Abstract：
Plitidepsin (or dehydrodidemnin B), an approved anticancer drug, belongs to the didemnin family of cyclic depsipeptides, which are found in limited quantities in marine tunicate extracts. Herein, we introduce a new approach that integrates microbial and chemical synthesis to generate plitidepsin and its analogues. We screened a Tistrella strain library to identify a potent didemnin B producer, and then introduced a second copy of the didemnin biosynthetic gene cluster into its genome, resulting in a didemnin B titer of approximately 75 mg/L. Next, we developed two straightforward chemical strategies to convert didemnin B into plitidepsin, one of which involved a one-step synthetic route giving over 90 % overall yield. Furthermore, we synthesized 13 new didemnin derivatives and three didemnin probes, enabling research into structure-activity relationships and interactions between didemnin and proteins. Our study highlights the synergistic potential of biosynthesis and chemical synthesis in overcoming the challenge of producing complex natural products sustainably and at scale.
摘要：
Plitidepsin（或脱氢二定蛋白B），一种被批准的抗癌药物,属于环状缩肽的didemnin家族，在海洋被囊动物提取物中发现的数量有限。这里,我们介绍了一种整合微生物和化学合成的新方法，以产生plitidepsin及其类似物。我们筛选了Tistrella菌株文库，以鉴定有效的DedemninB生产者，然后将第二拷贝的didemnin生物合成基因簇引入其基因组中，导致大约75mg/L的didemninB滴度。接下来,我们开发了两种直接的化学策略将DedemninB转化为plitidepsin，其中之一涉及一步合成路线，总收率超过90％。此外，我们合成了13个新的didemnin衍生物和3个didemnin探针,能够研究dedemnin和蛋白质之间的结构-活性关系和相互作用。我们的研究强调了生物合成和化学合成在克服可持续和大规模生产复杂天然产物的挑战方面的协同潜力。
