Emetine is a natural product alkaloid from ipecac species. It is one of the main active ingredients in ipecac syrup used as emetic, and has been used extensively in phytomedicine as an antiparasitic drug. It inhibits both ribosomal and mitochondrial protein synthesis and interferes with the synthesis and activities of DNA and RNA. For this reason, it has been a vital tool to pharmacologists and has demonstrated many biological properties, such as antiviral, anticancer, antiparasitic and contraceptive activities. Also, it has been reported to cause the up-regulation and down-regulation of a number of genes. Some synthetic analogs with interesting biological activities have been prepared. This article reviews the biological activities of emetine and some emetine derived molecules.

The N-2′ position of the natural product emetine has been derivatized to thiourea, urea, sulfonamide, dithiocarbamate, carbamate and pH responsive hydrolysable amide analogs. In-vitro studies of these analogs in PC3 and LNCaP prostate cancer cell lines showed that the analogs are generally less cytotoxic (average IC50 ranging from 0.079 μM to 10 μM) than emetine (IC50 ranging from 0.0237 to 0.0329 μM). The pH sensitive sodium dithiocarbamate salt 13 and the amide analogs 21, 22, 26 (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 13 and 26 were further shown to exhibit increased cytotoxicity in PC3 cell culture media that was already below pH 7.0 at the time of treatment.

This FAP activated prodrug of cytotoxic agent emetine further shows the crucial role of the N-2' position of emetine in controlling its cytotoxicity. Significantly reduced toxicity observed in the PrEC cell line in the absence of FAP and DPPIV shows that prodrug 11 could be systemically delivered to regions of metastatic prostate cancer or other solid tumor for activation by cancer selective enzymes within the cancer microenvironment, such as FAP that is overexpressed by the carcinoma-associated fibroblasts. The two-step tandem enzymatic activation of prodrug 11 by FAP and DPPIV is a strategy for overcoming steric hindrance.

The antitrypanosomal activities, cytotoxicity, and selectivity indices of eleven imido-substituted 1,4-naphthoquinone derivatives and nifurtimox have been studied. Compared to nifurtimox (IC50 = 10.67 µM), all the imido-naphthoquinone analogs (IMDNQ1-IMDNQ11) are more potent on Trypanosoma cruzi with IC50 values ranging from 0.7 µM to 6.1 µM (p < 0.05). Studies of the cytotoxic activities of these compounds on a Balb/C 3T3 mouse fibroblast cell line revealed that four of these compounds, IMDNQ1, IMDNQ2, IMDNQ3, and IMDNQ10 displayed selectivity indices of 60.25, 53.97, 31.83, and 275.3, respectively, rendering them significantly (p < 0.05) more selective in inhibiting the parasite growth than nifurtimox (selectivity index = 10.86).