Effects of multifunctional antioxidants on mitochondrial dysfunction and amyloid-ß metal dyshomeostasis.

BACKGROUND: Redox-active metal dyshomeostasis and oxidative stress are associated with mitochondrial dysfunction and amyloid-ß (Aß) neurotoxicity that are linked to both the development of age-related macular degeneration (AMD) and Alzheimer's disease (AD). As potential therapeutic agents, orally active multifunctional antioxidants (MFAOs) possessing two independent functional groups capable of binding redox-active metals and scavenging free radicals have been synthesized. OBJECTIVE: To determine whether MFAOs affect mitochondrial function and reduce the presence of Aß plaque formation. METHODS: The MFAOs were evaluated in cultured SH-SY5Y cells and ARPE-19 cells. MFAO effects on mitochondrial function were investigated using rhodamine 123 staining after 2 hour exposure to MnCl2. MFAO effects on Aß:Zn complex formation were evaluated with Zinquin staining and the ability of the Aß:Zn complex to be degraded by matrix metalloproteinase-2 (MMP-2). The ability of MFAOs to reduce Aß plaque in the brain was determined by orally feeding MFAO for one year to B6;129-Psen1tm1Mpm Tg(AßPPSwe,tauP301L) 1Lfa/Mmjax transgenic mice. Aß levels were determined by ELISA. RESULTS: MFAOs neither adversely affected mitochondrial signaling nor labile cytoplasmic zinc levels. MFAOs protected cells against Mn2+-induced mitochondrial dysfunction. MFAOs also removed zinc from the Aß:Zn complex so that Aß plaque could be degraded by MMP-2. Zinquin staining indicated that the removed zinc was present in the cytoplasm as labile zinc. Orally administered MFAOs reduced the brain levels of both Aß40 and Aß42 isoforms of Aß. CONCLUSION: These studies demonstrate that these MFAOs have metal attenuating properties with therapeutic potential in the treatment of both AMD and AD.

Understanding the molecular properties and metabolism of top prescribed drugs.

Molecular properties such as the molecular weight, hydrophobicity parameter logP, and the total polar surface area (TPSA) have been used extensively in modern drug discovery. We investigated these properties and ADMET scores of the top 200 therapeutic drugs by the U.S. retail sales (2010) and classified them according to the clinical indications and/or routes of administration. This list of drugs provides ample information of these molecular descriptors for successfully approved drugs. The mean logP for oral drugs is 2.5 while the logP for injectable drugs seems to be smaller. Among different types of clinical indications, drugs used for anti-HIV, and antibiotics tend to have lower logP. The molecular weights of anti-HIV drugs, antihypertensives and antibiotics appear to be larger. The ADMET scores, derived from a combination of molecular weights and logP, are consistent for oral drugs, with a mean score of 1.5 and a standard deviation of 1.0. Many clinical drugs that violate Lipinski's rule of five criteria can still exhibit ADMET scores that are very close to the mean value for oral drugs (1.5) and lie within the acceptable standard deviation. The molecular properties of MW, logP, and TPSA appear to vary according to their clinical indications. Many drugs form salts or cocrystals with acids or solvents that increase their solubility. Our data show that addition of hydrochloride is the most common method to increase solubility of drug ingredients. Cytochrome P450 isozymes 3A4, 2D6, 2C9, 2C8 and 3C5 are the top five proteins that metabolize the 200 most prescribed drugs. Drugs metabolized by 3A4 appear to have larger molecular weights and those metabolized by 2D6 have lower molecular weights. CYP2C8-metabolized drugs appear to be most hydrophilic, with the smallest logP and the largest polar surface areas.