Synthesis and Biological Evaluation of N-2' Derived Emetine Analogs and pH-Activatable Prodrugs as Potential Chemotherapy for Prostate Cancer

While progress has been made in the treatment of metastatic prostate cancer, improvement in survival has been modest for men with castration resistant advanced stage disease. New treatments remain urgently needed. Emetine is a bioactive natural product already recognized as an anticancer agent with novel mechanisms of action but associated side effects have limited its use. Recognizing that the N-2´ position of emetine is vital to its biological activities, chemical modification at this position is expected to produce molecules of reduced systemic toxicity. We describe preliminary studies in the development of emetine analogs as therapy for prostate cancer by chemically modifying the N-2´ position. The N-2´ secondary amine of emetine was derivatized to dithiocarbamate, thiourea, urea, sulfonamide and pH responsive hydrolysable amide analogs of emetine. The amide analogs are designed to be pH-activated prodrugs.;The dithiocarbarmate ester analogs were synthesized in 23-86% yield in a two step reaction via the dithiocarbamate salt (82% yield). The thiourea analogs were obtained via the isothiocyanate in a yield of 31-67%, while the urea analogs were obtained in 41-85% yield by the reaction of emetine with isocyanates. The sulfonamide analogs were obtained in a yield of 65-86% by reacting emetine with appropriate sulfonyl chlorides. The amide analogs were obtained from cyclic anhydrides in a yield of 79-90%. All the analogs of emetine synthesized were characterized by 1H-NMR, 13C-NMR, MALDI-TOF-MS, ESI-TOF-MS, FT-IR, and HPLC.;In-vitro studies of the cytotoxicity of these analogs were carried out on LNCaP, PC3 and DU145 prostate cancer cell lines. Though these analogs are potent anticancer agents, they are generally less cytotoxic (average IC 50 ranging from 0.079 microM to 10 microM) than emetine (IC 50 ranging from 0.0237 to 0.0329 microM). The pH sensitive sodium dithiocarbamate salt and the amide analogs (obtained from maleic and citraconic anhydrides) showed the most promise as acid-activatable prodrugs under mildly acidic conditions found in the cancer micro-environment. These prodrugs released 12--83% of emetine at pH 6.5 and 41-- 95% emetine at pH 5.5. Compounds 37 and 113 were further shown to exhibit increased cytotoxicity in PC3 cell culture media that was already below pH 7.0 at the time of treatment. Also, while an emetine dose of 100 mg/Kg body weight given intravenously to mice in in-vivo toxicity studies was lethal within 48 hrs to all the mice, prodrugs 37 and 113 at 100 mg/Kg were safe, and the mice to which they were given did not show any sign of toxicity when this dose was given daily for five days.