱性介质中释放紫杉醇的能力。紫杉醇释放后会出现类似紫杉醇的微管稳定活性。在体外，这些前体药物对肿瘤细胞系具有与紫杉醇相当的细胞毒性；此外，人血浆可催化活性紫杉醇的释放。与母体化合物紫杉醇和多西他赛相比，这些前体紫杉醇作为抗癌剂具有更大的潜力（图1a）。
