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

用作光保护银的硫辛酸和生育酚/生育胺的复合药物

基本信息

批准号：
8179947
负责人：
Martha A. Hass
金额：
$ 45.39万
依托单位：
ALBANY COLLEGE OF PHARMACY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-18 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8179947
关键词：
Acute Aging Amides Antioxidants Area Ascorbic Acid Behavior Biological Carbamates Carbonates Carboxylic Acids Characteristics Chemicals Chronic Cleaved cell Data Disease Drug Delivery Systems Drug Formulations Drug Industry Drug usage Epidermis Esters Exhibits Exposure to Family suidae Generations Goals Health Human Hydrolysis Immunosuppression In Vitro Link Liquid substance Masks Metabolic Modeling Molecular Monitor Parents Pathway interactions Penetration Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacy (field)Photosensitivity Positioning Attribute Predisposition Process Property Radiation Radiation induced damage Reactive Oxygen Species Relative (related person)Reporting Series Skin Skin Cancer Solar Energy Stratum corneum Structure Students Sunburn The Sun Thioctic Acid Time Tocopherols Topical agent Topical application Training UV Radiation Exposure UV induced Ultraviolet A radiation Ultraviolet B Radiation Ultraviolet Rays Vitamin E Work analog carcinogenesis design drug development drug efficacy drug synthesis functional group graduate student improved novel oxidative damage photoprotection receptor research study skin irritation sunlight-induced

项目摘要

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.

描述(由申请人提供)：皮肤在自然阳光下急性和长期暴露在紫外线辐射(UVR)下会导致损害效应，包括晒伤、光老化、光敏和皮肤癌。紫外线对皮肤造成的损害与高活性氧物种(ROS)的产生有关，ROS会氧化皮肤的关键成分，导致皮肤损伤和疾病。这项拟议项目的目的是合成一系列新的抗氧化剂化合物，这些化合物被设计为局部使用，以保护皮肤免受紫外线辐射的伤害。这些新化合物来自天然维生素E(TOC，生育酚)和维生素E类似物(生育胺)和硫辛酸或硫辛酸衍生物(LA)。TOC和LA部分通过化学键连接，在化合物被输送到有活力的表皮后，化学键被切断，在那里两种活性抗氧化剂被释放。TOC和LA都是强有力的抗氧化剂，众所周知，它们可以抑制ROS，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，当它们联合输送到皮肤上时，可以增强和延长它们的抗氧化效果。这项建议中提出的新化合物克服了以前准备的TOC、LA和这些抗氧化剂的组合的局部配方的一些限制。具体地说，我们的化合物本质上比TOC单独配方更稳定，因为TOC和LA之间的化学连接掩盖了TOC的敏感酚基，TOC往往在化学上不稳定，特别是在UVR存在的情况下。LA的羧酸也被我们的化合物掩盖了，这就消除了低pH配方的需要，因为低pH配方容易引起皮肤刺激。最后，这些新的化合物允许在单一配方中将这两种抗氧化剂精确地传递和共定位到可存活的表皮，以便充分利用这些化合物之间的协同活性。我们的目标是制备多达20种新化合物，并使用可存活的微型尤卡坦猪皮作为模型来模拟化合物在人类皮肤中的行为，评估这些化合物对可存活表皮的渗透特性。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，并将评估交付的化合物保护皮肤免受紫外线照射造成的氧化损伤的能力。拟议的项目为本科生和研究生在药物合成、药物配方、局部药物输送和药物疗效评估方面提供了一个独特的培训机会。该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，并将有助于为学生在制药行业的职位或在药物化学或药剂学方面进行高级研究生培训做准备。与公众健康相关：皮肤在自然阳光下急性和长期暴露在紫外线辐射(UVR)下会导致破坏性影响，包括晒伤、光老化、免疫抑制3和皮肤癌。1、4皮肤暴露在太阳辐射下，特别是UVA(315-400 nm)和UVB(280-315 nm)辐射，也被证明会消耗有助于保护皮肤免受阳光损害的天然抗氧化剂。这项提议的目标是准备一系列新药，作为局部药物来保护皮肤免受紫外线照射造成的损害。这些制剂旨在补充皮肤中的天然抗氧化剂，以增强和延长相对于现有局部产品的防晒能力。1.Mackie，R.M.紫外线辐射对人类健康的影响拉德。保护好自己。杜斯。91(1-3)15-18,20002.紫外线辐射对人体皮肤的生物效应：与光老化和光皮肤病的相关性。J.皮马托尔。SCI。23(补充1)2000年第22-26条。3.Beissert，S.；Schwartz，T.紫外光诱导免疫抑制的机制。J.投资。德姆。交响乐。文集4.61--，1999。4.Sarasin，A.紫外线致癌的分子途径。穆塔特。结果428，5-10,1999。5.Podda，M.；Traber，M.G.Weber，C.；Yan，L.J.；Packer，L.紫外线辐射在人体皮肤模型中耗尽抗氧化剂并导致氧化损伤。自由自在。比奥尔。地中海医院。24，55-65,1998。