<br>海洋抗肿瘤肽多拉司他汀10：生物活性、结构修饰和合成化学,Marine Drugs

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海洋抗肿瘤肽多拉司他汀10：生物活性、结构修饰和合成化学
Marine Drugs ( IF 4.9 ) Pub Date : 2021-06-24 , DOI: 10.3390/md19070363
Gang Gao _{1,

2} , Yanbing Wang ₃ , Huiming Hua ₂ , Dahong Li ₂ , Chunlan Tang ₁

Affiliation

Dolastatin 10 (Dol-10) 是一种从印度洋软体动物Dolabella aurillaryia中分离出来的主要海洋五肽，含有三个独特的氨基酸残基。 Dol-10在纳摩尔浓度下可以有效诱导肺癌细胞和其他肿瘤细胞凋亡，并已开发成治疗某些特定淋巴瘤的商业药物，因此近年来受到广泛关注。体外实验表明，Dol-10及其衍生物对常见肿瘤细胞具有高度致死性，如L1210白血病细胞（IC ₅₀ = 0.03 nM）、小细胞肺癌NCI-H69细胞（IC ₅₀ = 0.059 nM）和人类肿瘤细胞。前列腺癌DU-145细胞（IC ₅₀ = 0.5 nM）等。随着抗体药物偶联物（ADC）的兴起，基于Dol-10的临床研究取得了里程碑式的进展。 MMAE或MMAF（Dol-10衍生物）与特异性抗体结合构建的多种ADC不仅保证了药物本身的抗肿瘤活性，而且提高了其肿瘤靶向性并降低了全身毒性。目前正在进行临床试验或已获批上市，如^Adcetris®已被批准用于治疗间变性大T细胞系统性恶性淋巴瘤和霍奇金淋巴瘤。 Dol-10作为迄今为止发现的最具医学价值的天然化合物之一，为肿瘤治疗带来了前所未有的希望。尤其值得注意的是，通过对Dol-10的化学结构进行修饰，并结合ADCs技术的应用，Dol-10作为新候选药物仍然具有巨大的发展潜力。本综述将总结近35年来Dol-10在抗肿瘤药物进展中的生物活性和化学工作，为有兴趣引领抗肿瘤海洋肽探索的药学研究人员提供支持。

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Marine Antitumor Peptide Dolastatin 10: Biological Activity, Structural Modification and Synthetic Chemistry

Dolastatin 10 (Dol-10), a leading marine pentapeptide isolated from the Indian Ocean mollusk Dolabella auricularia, contains three unique amino acid residues. Dol-10 can effectively induce apoptosis of lung cancer cells and other tumor cells at nanomolar concentration, and it has been developed into commercial drugs for treating some specific lymphomas, so it has received wide attention in recent years. In vitro experiments showed that Dol-10 and its derivatives were highly lethal to common tumor cells, such as L1210 leukemia cells (IC₅₀ = 0.03 nM), small cell lung cancer NCI-H69 cells (IC₅₀ = 0.059 nM), and human prostate cancer DU-145 cells (IC₅₀ = 0.5 nM), etc. With the rise of antibody-drug conjugates (ADCs), milestone progress was made in clinical research based on Dol-10. A variety of ADCs constructed by combining MMAE or MMAF (Dol-10 derivatives) with a specific antibody not only ensured the antitumor activity of the drugs themself but also improved their tumor targeting and reduced the systemic toxicity. They are currently undergoing clinical trials or have been approved for marketing, such as Adcetris^®, which had been approved for the treatment of anaplastic large T-cell systemic malignant lymphoma and Hodgkin lymphoma. Dol-10, as one of the most medically valuable natural compounds discovered up to now, has brought unprecedented hope for tumor treatment. It is particularly noteworthy that, by modifying the chemical structure of Dol-10 and combining with the application of ADCs technology, Dol-10 as a new drug candidate still has great potential for development. In this review, the biological activity and chemical work of Dol-10 in the advance of antitumor drugs in the last 35 years will be summarized, which will provide the support for pharmaceutical researchers interested in leading exploration of antitumor marine peptides.

更新日期：2021-06-24

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