BCI-215, a Dual-Specificity Phosphatase Inhibitor, Reduces UVB-Induced Pigmentation in Human Skin by Activating Mitogen-Activated Protein Kinase Pathways.

BACKGROUND: The dysregulation of melanin production causes skin-disfiguring ultraviolet (UV)-associated hyperpigmented spots. Previously, we found that the activation of c-Jun N-terminal kinase (JNK), a mitogen-activated protein kinase (MAPK), inhibited melanogenesis. METHODS: We selected BCI-215 as it may modify MAPK expression via a known function of a dual-specificity phosphatase (DUSP) 1/6 inhibitor. B16F10 melanoma cells, Mel-ab cells, human melanocytes, and a coculture were used to assess the anti-melanogenic activity of BCI-215. The molecular mechanisms were deciphered by assaying the melanin content and cellular tyrosinase activity via immunoblotting and RT-PCR. RESULTS: BCI-215 was found to suppress basal and cAMP-stimulated melanin production and cellular tyrosinase activity in vitro through the downregulation of microphthalmia-associated transcription factor (MITF) protein and its downstream enzymes. The reduction in MITF expression caused by BCI-215 was found to be due to all three types of MAPK activation, including extracellular signal-regulated kinase (ERK), JNK, and p38. The degree of activation was greater in ERK. A phosphorylation of the ß-catenin pathway was also demonstrated. The melanin index, expression of MITF, and downstream enzymes were well-reduced in UVB-irradiated ex vivo human skin by BCI-215. CONCLUSIONS: As BCI-215 potently inhibits UV-stimulated melanogenesis, small molecules of DUSP-related signaling modulators may provide therapeutic benefits against pigmentation disorders.

Antioxidative and anti-inflammatory activity of psiguadial B and its halogenated analogues as potential neuroprotective agents.

Psiguadial B (8), and its fluoro- (8a), chloro- (8b), and bromo- (8c) derivatives were synthesized using a sodium acetate-catalyzed single step coupling of three components: ß-caryophyllene (5), diformylphloroglucinol (11), and benzaldehyde (12). These compounds efficiently and dose-dependently decreased H2O2-induced cell death, a quantitative marker of cell death, in primary cultures of mouse cortical neurons. Psiguadial B also decreased neuronal death and accumulation of ROS induced by FeCl2 in cortical cultures. The in vitro effects of these compounds in lipopolysaccharide (LPS)-induced expression of nitric oxide (NO), and TNF-α and IL-6 by suppressing the NF-κB pathway in immune cells demonstrated their antioxidative and anti-inflammatory activity. The present findings warrant further research on the development of psiguadial B-based neuroprotective agents for the treatment of neurodegenerative diseases, acute brain injuries and immunological disorders.

Asymmetric Total Synthesis of (+)-(3E)-Pinnatifidenyne via Abnormally Regioselective Pd(0)-Catalyzed Endocyclization.

The asymmetric total synthesis of the marine natural product (+)-(3E)-pinnatifidenyne was accomplished. The key features of the synthesis involve the construction of an eight-membered cyclic ether by the abnormally regioselective Pd(0)-catalyzed cyclization, the installation of a double bond in the oxocene skeleton by sequential in situ deconjugative isomerization, and the efficient introduction of the crucial chloride mediated by the substrate-controlled diastereoselective reduction.

Conformation-Enabled Total Syntheses of Ohmyungsamycins†A and B and Structural Revision of Ohmyungsamycin†B.

The first total syntheses of the bioactive cyclodepsipeptides ohmyungsamycin A and B are described. Key features of our synthesis include the concise preparation of a linear cyclization precursor that consists of N-methyl amides and non-proteinogenic amino acids, and its macrolactamization from a bent conformation. The proposed structure of ohmyungsamycin B was revised based on its synthesis. The cyclic core of the ohmyungsamycins was shown to be responsible for the excellent antituberculosis activity, and ohmyungsamycin variants with truncated chains were evaluated for their biological activity.

Asymmetric synthesis of vinylogous ß-amino acids and their incorporation into mixed backbone oligomers.

