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Ultraviolet (UV) irradiation induces detrimental changes in human skin which result in photoaging. UV-induced intracellular changes cause degradation of extracellular matrix (ECM). UV-stimulated cleavage of collagen in ECM occurs via matrix metalloproteinases (MMPs). (&plusmn, )-syringaresinol (SYR), a phytochemical which belongs to the lignan group of polyphenols, was investigated for its ability to reverse the UVA-induced changes in human HaCaT keratinocytes and dermal fibroblasts (HDFs) in vitro. Effect of SYR on UVA-induced changes was investigated by production and activation of MMPs and its transcriptional upstream effectors, mitogen-activated protein kinases (MAPKs) and pro-inflammatory mediators. Levels of expression were determined using ELISA, RT-PCR and immunoblotting. UVA irradiation stimulated the production of MMP-1 and inhibited collagen production. SYR treatment suppressed MMP-1 and enhanced collagen production in UVA-irradiated HaCaT keratinocytes and HDFs. SYR repressed the UV-induced phosphorylation of p38, ERK and JNK MAPKs in HaCaT keratinocytes while only suppressing JNK phosphorylation in HDFs. In addition, SYR was able to inhibit UVA-induced production of inflammatory cytokines, TNF-&alpha, COX-2, IL-1&beta, and IL-6. Moreover, SYR suppressed the activator protein-1 (AP-1), a heterodimer of phosphorylated transcription factors c-Jun and c-Fos. SYR-treatment decreased nuclear levels of activated c-Fos and c-Jun as a mechanism to inhibit UVA-induced transcriptional activities leading to MMP-1 production. In conclusion, current results demonstrated that SYR could inhibit UVA-induced upregulation of MMP-1 by suppressing MAPK/AP-1 signaling in HaCaT keratinocytes and HDFs. Therefore, SYR was suggested as a potential compound with antiphotoaging properties against UVA-induced skin aging.

AP736 itself is a novel skin whitening agent reported to exhibit anti-melanogenic and tyrosinase inhibitory activity. However, formulating a topical product has been difficult because AP736 is insoluble in water as well as in many oils. In this study, we aimed to develop a new topical delivery system in which AP736 is not only physically stable, but also suitably delivered to the skin. By calculating each HSP (Hansen Solubility Parameters), ethylenedioxy moiety-containing compounds could be easily selected for the formulation ingredients of AP736. Although diethylene glycol monoethyl ether with the highest solubility of AP736 enalbes to make AP736-incorporated water-in-oil emulsions well, the recrystallization of AP736 was observed in oil-in-water emulsions. Therefore, we fabricated polymeric nanoparticles (PNPs) in order to encapsulate AP736 to prevent its recrystallization. We used three different PEG-PCL polymers with various chain lengths and ethylenedioxy moiety-containing surfactants (i.e. Choleth) for fabricating PNPs. The prepared PNPs had a mean particle size from 50 nm to 200 nm. Most of PNPs showed the good encapsulation efficiency up to 90%. In particular, Choleth-24 had a significant role in encapsulating AP736 in PNPs. After encapsulation of AP736, no significant changes were observed in the sizes of tested PNPs within 4 weeks. Further, the recrystallization of AP736 was not observed in oil-in-water emulsions after 24 weeks of storage at 40 °C. In vitro permeation study using Strat-M showed that PNPs containing Choleth-24 has the faster release pattern compared to PNPs using Tween 80 and saturated in D.I. water. These results are demonstrating that PNPs might be an effective vehicle for stabilization in oil-in-water emulsions and topical application of AP736.

