A Review on Biological Properties and Synthetic Methodologies of Diarylpentadienones.

Medicinal chemists have continuously shown interest in new curcuminoid derivatives, diarylpentadienones, owing to their enhanced stability feature and easy preparation using a one-pot synthesis. Thus far, methods such as Claisen-Schmidt condensation and Julia- Kocienski olefination have been utilised for the synthesis of these compounds. Diarylpentadienones possess a high potential as a chemical source for designing and developing new and effective drugs for the treatment of diseases, including inflammation, cancer, and malaria. In brief, this review article focuses on the broad pharmacological applications and the summary of the structure-activity relationship of molecules, which can be employed to further explore the structure of diarylpentadienone. The current methodological developments towards the synthesis of diarylpentadienones are also discussed.

Therapeutic nuclear shuttling of YB-1 reduces renal damage and fibrosis.

Virtually all chronic kidney diseases progress towards tubulointerstitial fibrosis. In vitro, Y-box protein-1 (YB-1) acts as a central regulator of gene transcription and translation of several fibrosis-related genes. However, it remains to be determined whether its pro- or antifibrotic propensities prevail in disease. Therefore, we investigated the outcome of mice with half-maximal YB-1 expression in a model of renal fibrosis induced by unilateral ureteral obstruction. Yb1+/- animals displayed markedly reduced tubular injury, immune cell infiltration and renal fibrosis following ureteral obstruction. The increase in renal YB-1 was limited to a YB-1 variant nonphosphorylated at serine 102 but phosphorylated at tyrosine 99. During ureteral obstruction, YB-1 localized to the cytoplasm, directly stabilizing Col1a1 mRNA, thus promoting fibrosis. Conversely, the therapeutic forced nuclear compartmentalization of phosphorylated YB-1 by the small molecule HSc025 mediated repression of the Col1a1 promoter and attenuated fibrosis following ureteral obstruction. Blunting of these effects in Yb1+/- mice confirmed involvement of YB-1. HSc025 even reduced tubulointerstitial damage when applied at later time points during maximum renal damage. Thus, phosphorylation and subcellular localization of YB-1 determines its effect on renal fibrosis in vivo. Hence, induced nuclear YB-1 shuttling may be a novel antifibrotic treatment strategy in renal diseases with the potential of damage reversal.

In vivo and in vitro inhibitory activity of an ethanolic extract of Sargassum fulvellum and its component grasshopper ketone on atopic dermatitis.

The present study investigated the effect of Sargassum fulvellum ethanol extract (SFEE) on 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD)-like skin lesions in BALB/c mice. The severity of skin dermatitis, production of cytokines, and total IgE content were measured, and the histopathological features were analyzed. SFEE decreased the severity of DNCB-induced dermatitis and suppressed the serum levels of total immunoglobulin E (IgE), tumor necrosis factor (TNF)-α, and interleukin (IL)-4. In addition, SFEE reduced the production of IL-4, IL-5, and IL-13 in mice splenocytes. However, the levels of IL-10 and interferon (IFN)-γ significantly increased in mice sera and splenocytes. Histological examination revealed decreased dermal thickness and infiltration by mast cells after treatment with SFEE. Furthermore, grasshopper ketone, a compound isolated from SFEE, was found to significantly decrease cytokine production in concanavalin A-stimulated splenocytes from BALB/c mice with no cytotoxicity. Taken together, these results indicate that SFEE and the isolated grasshopper ketone have an inhibitory effect on AD by regulating immune mediators and cells and may be a potential effective alternative therapy for AD.

A novel small compound accelerates dermal wound healing by modifying infiltration, proliferation and migration of distinct cellular components in mice.

