Moonsun Kim

Identification of α-dicarbonyl scavengers for cellular protection against carbonyl stress

Abstract Tissue deterioration and aging have long been associated with the accumulation of chemically induced protein and DNA damage. Reactive oxygen species (ROS) and reactive carbonyl species (RCS), especially α-dicarbonyl compounds, are key mediators of damage caused by oxidative stress, glycation, and UV-irradiation. The toxic effects of ROS are counteracted in vivo by antioxidants and antioxidant enzymes, and the deleterious effects of one RCS, methylglyoxal, are counteracted by a ubiquitous glyoxalase system. Carbonyl stress as a result of toxic effects of various mono-dicarbonyls (e.g. 4-hydroxynonenal) and α-dicarbonyls (e.g. glyoxal and deoxyosones) cannot be directly antagonized by antioxidants, and only a small number of biological carbonyl scavengers like glutathione (GSH) have been identified to date. We have developed a new screening method for the identification of carbonyl scavengers using a rapid glycation system that proceeds independent of oxygen and therefore, excludes identification of inhibitory compounds acting as antioxidants. Using this screening assay adapted to 96-well microtiter plates, we have identified the cysteine derivative 3,3-dimethyl- d -cysteine as a potent inhibitor of non-oxidative advanced glycation. Comparative kinetic analyses demonstrated the superior α-oxoaldehyde-scavenging activity of d -penicillamine over that of aminoguanidine. d -Penicillamine traps α-oxoaldehydes by forming a 2-acylthiazolidine derivative as shown by structure elucidation of reaction products between d -penicillamine and methylglyoxal or phenylglyoxal. We demonstrated that upon co-incubation, d -penicillamine protects human skin keratinocytes and fibroblasts (CF3 cells) against glyoxal- and methylglyoxal-induced carbonyl toxicity. Our research qualifies α-amino-β-mercapto-β,β-dimethyl-ethane as a promising pharmacophore for the development of related α-dicarbonyl scavengers as therapeutic agents to protect cells against carbonyl stress.

A topical lipophilic niacin derivative increases NAD, epidermal differentiation and barrier function in photodamaged skin

Abstract:  The effects of myristyl nicotinate (MN), a nicotinic acid derivative designed to deliver nicotinic acid to skin without vasodilatation, on subjects with photodamaged skin have been studied. MN increased skin cell nicotinamide adenine dinucleotide (NAD) by 25% (P = 0.001) demonstrating effective delivery of nicotinic acid to skin. Relative to placebo, MN treatment of photodamaged facial skin increased stratum corneum thickness by approximately 70% (P = 0.0001) and increased epidermal thickness by approximately 20% (P = 0.001). In two separate studies, MN treatment increased rates of epidermal renewal by 6% (P = 0.003) to 11% (P = 0.001) and increased the minimal erythemal dose by 8.9 (P = 0.07) and 10% (P = 0.05) relative to placebo. MN treatment resulted in reductions in the rates of transepidermal water loss (TEWL) of approximately 20% relative to placebo on cheeks (P = 0.012) and arms (P = 0.017) of study subjects. Results of a tape stripping challenge before and after MN treatment demonstrated a significant correlation (P = 0.03) between increased skin NAD content and resistance to changes in TEWL for MN treated but not placebo subjects. Rates of TEWL changed more rapidly and to a greater extent in atopic subjects compared with normal subjects. The results indicate that MN enhances epidermal differentiation and barrier function in skin, suggesting that this method of nicotinic acid delivery may prove useful in limiting progression of actinic skin damage and possibly in treating other conditions involving skin barrier impairment.

A pilot study evaluating the efficacy of topically applied niacin derivatives for treatment of female pattern alopecia.

Background  Female pattern alopecia is a common dermatologic condition that manifests after puberty. The only approved drug treatment for this condition is 2% minoxidil for topical application.

An enantioselective total synthesis of (+)-picrasin B

Abstract An enantioselective total synthesis of (+)-picrasin B (1) from the R-(-)-enantiomer of the Wieland-Miescher ketone (4) employed an A-AB-ABC-ABCD sequence to assemble the tetracyclic skeleton and relied upon a free radical cyclization of an α-bromoacetal to an enone in order to introduce the D ring and a manganese(III) acetate oxidation of a tricyclic enone intermediate in order to introduce the C-11 oxygen substituent.