Tyrosinase 1 is a copper-containing enzyme which is widely distributed in nature. This enzyme is associated with the production of melanin for the protection of the skin from solar irradiation. However, overproduction of melanin in the skin is of particular concern to woman, for example, in the conditions melasma and lentigo. 2 Tyrosinase catalyzes the first two steps of melanin biosynthesis, namely the hydroxylation of L-tyrosine to L-dopa and the subsequent oxidation of L-dopa to dopaquinone. Tyrosinase is contained in vegetables and fruits and is responsible for the undesirable enzymatic browning that occurs upon long term storage of these. 3 Therefore, tyrosinase inhibitors have attracted attention as important depigmenting agents for the treatment of hyperpigmentation and as anti-browning agents in vegetables and fruits. Kojic acid 4 (1) is a well known tyrosinase inhibitor. However, its inhibitory activity is not potent enough for the above purposes. To overcome this drawback, many semisynthetic kojic acid derivatives have been synthesized, usually by modification of the C-2 hydroxyl group. 5 Recently, we synthesized kojic acid derivatives containing thioether 6 and ester 7 linkers and evaluated their tyrosinase inhibitory activities. Among them, 2-((cyclohexylthio)methyl)-5-hydroxy-4H-pyran-4-one (2b), showed the most potent inhibitory activity. Compound 2b is composed of three parts, including the kojic acid moiety, a thioether linker, and a hydrophobic cyclohexane group. We synthesized and evaluated additional compounds to get more structural insight into the tyrosinase inhibitory activity of the kojic acid derivatives. The crystallographic structure of tyrosinase has recently been established, enabling closer examination of its three-dimensional structure, which revealed the presence of a hydrophobic protein pocket adjoining the binuclear copper active site. 8 We also conducted a molecular docking study to elucidate the structural importance of the kojic acid derivatives in binding with the active site of tyrosinase. The synthetic pathways of the kojic acid derivatives are shown in Scheme 1. Thioether derivatives (2a-2e) were synthesized by the condensation of kojyl chloride 4 with the potassium salts of thiols. Ester derivatives (3a-3e) were synthesized by the condensation of kojyl chloride 4 with the potassium salts of acids. The inhibitory activities of the kojic acid derivatives on mushroom tyrosinase were investigated using kojic acid as a positive control. The results are summarized in Table 1.

Hyper-pigmentation causes skin darkness and medical disorders, such as post-inflammatory melanoderma and melasma. Therefore, the development of anti-melanogenic agents is important for treating these conditions and for cosmetic production. In our previous paper, we demonstrated that the anti-diabetic drug voglibose, a valiolamine derivative, is a potent anti-melanogenic agent. In addition, we proposed an alternative screening strategy to identify valiolamine derivatives with high skin permeability that act as anti-melanogenic agents when applied topically. In this study, we synthesized several valiolamine derivatives with enhanced lipophilicity and examined their inhibitory effects in a human skin model. N-(2-hydroxycyclohexyl)valiolamine (HV) possesses a stronger inhibitory effect on melanin production than voglibose in a human skin model, suggesting that HV is a more potent anti-melanogenic agent for the skin.

3-Alkyl-2-aryl-2-cyclopenten-1-one oxime derivatives (1) were studied as a novel class of inhibitors of tumor necrosis factor α (TNF-α) with regard to synthesis and in vitro SAR inhibition of TNF-α. The in vitro IC50 values of these compounds in rat and human peripheral blood mononuclear cells were at the sub-micromolar level.

E-mail: snpark@seoultech.ac.krReceived June 13, 2011, Accepted December 26, 2011Key Words : Depigmenting activity, Hydroxyl carboxamide, Hydrophobic moietySkin pigmentation results from an increase in either thenumber of melanocytes or the activity of tyrosinase, wherethe latter is responsible for melanin synthesis.

A novel kojic acid derivative containing a trolox moiety, (±)-5-hydroxy-4-oxo-4H-pyran-2-yl methyl 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate (3a), was synthesized. The two biologically active compounds, namely, kojic acid and trolox, were conjugated via an ester bond as they are expected to behave synergistically. The antioxidant activity and the tyrosinase inhibitory activity of this novel kojic acid derivative on melanogenesis were evaluated. Compound 3a exhibited potent tyrosinase inhibitory activity and radical scavenging activity. Limited structure–activity relationship (SAR) investigations indicated that the tyrosinase inhibitory activities may originate from the kojic acid moiety, and the radical scavenging activity may be due to the phenolic hydroxyl group of trolox. Compound 3a also exhibited potent depigmenting activity in a cell-based assay. The limited SAR investigations revealed that the depigmenting activity of 3a may be due to the synergistic activities of kojic acid and its trolox moiety.

