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）：天然阳光中皮肤急性和慢性暴露于紫外线辐射（UVR）会引起损害效果，包括晒伤，照相老化，光敏性和皮肤癌。 UVR引起的皮肤的损害与高活性氧（ROS）的产生有关，从而氧化了皮肤的关键成分，从而导致皮肤损伤和疾病。该提议的项目的目的是合成一系列新的抗氧化剂化合物，这些化合物旨在用作局部剂，以保护皮肤免受UVR的侵害。这些新颖的化合物来自天然存在的维生素E（TOC，生育酚）和维生素E类似物（作用者）和氟酸或氟酸衍生物（LA）。 TOC和LA部分是通过化合物递送到可行表皮后切割的化学连接的，在该表皮上释放了两种活性抗氧化剂。 TOC和LA都是有效的抗氧化剂，已知可以失活ROS并限制皮肤中这些化合物造成的随后损害。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时，将其延长到皮肤中。本提案中提出的新化合物克服了与先前制备的TOC，LA和这些抗氧化剂组合的局部制剂相关的局限性。具体而言，我们的化合物本质上比单独的TOC配方更稳定，因为TOC和LA掩盖之间的化学连接易感TOC的易感酚类群体，该基团往往是化学上不稳定的，尤其是在UVR的情况下。 LA的羧酸也被掩盖在我们的化合物中，这消除了容易引起皮肤刺激的低pH配方的需求。最后，这些新颖的化合物允许将两种抗氧化剂的精确递送和共定位到单个配方中，以便完全利用这些化合物之间的协同活性。我们的目标是准备多达20种新化合物，并使用可行的微乳腺猪皮肤来评估这些化合物在活力表皮中的渗透特性，以模仿人类皮肤中化合物的行为。我们还将监测表皮中这些化合物的活性抗氧化剂的裂解和释放，并评估递送化合物保护皮肤免受因UVR暴露引起的氧化损伤的能力。拟议的项目为药物合成，药物配方，局部药物输送和药物功效评估领域的本科生和研究生提供了独特的培训机会。该项目中描述的多学科方法非常适合使学生接触药物开发过程，并将为学生准备制药行业的职位，或从事药物化学或药剂学领域的高级研究生培训。公共卫生相关性：自然阳光中皮肤上皮肤上的急性和长期暴露于紫外线辐射（UVR）会引起损害效果，包括晒伤，1光照，2个免疫抑制3和皮肤癌。1，4皮肤暴露于太阳辐射中保护皮肤免受阳光损伤。该提案的目的是准备一系列新药，以用作局部药物，以保护皮肤免受UVR诱导的损害。这些试剂旨在补充皮肤中的天然抗氧化剂，以增强相对于现有局部产品的增强和扩展的照片保护。 1。Mackie，R.M。紫外线辐射对人类健康的影响。 rad。保护。 dos。 91（1-3）15-18，2000。2。Krutman，J。UltravioletA辐射诱导的人体皮肤生物学作用：与照片衰老和光性细胞增多相关。 J. Dermatol。科学。 23（Suppl1）S22-26，2000。3。Beissert，S。; Schwartz，T。参与紫外线诱导免疫抑制的机制。 J. Invest。真皮。 SYMP。 Proc 4。61-64，1999。4。Sarasin，A。紫外线诱导的癌变的分子途径。变形。 res。 428，5-10，1999。5。Podda，M。; Traber，M.G。韦伯，c。 Yan，L.J。; Packer，L。紫外线辐射会耗尽抗氧化剂，并在人体皮肤模型中造成氧化损伤。自由rad。生物。医学24，55-65，1998。