Emetine is a small molecule protein synthesis inhibitor that is toxic to all cell types and therefore suitable for complete killing of all types of heterogeneous cancer cells within a tumor. It becomes significantly inactive (non-toxic) when derivatized at its N-2′ secondary amine. This provides a strategy for targeting emetine to cancerous tumor without killing normal cells. In this report, PSA activatable peptide prodrugs of emetine were synthesized. To overcome steric hindrances and enhance protease specific cleavage, a 2-stage prodrug activation process was needed to release emetine in cancer cells. In this 2-stage process, emetine prodrug intermediates are coupled to PSA peptide substrate (Ac-His-Ser-Ser-Lys-Leu-Gln) to obtain the full prodrug. Both prodrug intermediates 10 (Ala-Pro-PABC-Emetine) and 14 (Ser-Leu-PABC-Emetine) were evaluated for kinetics of hydrolysis to emetine and potency [Where PABC = p-aminobenzyloxycarbonyl]. While both intermediates quantitatively liberate emetine when incubated under appropriate conditions, upon coupling of PSA substrate to give the full prodrugs, only prodrug 16, the prodrug obtained from 14 was hydrolyzable by PSA. Cytotoxicity studies in PSA producing LNCaP and CWR22Rv1 confirm the activation of the prodrug by PSA with an IC₅₀ of 75 nM and 59 nM respectively. The cytotoxicity of 16 is significantly reduced in cell lines that do not produce PSA. Further, in vivo toxicity studies are done on these prodrugs and other derivatives of emetine. The results show the significance of conformational modulation in obtaining safe emetine prodrugs.

Emetine是一种小分子蛋白质合成抑制剂，对所有细胞类型均具有毒性，因此适合完全杀死肿瘤中所有类型的异质癌细胞。当在其N-2'仲胺上衍生化时，它变得非常不活泼（无毒）。这提供了将曲美汀靶向癌性肿瘤而不杀死正常细胞的策略。在此报告中，合成了PSA可活化的依替丁的肽前药。为了克服空间障碍并增强蛋白酶特异性切割，需要2阶段的前药活化过程以在癌细胞中释放曲美汀。在此两阶段方法中，将依米汀前药中间体与PSA肽底物（Ac-His-Ser-Ser-Lys-Leu-Gln）偶联以获得完整的前药。前药中间体10（Ala-Pro-PABC-Emetine）和评价了14（Ser-Leu-PABC-艾美汀）的水解成盐酸艾美汀的动力学和效力[其中PABC ＝对氨基苄氧基羰基 ]。尽管在适当条件下孵育时，两种中间体都定量释放出依替丁，但在偶联PSA底物以产生完整的前药时，只有前药16才可通过PSA水解从14中获得的前药。在产生LNCaP和CWR22Rv1的PSA中的细胞毒性研究证实PSA对前药的激活作用，其IC _50分别为75 nM和59 nM。16的细胞毒性在不产生PSA的细胞系中，其显着降低。此外，对这些前药和依替丁的其他衍生物进行了体内毒性研究。结果表明构象调节在获得安全的依替丁前药中的重要性。