Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio-Bizkaia, Spain.
Nat Chem. 2022 Jul;14(7):754-765. doi: 10.1038/s41557-022-00964-7. Epub 2022 Jun 27.
Natural products that contain ortho-quinones show great potential as anticancer agents but have been largely discarded from clinical development because their redox-cycling behaviour results in general systemic toxicity. Here we report conjugation of ortho-quinones to a carrier, which simultaneously masks their underlying redox activity. C-benzylation at a quinone carbonyl forms a redox-inactive benzyl ketol. Upon a specific enzymatic trigger, an acid-promoted, self-immolative C-C bond-cleaving 1,6-elimination mechanism releases the redox-active hydroquinone inside cells. By using a 5-lipoxygenase modulator, β-lapachone, we created cathepsin-B-cleavable quinone prodrugs. We applied the strategy for intracellular release of β-lapachone upon antibody-mediated delivery. Conjugation of protected β-lapachone to Gem-IgG1 antibodies, which contain the variable region of gemtuzumab, results in homogeneous, systemically non-toxic and conditionally stable CD33+-specific antibody-drug conjugates with in vivo efficacy against a xenograft murine model of acute myeloid leukaemia. This protection strategy could allow the use of previously overlooked natural products as anticancer agents, thus extending the range of drugs available for next-generation targeted therapeutics.
含有邻醌的天然产物具有很大的抗癌潜力，但由于其氧化还原循环行为会导致全身性毒性，因此在很大程度上已被排除在临床开发之外。在这里，我们报告了将邻醌与载体偶联，同时掩盖其潜在的氧化还原活性。醌羰基的 C-苄基化形成氧化还原惰性的苄基酮醇。在特定的酶触发下，酸促进的、自消除的 C-C 键断裂 1,6-消除机制在细胞内释放氧化还原活性的对苯二酚。通过使用 5-脂氧合酶调节剂，β-拉帕醌，我们创建了组织蛋白酶 B 可切割的醌前药。我们应用该策略通过抗体介导的递送来实现β-拉帕醌的细胞内释放。将受保护的β-拉帕醌与含有 gemtuzumab 可变区的 Gem-IgG1 抗体偶联，可得到均匀、系统无毒且条件稳定的 CD33+特异性抗体药物偶联物，对急性髓系白血病的异种移植小鼠模型具有体内疗效。这种保护策略可以使先前被忽视的天然产物作为抗癌药物使用，从而扩大下一代靶向治疗药物的范围。
