Human skin is the most susceptible organ to be damaged by ultraviolet (UV) irradiation as it is directly exposed to UV light. Increased evidence has shown the generation of reactive oxygen species (ROS) in the skin upon UV exposure.
1-3)Increased ROS generation can overwhelm the intracellular antioxidant-defense mechanism, resulting in oxidative stress and oxidative photo-damage to proteins and other macromolecules in the skin. Oxidative stress is thought to play a central role in initiating and driving the signaling events that lead to the cell response following exposure to UV irradiation. 4,5) Exposure of human skin to UV radiation causes numerous biological effects in the skin, including premature aging characterized by wrinkles, leathery texture and mottled pigmentation.6,7) The mechanism of skin wrinkles is primarily due to the loss of macromolecules making up the dermal matrix, among which collagen is the major component. The degradation of collagens is normally tightly controlled by the activity of a family of zinc-dependent matrix metalloproteinases (MMPs) and their natural inhibitors, the tissue inhibitors of MMPs (TIMPs). 8) Although several MMPs are expressed in mammalian skin, studies by Brennan et al. 3) showed that the neutralization of MMP-1 removed virtually all the collagen-degrading activity elaborated by UV-treated human skin.Cinnamates and salicylates are the chemical UV filter widely used throughout the world. 9) In this study, the ethyl and 2-ethylhexyl esters of these compounds were synthesized, as the presence of these groups may diminish the water solubility of these compounds to various degree, thus, may help to develop waterproof sunscreen formulation. 9) Because the radical scavenging ability of mercaptans and disulfides is well-documented, we speculated that the introduction of these important functional groups into cinnamates or salicylates might yield potent antioxidants and UV protectants. In addition, we reasoned that the disulfides 10,11) and a-mercaptocarbonyl group 12) would chelate zinc ion at the active-site of MMP-1, which renders them to be potential MMP inhibitors. In this work, the sulfur-containing cinnamates and salicylates of substituted ester group were synthesized and the potency of these compounds as UV protective agents was evaluated by analyzing their free radical scavenging and for MMP-1 inhibitory activities.Chemistry The synthetic routes [13][14][15] to the target compounds 5a, 5b, 6a, 6b and 7a, 7b are outlined in Charts 1 and 2. Reduction of 2-mercaptobenzoic acid with lithium aluminum hydride (LiAlH 4 ) in tetrahydrofuran resulted 2-mercaptobenzyl alcohol (1), followed by oxidation of 1 with pyridinium chlorochromate (PCC) in dichloromethane at room temperature afforded 2,2Ј-dithiodibenzadehyde (2). Triphenyl-phosphanylidene-acetic acid 2-ethyl-hexyl ester (4) was prepared from triphenylphosphine and bromo-acetic 2-ethyl-hexyl ester, which obtained from the reaction of bromoacetic acid with 2-ethyl-hexanol under toluenesulfonic acid in toluene at reflux te...
