Codrugs of Lipoic Acid and Tocopherol/Tocopheramine for Use as Photoprotective Ag

描述（由申请人提供）：皮肤在自然阳光下急性和慢性暴露于紫外线辐射（UVR）会引起损伤，包括晒伤，光老化，光敏性和皮肤癌。紫外线辐射引起的皮肤损伤与高活性氧（ROS）的产生有关，ROS氧化皮肤的关键成分，导致皮肤损伤和疾病。该项目的目的是合成一系列新的抗氧化化合物，用于局部保护皮肤免受紫外线辐射。这些新型化合物来源于天然存在的维生素E （TOC，生育酚）和维生素E类似物（生育酚胺）以及硫辛酸或硫辛酸衍生物（LA）。TOC和LA部分通过化学连接连接，在化合物被递送到活的表皮后被切割，在那里两种活性抗氧化剂被释放。TOC和LA都是有效的抗氧化剂，可以使ROS失活，并限制这些化合物对皮肤造成的后续损害。此外，TOC和LA直接或通过内源性抗坏血酸（ASC）相互作用，以增强和延长其抗氧化作用。本提案中提出的新化合物克服了以前制备的TOC， LA和这些抗氧化剂组合的局部配方的一些局限性。具体来说，我们的化合物本质上比单独的TOC配方更稳定，因为TOC和LA之间的化学联系掩盖了TOC的易感酚基团，这往往是化学不稳定的，特别是在UVR存在下。LA的羧酸也在我们的化合物中被掩盖，从而消除了对容易引起皮肤刺激的低pH值配方的需要。最后，这些新化合物允许两种抗氧化剂在单一配方中精确递送和共定位到活的表皮，以便这些化合物之间的协同活性可以充分利用。我们的目标是制备多达20种新化合物，并以微尤卡坦猪皮肤为模型，模拟化合物在人皮肤中的行为，评估这些化合物在活的表皮中的渗透特性。我们还将监测这些化合物在表皮中的活性抗氧化剂的裂解和释放，并评估所递送的化合物保护皮肤免受紫外线照射引起的氧化损伤的能力。该项目为本科生和研究生在药物合成、药物配方、局部给药和药物疗效评估等领域提供了独特的培训机会。项目中描述的多学科方法非常适合让学生接触药物开发过程，并将为学生在制药行业的职位或追求药物化学或药剂学的高级研究生培训做好准备。

DESCRIPTION (provided by applicant): Acute and chronic exposure of the skin to ultraviolet radiation (UVR) in natural sunlight induces damaging effects including sunburn, photo aging, photosensitivity and skin cancer. The damage to the skin caused by UVR is associated with the generation of highly reactive oxygen species (ROS) that oxidize critical components of the skin, leading to skin damage and disease. The aim of this proposed project is to synthesize a series of new antioxidant compounds that are designed for use as topical agents to protect the skin against UVR. These novel compounds are derived from naturally-occurring vitamin E (TOC, tocopherols) and vitamin E analogs (tocopheramines) and lipoic acid or lipoic acid derivatives (LA). The TOC and LA moieties are connected through a chemical link that is cleaved after the compounds are delivered to the viable epidermis, where the two active antioxidants are released. Both TOC and LA are potent antioxidants that are known to deactivate ROS and limit the subsequent damage caused by these compounds in the skin. In addition, TOC and LA interact directly or through endogenous ascorbic acid (ASC) to enhance and prolong their antioxidant effects when delivered to the skin in combination. The new compounds presented in this proposal overcome some of the limitations associated with previously prepared topical formulations of TOC, LA and combinations of these antioxidants. Specifically, our compounds are inherently more stable than formulations of TOC alone because the chemical connection between TOC and LA masks the susceptible phenolic group of TOC, which tends to be chemically unstable, especially in the presence of UVR. The carboxylic acid of LA is also masked in our compounds which eliminates the need for low pH formulations that are prone to causing skin irritation. Finally, these novel compounds allow for precise delivery and co-localization of the two antioxidants to the viable epidermis in a single formulation so that the synergistic activity between these compounds can be fully exploited. We aim to prepare up to 20 new compounds and to evaluate the penetration characteristics of these compounds into the viable epidermis using viable Micro-Yucatan pig skin as a model to mimic the compounds' behavior in human skin. We will also monitor the cleavage and release of the active antioxidants from these compounds in the epidermis and will assess the ability of the delivered compound to protect the skin against oxidative damage caused by exposure to UVR. The proposed project offers a unique training opportunity for both undergraduate and graduate students in the areas of drug synthesis, pharmaceutical formulation, topical drug delivery and assessment of drug efficacy. The multi-disciplinary approach described in the project is ideally suited to expose students to the drug development process and will serve to prepare students for positions in the pharmaceutical industry or to pursue advanced graduate training in medicinal chemistry or pharmaceutics. PUBLIC HEALTH RELEVANCE: Acute and chronic exposure of the skin to ultraviolet radiation (UVR) in natural sunlight induces damaging effects including sunburn,1 photoaging,2 immunosuppression3 and skin cancer.1, 4 Exposure of the skin to solar radiation, specifically UVA (315-400nm) and UVB (280- 315nm) radiation, has also been shown to deplete natural antioxidants that help to protect the skin against sun damage. The goal of this proposal is to prepare a series of new drugs for use as topical agents to protect the skin from UVR-induced damage. These agents are designed to replenish natural antioxidants in the skin for enhanced and extended photo protection relative to existing topical products. 1. MacKie, R.M. Effects of ultraviolet radiation on human health. Rad. Protect. Dos. 91 (1-3) 15-18, 2000. 2. Krutman, J. Ultraviolet A radiation-induced biological effects in human skin: relevance for photo aging and photodermatosis. J. Dermatol. Sci. 23 (Suppl1) S22-26, 2000. 3. Beissert, S.; Schwartz, T. Mechanisms involved in ultraviolet light-induce immunosuppression. J. Invest. Derm. Symp. Proc 4. 61-64, 1999. 4. Sarasin, A. The molecular pathways of ultraviolet-induced carcinogenesis. Mutat. Res. 428, 5-10, 1999. 5. Podda, M.; Traber, M.G. Weber, C.; Yan, L.J.; Packer, L. UV-radiation depletes antioxidants and causes oxidative damage in a model of human skin. Free Rad. Biol. Med. 24, 55-65, 1998.