Yoshimitsu Takehiko, Tun Han W
a Graduate School of Pharmaceutical Sciences , Osaka University , Osaka , Japan.
b Department of Cancer Biology and Department of Hematology/Oncology , Mayo Clinic Florida , Jacksonville , FL , USA.
Expert Opin Ther Pat. 2017 Feb;27(2):113-119. doi: 10.1080/13543776.2017.1273902. Epub 2017 Jan 5.
Agelastatins are a family of tetracyclic alkaloids isolated from marine sponges. The patent examined in this publication covers the chemical synthesis of agelastatins A to F and eight analogues and their therapeutic use against hematologic malignancies. The claim on the chemical synthesis features a novel biomimetic cyclization of a tricyclic precursor, which streamlines scalable access to agelastatins and their analogues. This new synthetic approach can potentially expedite the research on these compounds for therapeutic use against cancers by making them more easily available. The claim on the therapeutic use against hematologic malignancies is based on the in vitro cytotoxicity against a limited number of cell lines and can be further strengthened by in vivo therapeutic evaluations focusing on specific hematologic malignancies. The comparative evaluation of the cytotoxicities of the natural alkaloids described in the application greatly enhances the understanding of their structure-activity relationships (SARs) relevant to the development of novel medicinal leads. Overall, the patent application is strong and has the potential to advance the rapidly expanding agelastatin research.
阿吉他汀是从海洋海绵中分离出的一类四环生物碱。本出版物中审查的专利涵盖了阿吉他汀A至F及其八个类似物的化学合成以及它们对血液系统恶性肿瘤的治疗用途。关于化学合成的权利要求的特点是一种新型的三环前体仿生环化反应，这简化了可扩展地获取阿吉他汀及其类似物的途径。这种新的合成方法有可能通过使这些化合物更容易获得，从而加速对它们用于癌症治疗的研究。关于对血液系统恶性肿瘤治疗用途的权利要求基于对有限数量细胞系的体外细胞毒性，并且可以通过针对特定血液系统恶性肿瘤的体内治疗评估进一步加强。该申请中对天然生物碱细胞毒性的比较评估极大地增进了对与新型药用先导物开发相关的结构-活性关系（SARs）的理解。总体而言，该专利申请很有力，有潜力推动迅速扩展的阿吉他汀研究。