Chiral vinylogous ß-amino acids (VBAA) were synthesized using enantioselective Mannich reactions of aldehydes with in situ generated N-carbamoyl imines followed by a Horner-Wadsworth-Emmons reaction. The efficiency with which these units could be incorporated into oligomers with different moieties on the C- and N-terminal sides was established, as was the feasibility of sequencing oligomers containing VBAAs by tandem mass spectrometry. The data show that VBAAs will be useful building blocks for the construction of combinatorial libraries of peptidomimetic compounds.

Identification of a novel circadian clock modulator controlling BMAL1 expression through a ROR/REV-ERB-response element-dependent mechanism.

Circadian rhythms, biological oscillations with a period of about 24 h, are maintained by an innate genetically determined time-keeping system called the molecular circadian clockwork. Despite the physiological and clinical importance of the circadian clock, development of small molecule modulators targeting the core clock machinery has only recently been initiated. BMAL1, a core clock gene, is controlled by a ROR/REV-ERB-response element (RORE)-dependent mechanism, which plays an important role in stabilizing the period of the molecular circadian clock. Therefore, we aimed to identify a novel small molecule modulator that regulates Bmal1 gene expression in RORE-dependency, thereby influencing the molecular feedback loop of the circadian clock. For this purpose, we carried out a cell-based screen of more than 1000 drug-like compounds, using a luciferase reporter driven by the proximal region of the mouse Bmal1 promoter. One compound, designated KK-S6, repressed the RORE-dependent transcriptional activity of the mBmal1 promoter and reduced endogenous BMAL1 protein expression. More importantly, KK-S6 significantly altered the amplitude of circadian oscillations of Bmal1 and Per2 promoter activities in a dose-dependent manner, but barely affected the period length. KK-S6 effectively decreased mRNA expression of metabolic genes acting downstream of REV-ERBα, Pai-1 and Citrate synthase, that contain RORE cis-element in their promoter. KK-S6 likely acts in a RORE-dependent manner by reinforcing the REV-ERBα activity, though not by the same mechanism as known REV-ERB agonists. In conclusion, the present study demonstrates that KK-S6 functions as a novel modulator of the amplitude of molecular circadian rhythms by influencing RORE-mediated BMAL1 expression.

Identification and Structural Analysis of New Nrf2 Activators by Mechanism-Based Chemical Transformation of 15-Deoxy-Δ12, 14 -PGJ2.

Mechanism-based chemical transformation of 15-deoxy-Δ12, 14 -PGJ2 (15d-PGJ2 ) resulted in a series of new NF-E2-related factor-2 (Nrf2) activators and detailed elucidation of the function of each electrophilic binding site. In addition, HO-1 expression resulting from Nrf2 activation through enhanced dissociation of the Keap1-Nrf2 complex by the new activators was proved.

Divergent synthetic route to new cyclopenta[c]pyran iridoids: syntheses of jatamanin A, F, G and J, gastrolactone and nepetalactone.

Six natural iridoids including jatamanin A, F, G and J, gastrolactone and nepetalactone have been synthesized via the efficient transformation of a core cyclopenta[c]pyran intermediate. Key features of the syntheses include the stereoselective construction of the core cyclopenta[c]pyran skeleton of the iridoid lactones via a Pd(0)-catalyzed intramolecular allylic alkylation, and the facile transformation of the common intermediate into natural iridoids.

Diastereoselective Total Synthesis of (-)-Galiellalactone.

An enantioselective total synthesis of (-)-galiellalactone has been accomplished. The key features of the synthesis involve the highly stereoselective construction of the cis-trisubstituted cyclopentane intermediate by a Pd(0)-catalyzed cyclization, the stereospecific introduction of an angular hydroxyl group by Riley oxidation, and the efficient construction of the tricyclic system of (-)-galiellalactone via a combination of diastereoselective Hosomi-Sakurai crotylation and ring-closing metathesis (RCM).

Identification of small molecule inhibitors of the STAT3 signaling pathway: Insights into their structural features and mode of action.