Folate in Skin Cancer Prevention

Skin, the largest, most exposed organ of the body, provides a protective interface between humans and the environment. One of its primary roles is protection against exposure to sunlight, a major source of skin damage where the UV radiation (UVR) component functions as a complete carcinogen. Melanin pigmentation and the evolution of dark skin is an adaptive protective mechanism against high levels of UVR exposure. Recently, the hypothesis that skin pigmentation balances folate preservation and Vitamin D production has emerged. Both micronutrients are essential for reproductive success. Photodegradation of bioactive folates suggests a mechanism for the increased tendency of populations of low melanin pigmentation residing in areas of high UV exposure to develop skin cancers. Folate is proposed as a cancer prevention target for its role in providing precursors for DNA repair and replication, as well as its ability to promote genomic integrity through the generation of methyl groups needed for control of gene expression. The cancer prevention potential of folate has been demonstrated by large-scale epidemiological and nutritional studies indicating that decreased folate status increases the risk of developing certain cancers. While folate deficiency has been extensively documented by analysis of human plasma, folate status within skin has not been widely investigated. Nevertheless, inefficient delivery of micronutrients to skin and photolysis of folate argue that documented folate deficiencies will be present if not exacerbated in skin. Our studies indicate a critical role for folate in skin and the potential to protect sun exposed skin by effective topical delivery as a strategy for cancer prevention.

Niacin: Vitamin and Antidyslipidemic Drug

Niacin is defined collectively as nicotinamide and nicotinic acid, both of which fulfill the vitamin functions of niacin carried out by the bioactive forms NAD(P). In the last few decades numerous new enzymes that consume NAD(P) as substrates have been identified. The functions of these enzymes are emerging as exciting paradigm shifts, even though they are in early stages of discovery. The recent identification of the nicotinic acid receptor has allowed distinction of the drug-like roles of nicotinic acid from its vitamin functions, specifically in modulating blood lipid levels and undesirable side effects such as skin vasodilation and the more rare hepatic toxicities. This information has led to a new strategy for drug delivery for niacin, which, if successful, could have a major impact on human health through decreasing risk for cardiovascular disease. Understanding the many other effects of niacin has much broader potential for disease intervention and treatment in numerous diseases including cancer.

Synthesis of 3, 4, 4a, 5, 6, 7, 8, 8a α-Octahydro-4a β, 8α-Dimethyl-2(1H)-Naphthalenones from the Wieland-Miescher Ketone

Abstract Conversion of the Wieland-Miescher ketone to a bicyclic dienophile capable of providing the AB rings of the picrasane skeleton of the guassinoids required the introduction of a C-8α methyl group in a 2-decalone. Among the routes explored, the conversion of the Wieland-Miescher ketone to a 4,4a,5,6,7,8-hexahydro-4aβ-methyl-8-methylene-2(3H)-napthalenone and subsequent reduction to a 3,4,4a,5,6,7,8,8aα-octahydro-4aβ,8α-dimethyl-2(1H)-napthalenone proved most useful.

Effect of myristyl nicotinate on retinoic acid therapy for facial photodamage

Abstract:  Based on the hypothesis that skin barrier impairment is a contributor to side‐effects associated with retinoic acid therapy, a double‐blind, placebo‐controlled pilot study examined the combined use of retinoic acid with myristyl nicotinate (MN), a lipophilic derivative of niacin that enhances skin barrier function, in female subjects with mild to moderate facial photodamage. The study involved a 1‐month run‐in period with placebo or MN prior to initiation of retinoic acid therapy for 3 months. Analysis of skin biopsies revealed that retinoic acid therapy resulted in stratum corneum thinning of approximately 25% (P = 0.006 versus baseline) that was ameliorated by MN use (P < 0.005). Therapy resulted in an increased rate of transepidermal water loss (TEWL) of approximately 45% (P = 0.001 versus baseline) and use of MN protected against the increase in TEWL with the strongest protection provided by prior use of MN (P = 0.056 versus placebo). MN use reduced the incidence of side‐effects of the therapy and again prior use provided the greatest reduction of side‐effects. Subjects showed statistically significant clinical improvement (P < 0.05 versus baseline) during the study. MN use did not interfere with any clinical improvement parameters and improved effects on temple laxity (P = 0.01 versus placebo). Analysis of changes in epidermal thickness, Ki67‐positive cells and intensity of loricrin staining demonstrated that MN either improved or did not interfere with retinoic acid efficacy. These results show that prior and concurrent use of MN can mitigate barrier impairment and improve the tolerability of retinoic acid therapy for facial photodamage without interfering with efficacy.

Application of the Saegusa Oxidation to Trimethylsilyl Ethers of Diosphenols

Abstract The Saegusa oxidation of trimethylsilyl ethers of diosphenols provided enediones and served as a key reaction in the conversion of δ2-picrasin B to 1β-hydroxy-12-methoxy-picrasa-3,12-diene-2,11-dione, a model for the A ring functionality of many guassinoids.

Compatibility of Proximal Functionality with the Manganese Triacetate Oxidation of Hindered Enones in Podocarpane-Like Systems

Abstract The scope of the manganese triacetate oxidation of enones to α′-acetoxyenones was examined using various 18, 19-desmethylpodocarp-13-en-12-ones: the process will not accommodate hydroxyl or ketone functionality elsewhere in the substrate but will accomodate ester, ether, and acetal functionality provided that it does not sterically block the oxidation site.