Numerous medications are used to treat hyperpigmentation. However, several reports have indicated that repeated application of some agents, such as rhododendrol (RD), raspberry ketone (RK) and monobenzone (MB), can be toxic to melanocytes. Although these agents had severe side effects in human trials, no current in vitro methods can predict the safety of such drugs. This study assessed the in vitro effects of five depigmentary compounds including leukoderma-inducing agents. In particular, we determined the effects of different concentrations and exposure times of different depigmentary agents on cell viability and melanogenesis in the presence and absence of ultraviolet B (UVB) radiation. Concentrations of RD, RK and MB that inhibit melanogenesis are similar to concentrations that are cytotoxic; however, concentrations of rucinol (RC) and AP736 that inhibit melanogenesis are much lower than concentrations that are cytotoxic. Furthermore, the concentrations that cause toxic effects depend on exposure duration, and prolonged exposure to RD, RK and MB had more cytotoxic effects than prolonged exposure to RC and AP736. The cytotoxic effects of RD and RK appear to be mediated by apoptosis due to increased expression of caspase-3 and caspase-8; UVB radiation increased the cytotoxicity of these agents and also increased caspase activity. Our results indicate that different leukoderma-inducing compounds have different effects on the viability of normal epidermal melanocytes and suggest that the in vitro assay used here can be used to predict whether an investigational compound that induces leukoderma may lead to adverse effects in human trials.

Background/Purpose AP736 is a novel compound with an adamantyl benzylbenzamide moiety that has shown antimelanogenic activity in melanocytes in vitro and in artificial skin equivalent through the inhibition of key melanogenic enzymes and suppression of the cAMP-phosphokinase A-cAMP response element-binding protein signaling pathway. To estimate the clinical effectiveness of AP736 for the treatment of facial hyperpigmentation, we examined the efficacy and safety of a topical formulation containing AP736 compared with a vehicle formulation in human facial skin. To evaluate the degree of whitening when used in a real-life situation, subjects with hyperpigmentation conditions were selected and the trial was performed from mid-May to the end of June, when there are strong UV rays in Korea. Materials and Methods Forty-eight healthy Korean women aged 20–60 years were enrolled in this study for 6 weeks. Women who were pregnant or undergoing any concurrent therapy were excluded. Subjects were instructed to apply a randomly assigned formulation containing 0.5% AP736 (test formulation; n = 24) or vehicle (vehicle control; n = 24) in addition to an assigned sunscreen with a twice-daily application protocol. The degree of facial pigmentation was measured objectively using a Mexameter MX18 and Chromameter CM700, in addition to assessment by physicians using clinical photographs. Results The AP736 formulation was significantly (P < 0.05) more effective than the vehicle control formation in reducing the appearance of pigmentation at 3- and 6-week follow-up visits. Conclusion A formulation containing a novel skin whitening ingredient, AP736, effectively reduced pigmentation and was well tolerated by study subjects in summer season.

Recently, much effort has been made to develop effective dermatological depigmenting compounds. In this study, we investigated the novel candidate compound, AP736 (an adamantyl benzylbenzamide derivative), and its effects on melanogenesis in B16F10 melanoma cells, as well as the mechanisms involved. AP736 has been reported to exert anti-melanogenic effects in melanocytes in vitro and in artificial skin equivalents through the inhibition of key melanogenic enzymes and the suppression of the cAMP-protein kinase A (PKA)-cAMP response element‑binding protein (CREB) signaling pathway. Thus, we examined another pathway of melanogenesis involving the effects of AP736 on the glycogen synthesis kinase 3β (GSK3β) pathway. Melanin content and tyrosinase activity were measured using a spectrophotometer after the cells were treated with AP736. The AP736-induced activation of signaling pathways was examined by western blot analysis. We confirmed that AP736 decreased melanin production in a dose-dependent manner; however, it did not directly inhibit tyrosinase, the rate-limiting melanogenic enzyme. The expression of microphthalmia-associated transcription factor, tyrosinase, and related signal transduction pathways was also investigated. The Wnt signaling pathway is deeply involved in melanogenesis; therefore, phosphorylation by GSK3β was assessed following treatment with AP736. AP736 induced GSK3β phosphorylation (inactivation), but it did not alter the level of β-catenin. Furthermore, the expression of α-melanocyte-stimulating hormone-induced tyrosinase was downregulated by AP736. Our data suggest that AP736 exerts hypopigmentary effects through the downregulation of tyrosinase via GSK3β phosphorylation.