A series of novel STAT3 inhibitors consisting of Michael acceptor has been identified through assays of the focused in-house library. In addition, their mode of action and structural feature responsible for the STAT3 inhibition were investigated. In particular, analog 6 revealed promising STAT3 inhibitory activity in HeLa cell lines. The analog also exhibited selective inhibition of STAT3 phosphorylation without affecting STAT1 phosphorylation and cytostatic effect in human breast epithelial cells (MCF10A-ras), which supports cancer cell-specific inhibitory properties.

Fine tuning of 4,6-bisphenyl-2-(3-alkoxyanilino)pyrimidine focusing on the activity-sensitive aminoalkoxy moiety for a therapeutically useful inhibitor of receptor for advanced glycation end products (RAGE).

Through the fine tuning of the activity-sensitive aminoalkoxy moiety of 4,6-bisphenyl-2-(3-alkoxyanilino)pyrimidine as a novel inhibitor of the receptor for advanced glycation end products (RAGE), the tertiary amine was elucidated as an essential part associated with RAGE inhibition. On the basis of this finding, a 3-(N,N-dimethylamino)pyrrolidine analog 12o was identified as a therapeutically useful RAGE inhibitor with improved activity and solubility. Molecular modeling studies predicted that the improved inhibitory activity is induced by additional hydrogen bonds between the nitrogen atom of the pyrrolidine ring and Arg48 and by an interaction between the dimethylamino-substituent of the pyrrolidine moiety and a relatively hydrophobic groove in the RAGE binding site.

Design and synthesis of a macrosphelide A-biotin chimera.

The rational design and synthesis of a biochemical probe of natural (+)-macrosphelide A, a potent cell-cell adhesion inhibitor, was completed to aid in the identification of its biological target. The key features of the synthesis include: (1) an efficient synthesis of the macrosphelide core structure using Yamaguchi-Hirao alkynylation, (2) a cross metathesis to connect a linker unit to the allyl-macrosphelide and (3) coupling of the linker-bound macrosphelide A with a chemical biotin tag.

Photocatalytic intermolecular bromonitroalkylation of styrenes: synthesis of cyclopropylamine derivatives and their evaluation as LSD1 inhibitors.

A mild and efficient method for photoredox-catalyzed bromonitroalkylation of alkenes is described herein. In this reaction, bromonitromethane serves as a source of both nitroalkyl and bromine for direct and regioselective formation of C-Br and C-C bonds from alkenes, and additional cyclization provides C-C bonds to the cyclopropylamine core as an LSD1 inhibitor.

Degrader-Antibody Conjugates: Emerging New Modality.

In order to deliver chemotherapeutics more efficiently, small-molecule-drug conjugates (SMDCs) and antibody-drug conjugates (ADCs) have been synthesized and explored. These conjugates not only provide selective delivery but also improve the therapeutic index of toxins. By merging this conjugate concept with target protein degradation (TPD), the degrader-antibody conjugate (DAC) field has emerged, and clinical trials have even begun in recent years. In this Perspective, we provide the concepts, applications, and recent advances in the area of DACs.

Thio(seleno)cyano-difluoroalkylation of Alkenes Using Visible-Light Photocatalysis.

A mild and efficient three-component thio(seleno)cyano-difluoroalkylation of simple alkenes is demonstrated using an iridium(ruthenium) photocatalyst. This protocol provides a direct and regioselective installation of both C-S(Se)CN [thio(seleno)cyanation] and C-CF (difluoroalkylation) bonds.

A bioisosteric approach to the discovery of novel N-aryl-N'-[4-(aryloxy)cyclohexyl]squaramide-based activators of eukaryotic initiation factor 2 alpha (eIF2α) phosphorylation.

