Cytotoxic and Proapototic Activities of Imidoselenocarbamate Derivatives Are Dependent on the Release of Methylselenol

In the search for new molecules with potential antiangiogenic activity, we found that several imidoselenocarbamate derivatives effectively suppressed the expression of vascular endothelial growth factor (VEGF) induced by hypoxia in NCI-H157 tumor cells. Mechanistic studies indicated that these compounds inhibited STAT3 phosphorylation triggered by hypoxia, suggesting that inhibition of STAT3 function may play a role in VEGF inhibition. Moreover, these molecules showed interesting proapoptotic and antiproliferative effects. Both the presence of selenium, but not sulfur, and the nature of the radical substituents were important for activity. Interestingly, under hypoxic conditions, several methyl imidoselenocarbamate derivatives released methylselenol, a highly reactive and cytotoxic gas, which was responsible for their biological activities. The kinetics of the release of methylselenol by these molecules was highly dependent on the nature of the substituent radicals and correlated with their early proapoptotic activity. Our results support the notion that pharmacological activities reported for methyl imidoselenocarbamate derivatives are dependent on the release of methylselenol. Given the well-known antitumor activities of this compound, imidoselenocarbamate derivatives represent a promising approach to develop new drugs that release methylselenol in a controlled way

Design, Synthesis, and Biological Evaluation of Novel Selenium (Se-NSAID) Molecules as Anticancer Agents

The synthesis and anticancer evaluation of novel selenium-nonsteroidal anti-inflammatory drug (Se-NSAID) hybrid molecules are reported. The Se-aspirin analogue <b>8</b> was identified as the most effective agent in reducing the viability of different cancer cell lines, particularly colorectal cancer (CRC) cells, was more selective toward cancer cells than normal cells, and was >10 times more potent than 5-FU, the current therapy for CRC. Compound <b>8</b> inhibits CRC growth via the inhibition of the cell cycle in G1 and G2/M phases and reduces the cell cycle markers like cyclin E1 and B1 in a dose dependent manner; the inhibition of the cell cycle may be dependent on the ability of <b>8</b> to induce p21 expression. Furthermore, <b>8</b> induces apoptosis by activating caspase 3/7 and PARP cleavage, and its longer exposure causes increase in intracellular ROS levels in CRC cells. Taken together, <b>8</b> has the potential to be developed further as a chemotherapeutic agent for CRC

Design, Synthesis, and Biological Evaluation of Novel Selenium (Se-NSAID) Molecules as Anticancer Agents

The synthesis and anticancer evaluation of novel selenium-nonsteroidal anti-inflammatory drug (Se-NSAID) hybrid molecules are reported. The Se-aspirin analogue <b>8</b> was identified as the most effective agent in reducing the viability of different cancer cell lines, particularly colorectal cancer (CRC) cells, was more selective toward cancer cells than normal cells, and was >10 times more potent than 5-FU, the current therapy for CRC. Compound <b>8</b> inhibits CRC growth via the inhibition of the cell cycle in G1 and G2/M phases and reduces the cell cycle markers like cyclin E1 and B1 in a dose dependent manner; the inhibition of the cell cycle may be dependent on the ability of <b>8</b> to induce p21 expression. Furthermore, <b>8</b> induces apoptosis by activating caspase 3/7 and PARP cleavage, and its longer exposure causes increase in intracellular ROS levels in CRC cells. Taken together, <b>8</b> has the potential to be developed further as a chemotherapeutic agent for CRC