Photoactivatable Prodrugs

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Photoactivatable prodrugs are a novel method of drug administration because they enter the body in an inactive state before becoming metabolized to an active state. To prevent detrimental side effects caused by certain cancer treatments, photoremovable protecting groups (PPGs) are used to cage the drug, allowing for temporal and spatial control over administration. This control is essential when the goal of the drug is to inhibit a gene. This leads to the question: what are the advantages and effectiveness of photoactivatable prodrugs with respect to cancer?
The first prodrug, defined in 1958 by Adrien Albert, was acetylsalicylic acid, which is hydrolyzed to salicylic acid resulting in more potency and less bodily irritation. Many different ways to design prodrugs have since been discovered such as adding a polar group to a drug to make it solubleA recent addition to the design of prodrugs include photoremovable protecting groups (PPGs). The first recognized instance of PPGs is the development of caged adenosine 5’ triphosphate (ATP) in 1978. …show more content…

displayed the ability of Vemurafenib (Figure 1), a current FDA approved drug for use in BRAFV600E mutant cancers, to hold PPGs. The binding of vemurafenib to BRAFV600E is facilitated through hydrogen bonding between protein residues of BRAFV600E (Figure 2) and two specific moities of vemurafenib: 7-azaindole moiety and sulfonamide NH residue. PPGs are bound to these moieties through nucleophilic substitution, creating caged prodrugs (Figure 3) with groups removable by UV light. The addition of these PPGs causes steric hindrance which inhibits the binding of vemurafenib to BRAFV600E,implementing temporal and spatial control of the administration of

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