Inhibition of translation initiation has emerging implications for the development of mechanism-based anticancer therapeutics. Phosphorylation of eIF2α is recognized as a key target that regulates the translation initiation cascade. Based on the bioisosteric replacement of urea-derived eIF2α phosphorylation activator 1, a novel series of N-aryl-N'-[4-(aryloxy)cyclohexyl]squaramide derivatives was designed and synthesized; their effects on the activation of eIF2α phosphorylation was assessed systematically. A brief structure-activity relationship analysis was established by stepwise structural optimization of the squaramide series. Subsequently, the antiproliferative activities of the selected analogues were determined in human leukemia K562 cells. We then identified 10 potent eIF2α phosphorylation activators with considerable anticancer activity. The most promising analogues 19 and 40 possessed higher cancer cell selectivity (SI = 6.16 and 4.83, respectively) than parent 1 (SI = 2.20). Finally, protein expression analysis revealed that compounds 19 and 40 induced eIF2α phosphorylation and its downstream effectors ATF4 and CHOP.

Design, synthesis and insight into the structure-activity relationship of 1,3-disubstituted indazoles as novel HIF-1 inhibitors.

Design, synthesis and insight into the structure-activity relationship (SAR) of 1,3-disubstituted indazoles as novel HIF-1 inhibitors are described. In particular, the substituted furan moiety on indazole skeleton as well as its substitution pattern turns out crucial for the high HIF-1 inhibition.

Targeting the Nuclear Receptor-Binding SET Domain Family of Histone Lysine Methyltransferases for Cancer Therapy: Recent Progress and Perspectives.

Nuclear receptor-binding SET domain (NSD) proteins are a class of histone lysine methyltransferases (HKMTases) that are amplified, mutated, translocated, or overexpressed in various types of cancers. Several campaigns to develop NSD inhibitors for cancer treatment have begun following recent advances in knowledge of NSD1, NSD2, and NSD3 structures and functions as well as the U.S. FDA approval of the first HKMTase inhibitor (tazemetostat, an EZH2 inhibitor) to treat follicular lymphoma and epithelioid sarcoma. This perspective highlights recent findings on the structures of catalytic su(var), enhancer-of-zeste, trithorax (SET) domains and other functional domains of NSD methyltransferases. In addition, recent progress and efforts to discover NSD-specific small molecule inhibitors against cancer-targeting catalytic SET domains, plant homeodomains, and proline-tryptophan-tryptophan-proline domains are summarized.

Physical and Functional Analysis of the Putative Rpn13 Inhibitor RA190.

Rpn13 is one of several ubiquitin receptors in the 26S proteasome. Cys88 of Rpn13 has been proposed to be the principal target of RA190, an electrophilic small molecule with interesting anti-cancer activities. Here, we examine the claim that RA190 mediates its cytotoxic effects through engagement with Rpn13. We find no evidence that this is the case. In vitro, RA190 is has no measurable effect on any of the known interactions of Rpn13. In cellulo, we see no physical engagement of Rpn13 by RA190, either on C88 or any other residue. However, chemical proteomics experiments in two different cell lines reveal that dozens of other proteins are heavily engaged by RA190. Finally, increasing or reducing the level of Rpn13 in HeLa and melanoma cells had no effect on the sensitivity of HeLa or melanoma cells to RA190. We conclude that Rpn13 is not the physiologically relevant target of RA190.

Targeting Peroxisome Proliferator-Activated Receptor Delta (PPARδ): A Medicinal Chemistry Perspective.

One of the three subtypes of the peroxisome proliferator-activated receptor (PPAR) functioning as a transcription factor is the PPARß or PPARδ. PPARδ is crucial to pathophysiological processes, including metabolic disorders, liver diseases, and cardiovascular diseases. In the past, the clinical development of PPARδ-selective agonist drugs has been stalled due to potential safety-related issues. Despite the elusiveness of such a drug, efforts continue in developing drugs that target PPARδ due to advances in the knowledge of the PPARδ receptor's structure and functions. While several preclinical and clinical studies are reported on PPARδ agonists, there is limited data with no clinical evidence available for PPARδ-selective antagonists. In this review, we mainly focus on the challenges of PPARδ selectivity and the medicinal chemistry of most active agonists discovered by different pharmaceutical companies and institutes. With this in mind, we also provide an update on the development status of PPARδ agonists that are undergoing clinical trials and their therapeutic promise for the treatment of various diseases.