Recently, 1,3-diarylalkyl thioureas have merged as one of the promising nonvanilloid TRPV1 antagonists possessing excellent therapeutic potential in pain regulation. In this paper, the full structure-activity relationship for TRPV1 antagonism of a novel series of 1,3-diarylalky thioureas is reported. Exploration of the structure-activity relationship, by systemically modulating three essential pharmacophoric regions, led to six examples of 1,3-dibenzyl thioureas, which exhibit Ca(2+) uptake inhibition in rat DRG neuron with IC(50) between 10 and 100 nM.

A series of N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butylbenzyl thioureas were prepared for the study of their agonistic/antagonistic activities to the vanilloid receptor in rat DRG neurons. Their structure-activity relationship reveals that there is a space for another hydrophobic binding interaction around 2-position in 4-tert-butylbenzyl region. Among the prepared derivatives, 6n show the highest antagonistic activity against the vanilloid receptor (IC(50)=15 nM).

The reaction of flavones with 2,4,4,6-tetrabromo-2,5-cyclohexadienone(1) gave the corresponding 3-bromoflavones under the mild reaction condition. Flavones containing easily oxidizable functional groups were also brominated without deleterious oxidation products.

Reaction of cyclic sulfates of vic-diols with sodium hydroxide in THF-MeOH produced the corresponding epoxides in excellent isolated yields at room temperature. Cyclic sulfates of trans-diols gave cis-epoxides, and cyclic sulfates of cis-diols afforded trans-epoxides exclusively. Various cyclic sulfates of vic-diols can be converted into the epoxides under the conditions.

The synthesis of 3-bromoflavones by bromination-debromination using pyridinium bromide perbromide is described.

Reaction of cyclic sulfates of vic-diols with magnesium iodide in acetonitrile produced the corresponding olefins in excellent isolated yields at room temperature. Cyclic sulfates of trans-diols gave trans-alkenes exclusively. Cyclic sulfates of cis-diols gave a mixture of cis- and trans- alkenes. However, the cyclic sulfate of cyclic cis-diol afforded the corresponding cis-alkene only.

Melanogenesis is essential for the protection of skin against UV, but excessive production of melanin causes unaesthetic hyperpigmentation. Much effort is being made to develop effective depigmenting agents. Here, we found that a tyrosinase inhibitor, AP736 (5-adamantan-1-yl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzamide) potently suppresses tyrosinase expression, and the mechanism underlying was elucidated. AP736 attenuated the melanin production induced by diverse melanogenic stimuli in murine and human melanocytes. It suppressed the expression of key melanogenic enzymes; tyrosinase, tyrosinase-related protein-1 and tyrosinase-related protein-2. The expression of microphthalmia-associated transcription factor (MiTF), a major promoter of melanogenesis was also decreased. AP736 inhibited the activation of cAMP response element-binding protein (CREB) and phosphokinase A (PKA), and cAMP elevation, reflecting that cAMP-PKA-CREB signalling axis was suppressed, resulting in the downregulation of MiTF and tyrosinase. Along with the previously reported tyrosinase inhibitory activity, the suppression of cAMP-PKA-CREB-mediated MiTF and tyrosinase expression by AP736 may be efficient for the treatment for hyperpigmentation.

Three-dimensional quantitative structure–activity relationship (3D-QSAR) modeling, comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) of polyhydroxylated N-benzylbenzamide derivatives containing an adamantyl moiety were performed to understand the mechanism of action and structure–activity relationship of these compounds. Contour map analysis indicated that steric contributions of the adamantyl moiety and electrostatic contributions of the hydroxyl group at the 3-position are important in the activity. Activities of the training set and test sets predicted by CoMFA fit well with actual activities, demonstrating that CoMFA, along with the best calculated q2 value, has the best predictive ability.

