Prodrug activation gated by a molecular "OR" logic trigger.

Molecular logic gates are increasingly important in attributing chemical reactivity to molecular devices. Specific input signals of basic logic gates can be programmed into single molecules that generate readable output signals, such as fluorescence or UV/Vis light. Here we show that the release of an active drug molecule through a prodrug activation process is a viable output signal. The term “prodrug” is used to indicate that a chemical derivatization has been applied to alter the physicochemical properties of a drug. The prodrug is converted into the active drug in vivo by metabolic processes or environmental conditions. Masking of a functional group in a targeted drug with a simple linker which contains two moieties that can be cleaved by different mechanisms can generate a molecular “OR” logic gate trigger. The gate is activated upon a cleavage signal from either of the two input ports. The signal will be translated into a bond cleavage that releases the active drug molecule. Several anticancer prodrugs have been designed for selective activation in malignant tissues by a specific enzyme secreted within the proximity of the tumor. A prodrug with a molecular “OR” logic gate triggering device could potentially target two different cancerous tissues with different enzyme-expression patterns. There are several examples for enzymes that are present in elevated levels in malignant tissues. The substrates of two of these enzymes could be introduced in the molecular “OR” logic trigger to generate an agent for dual-prodrug monotherapy. Prodrug strategies are sometimes based on the assumption that a particular enzyme is elevated in the tumor tissues and that activation of a prodrug in the tumor tissue will result in a significantly improved therapeutic index. While there is much evidence for overexpression of particular enzymes in tumors, consistent patterns of expression are elusive. Consequently, attempts to develop drugs activated by tumor-specific enzymes in general have not been very successful. Prodrugs with two modes of activation could offer an advantage over single-triggered prodrugs, particularly in circumstances where two different enzymes are present in elevated levels in various regions of the tumor. Herein, we report the design, synthesis, and bioactivation of a molecular “OR” logic trigger which is used to activate a prodrug with dual susceptibility to enzymatic activity. Classical “OR” logic gates have two input ports and one output port. An activating signal, which operates on either one of the input ports, activates the output signal of the gate (Figure 1). Obviously, positive input signals from both input ports should also activate the gate.