How Drug Photodegradation Studies Led to the Promise of New Therapies and Some Fundamental Carbanion Reaction Dynamics along the Way

Abstract

The photodegradation of nonsteroidal anti-inflammatory drugs (NSAIDs), a class of medications that includes aspirin and ibuprofen, has generated considerable interest since the 1990s, largely because of the phototoxic and photoallergic effects that frequently accompany their therapeutic use. Among NSAIDs, ketoprofen, which contains a benzophenone chromophore, has been extensively studied, reflecting both its notorious adverse effects and the fascination that photochemists have with benzophenone. The photochemistry of ketoprofen involves the intermediacy of an easily detectable carbanion with a remarkable lifetime of 200 ns in water; its life expectancy can in fact be extended to minutes under carefully controlled anhydrous conditions. Over the past decade, we have used some key properties of the ketoprofen carbanion to conduct mechanistic studies on carbanions under various conditions. In particular, its ease of photogeneration provides the temporal control required for kinetic studies, which, combined with its long lifetime and readily detectable visible absorption, have enabled extensive laser flash photolysis work. These studies have led to an intimate understanding of the reaction dynamics for carbanions in solution, including the determination of absolute rate constants for protonation, S(N)2, and elimination reactions. Together they provide excellent exemplars of reactivity patterns that today are part of all introductory curricula in organic chemistry and illustrate the fundamentals of nucleophilic substitution paradigms. More recently, we have begun to exploit the photochemistry of ketoprofenate and have developed the ketoprofenate photocage, a valuable tool for the photocontrolled cleavage of protecting groups and concomitant drug release. The photorelease has been illustrated with ibuprofen, among many other molecules. These photocages have been further improved with the use of the xanthone chromophore; the goal is the release of antiviral agents taking advantage of the improved UVA absorption of xanthone (xanthonate photocages). In this Account, we survey our work of the past few years on the photochemistry of ketoprofen and related chromophores. Beginning with studies on the phototoxicity of ketoprofen, we have made the journey to new prodrug candidates, unraveling mechanistic elements of aroyl-substituted benzyl carbanions along the way.

Photodecarboxylation of N-Adamantyl- and N-Phenylphthalimide Dipeptide Derivatives

“…6 A special interest was directed to the photodecarboxylation of ketoprofene and similar derivatives. 7 Although some controversy was encountered regarding the reactive excited state of ketoprofen, 8 it is generally accepted that the decarboxylation gives carbanionic species. 9 Synthesis of phthalimide derivatives attracts organic chemists due to their application in the amine protection, 10 as well as their biological activity.…”

Conical intersections in solution: Formulation, algorithm, and implementation with combined quantum mechanics/molecular mechanics method

“…However, relatively slow reactions, more than hundreds of picoseconds, remain ubiquitous in solution photochemistry and biophotochemistry. 27,28,[74][75][76][77] For such situations, it is impractical to perform an "on the fly" ab initio nonadiabatic dynamics simulations to study photochemical reactions. More importantly, one trajectory is statistically meaningless; hundreds even thousands of trajectories are in general required to gain statistical information to certain extent.…”

“…65,66,68,69 Recently, conical intersections of potential energy surfaces for reactions in solution or macromolecules have received much attention. [27][28][29][74][75][76][77] However, conical intersection optimizations in solution or macromolecules is more difficult than those in gas phase due to the large dimensionality of potential energy surfaces. Conical intersection optimization techniques used for small-and medium-size systems in gas phase could be inefficient for macromolecules or solution.…”

“…7,12,13,26,37,80,81,92 However, relatively slow reactions, more than hundreds of picoseconds, remain ubiquitous in solution photochemistry and biophotochemistry, where topological structures, such as conical intersections of potential of mean force surfaces, could be more useful and can provide valuable insights into mechanisms. 27,28,[74][75][76][77] In this work, we have combined our sequential optimization technique with the QM/MM and QM/MM-MFEP methods and developed two conical intersection optimization methods for small-and medium-size molecules in solution or macromolecules on potential energy surfaces and potential of mean force surfaces, respectively. The theoretical background, fundamental formulations, algorithms, and implementations are given in detail.…”

Photochemistry of 1,3-Dicarbonyl Compounds: DNA Photodamage vs. Photoprotection

“…[23] Filterfilter interactions have been examined as well using octyl methoxycinnamate, bis-ethylhexyloxyphenol methoxyphenyl triazine, octocrylene, diethylamino hydroxybenzoyl hexyl benzoate, octyl triazone and dioctyl butamido triazone. [30] Moreover, AB has also been stabilized by the use of antioxidants such as vitamin C, vitamin E, and ubiquinone. This latter has shown the most effective photostabilization together with an increase in the sun protection factor (SPF).…”