The liposidomycins are a family of novel lipid-containing nucleoside antibiotics that were recently found in the culture filterate and mycelia of Streptomyces griseosporeus.1 These antibiotics inhibit formation of the lipid intermediate in bacterial peptidoglycan synthesis.1,2 The primary site of action of liposidomycin C was found to be phospho-N-acetylmuramylpentapeptide transferase from E. coli Y-10 in peptidoglycan synthesis.3 The structures of liposidomycins A, B, and C were proposed as 1, 2, and 3, respectively, on the basis of degradation and spectroscopic studies,2,4 but six stereogenic centers in the lipid and diazepinone moieties remain unassigned. The overall structure as well as the diazepinone and 5-aminopentose 2-sulfate components are very unique. The present work reports synthetic studies related to the 5-amino-5-deoxy-P-Driboside 2-sulfate part of the liposidomycins.

In their reactions with phosphines, cyclic sulfates 9, 10, 11, and 12 afforded corresponding olefins by way of phosphonium sulfate salts whereas sugar cyclic sulfates 21 and 22 gave anhydrosugar 23.

We synthesized benzoate ester derivatives of kojic acid with and without adamantane moiety. Benzoate derivatives 2a-e that did not contain an adamantane moiety showed potent tyrosinase inhibitory activities. However, depigmenting activity was not noted in a cell-based assay. Contrasting results were obtained for benzoate derivatives (3a-e) containing an adamantane moiety. Compounds 3a-e showed potent depigmenting activities without tyrosinase inhibitory activities. To the best of our knowledge, this is the first study showing the depigmenting activities of kojic acid derivatives without tyrosinase inhibitory activities.

Treatment of cyclic sulfates of vic-diois with triphenylphosphine and iodine offers the corresponding olefins in high yields at room temperature. Both cyclic sulfates of d,l-hydrobenzoin and meso-hydrobenzoin give trans-stilbene.

Reaction of cyclic sulfates of vic-diols with magnesium iodide in acetonitrile produced the corresponding olefins in excellent isolated yields at room temperature. Cyclic sulfates of trans-diols gave trans-alkenes exclusively. Cyclic sulfates of cis-diols gave a mixture of cis- and trans- alkenes. However, the cyclic sulfate of cyclic cis-diol afforded the corresponding cis-alkene only.

The synthesis of 3-bromoflavones by bromination-debromination using pyridinium bromide perbromide is described.

Diels-Alder reaction is one of the most widely used reactions in organic synthesis due to its versatility and its high regioand stereoselectivity. Although the cis rule is quite generally followed, the endo addition rule appears to be obeyed only in the addition of cyclic dienes to cyclic dienophiles. It is well known that activated cyclic dienophiles in the rigid s-trans conformation such as maleic anhydride predominantly give endo cycloadducts in the reactions with cyclopentadiene. On the other hand, recent studies revealed that the Diels-Alder reaction of the cyclic dienophiles containing the exocyclic double bond in the rigid s-cis conformation such as itaconic anhydride, α-methylene-γ-butyrolactone, and 5-methylene-1,3-dioxolan-4-ones afforded predominantly exo cycloadducts. Conformationally unconstrained cyclic dienophiles such as 1 have not been fully explored. There have been only some scattered reports on Diels-Alder reactions of activated cyclic dienophiles in flexible conformation and their results are not consistent. We have previously observed complete exo selectivity in the Diels-Alder reaction of cyclopentadiene with activated cyclic sugar dienophiles in the flexible conformation. Therefore, we investigated the stereoselectivity of the DielsAlder reaction between cyclopentadiene and cyclic dienophiles having flexible conformation in order to know whether the exo selectivity in this type of reaction is general and in the hope to get some insight on the exo selectivity of the reaction. Although our theoretical study based on a part of the present results was published, it could not provid us clear picture for the origin of the exo selectivity. Moreover, the calculation failed to explain the exo selectivity in the reaction of cyclopentadiene with 1 and with 3. Herein we report the exo selective Diels-Alder reaction of cyclopentadiene with model cyclic dienophiles 1~4 and the temperature effect and Lewis acid effect on the exo selectivity. Reaction of 5-formyl-2,3-dihydrofuran (1) with cyclopentadiene provided a mixture of exo cycloadduct 5a and endo cycloadduct 5b in 5 : 1 ratio in 71% yield at 160 C in a sealed tube and 12 : 1 ratio in 33% yield at room temperature. On the other hand, complete exo selectivity was observed in the cycloaddition of 1 and cyclopentadiene in the presence of BF3·OEt2 at -78 C in methylene chloride. Cycloaddition of 1 with cyclopentadiene catalyzed by Et2AlCl also afforded predominantly the exo adduct, whereas the reaction in the presence of SnCl4 provided more

An efficient and practical one-pot synthesis of 4,5-diaryl-2,2-dimethyl-3(2H)-furanones has been achieved from 1,2-diarylethanones and 2-bromoisobutyryl cyanide in the presence of excess base, by employing the ‘hard soft acid base’ principle. The reaction scope of 2-bromoisobutyryl cyanide could be expanded to prepare a variety of 2,2-dimethyl-3(2H)-furanone derivatives other than 4,5-diaryl-2,2-dimethyl-3(2H)-furanones.

The reaction of flavones with 2,4,4,6-tetrabromo-2,5-cyclohexadienone(1) gave the corresponding 3-bromoflavones under the mild reaction condition. Flavones containing easily oxidizable functional groups were also brominated without deleterious oxidation products.

Seventeen biarylcarboxybenzamide derivatives were prepared for the study of their agonistic/antagonistic activities to the vanilloid receptor (VR1) in rat DRG neurons. The replacement of the piperazine moiety of the lead compound 1 with phenyl ring showed quite enhanced antagonistic activity. Among the prepared derivatives, N-(4-tert-butylphenyl)-4-pyridine-2-yl-benzamide (2, IC50 = 31 nM) and N-(4-tert-butylphenyl)-4-(3-methylpyridine-2-yl)benzamide (3g, IC50 = 31 nM), showed 5-fold higher antagonistic activity than 1 in 45Ca2+-influx assay.

A new series of cyclooxygenase-2 (COX-2) inhibitors with gamma-pyrone as central scaffold unit has been synthesized and their biological activities were evaluated against cyclooxygenase inhibitory activity. The changes of physical properties of the molecules were performed according to the medicinal chemistry principles and moderate oral anti-inflammatory activity was obtained with this series of inhibitors.

A series of chain-branched 1,3-dibenzylthiourea derivatives were synthesized, and tested their antagonist activity against vanilloid receptor 1. Chain-branching led to a significant change in the mode of action and the potency. ( R )-Methyl or ethyl-branched 1,3-dibenzylthiourea derivatives showed the most potent antagonist activity up to the IC 50 value of 0.05 μM which is 10-fold more potent than capsazepine.

A novel non-vanilloid VR1 antagonist consisting of a new vanilloid equivalent exhibits excellent analgesic effects as well as highly potent antagonistic activities in both capsaicin single channel and calcium uptake assays. In addition, the structural requirement for the vanilloid equivalent of the potent VR1 antagonist has also been elucidated.

A new series of cyclooxygenase-2(COX-2) inhibitors with naturally occurring flavone as the main skeleton has been synthesized and their biological activities were evaluated for cyclooxygenase inhibitory activity. Rational structural modifications were applied to potent COX-2 inhibitors to obtain the desired pharmacokinetic profiles for improved oral anti-inflammatory activity.

Reaction of cyclic sulfates of vic-diols with sodium hydroxide in THF-MeOH produced the corresponding epoxides in excellent isolated yields at room temperature. Cyclic sulfates of trans-diols gave cis-epoxides, and cyclic sulfates of cis-diols afforded trans-epoxides exclusively. Various cyclic sulfates of vic-diols can be converted into the epoxides under the conditions.