BACKGROUND: Impaired wound healing in skin ulcer is one of the major medical issues in the aged society. Wound healing is a complex process orchestrated by a number of humoral factors and cellular components. TGF-ß is known to stimulate collagen production in dermal fibroblasts while inhibiting proliferation of epidermal keratinocyte. A screening of small compounds that suppress type I collagen production in fibroblasts has identified HSc025 that antagonizes the TGF-ß/Smad signal. OBJECTIVE: We examined the effects of HSc025 on dermal wound healing and elucidated the underlying mechanisms. METHODS: Effects of HSc025 on the wound closure process were evaluated in a murine full-thickness excisional wound healing model. Cell proliferation and migration were estimated using primary cultures of human keratinocytes and fibroblasts. Comprehensive analyses of gene expression profiles were performed using untreated and HSc025-treated fibroblasts. RESULTS: Oral HSc025 administration suppressed macrophage infiltration and accelerated wound closure as early as at day 2 after the dermal excision. Treatment of cultured keratinocytes with HSc025 counteracted the inhibitory effects of TGF-ß on cell proliferation and migration. On the other hand, HSc025 stimulated migration, but not proliferation, of dermal fibroblasts independently of TGF-ß. Experiments using an artificial dermis graft revealed that HSc025 stimulated migration of collagen-producing cells into the graft tissue. A cDNA microarray analysis of untreated and HSc025-treated fibroblasts identified pirin as a critical mediator accelerating fibroblast migration. CONCLUSION: HSc025 accelerates wound healing by modifying infiltration, proliferation and migration of distinct cellular components, which provides a novel insight into the therapy for intractable skin ulcer.

Occipital nerve stimulation with the Bion® microstimulator for the treatment of medically refractory chronic cluster headache.

BACKGROUND: Chronic cluster headache is a severely disabling neurological disorder. Evidence from open-label case series suggest that occipital nerve stimulation may be effective for the treatment of chronic cluster headache. OBJECTIVE: To evaluate the effectiveness of a microstimulator for chronic cluster headache. STUDY DESIGN: Prospective, observational feasibility study plus medical record review. SETTINGS: Academic medical center. METHODS: Four patients with medically refractory chronic cluster headache underwent implantation of a unilateral bion microstimulator. In-person follow-up was conducted for 12 months after implantation, and a prospective follow-up chart review was carried out to assess long term outcome. RESULTS: Three of the participants returned their headache diaries for evaluation. The mean duration of chronic cluster headache was 14.3 years (range 3 to 29 years). Pain was predominantly or exclusively retroocular/periocular. One participant demonstrated a positive response (> 50% reduction in cluster headache frequency) at 3 months post-implant, while there were 2 responders at 6 months. At least one of the participants continued to show > 60% reduction in headache frequency at 12 months. A chart review showed that at 58-67 months post-implant, all 3 participants reported continued use and benefit from stimulation. No side-shift in attacks was noted in any participant. Adverse events were limited to 2 participants with neck pain and/or cramping with stimulation at high amplitudes; one required revision for a faulty battery. LIMITATIONS: Small patient population without control group. Not blinded or randomized. CONCLUSION: Unilateral occipital nerve stimulation, using a minimally invasive microstimulator, may be effective for the treatment of medically refractory chronic cluster headache. This benefit may occur immediately after implantation, remain sustained up to 5 years after implantation, and occur despite the anterior location of the pain. Prospective, randomized controlled trials of occipital nerve stimulation in chronic cluster headache should proceed.  

Synthesis of 86 species of 1,5-diaryl-3-oxo-1,4-pentadienes analogs of curcumin can yield a good lead in vivo.

BACKGROUND: Curcumin is known to possess many anti-tumor properties such as inhibition of tumor growth and induction of apotosis. However, limited bioavailability of curcumin prevents its clinical application. A synthesized curcumin analog, 1,5-diaryl-3-oxo-1,4-pentadiene such as GO-Y030, has the improved anti-tumor potential in vitro as well as in mouse model of colorectal carcinogenesis. RESULTS: These compounds were divided into two groups; one is the higher anti-proliferative group, in which 79.7% of 1,5-diaryl-3-oxo-1,4-pentadienes were clustered. One of the 1,5-diaryl-3-oxo-1,4-pentadiene analogs, GO-Y078 has the most enhanced growth inhibition, and its solubility was improved, compared with curcumin. GO-Y078 inhibits NF-κB transactivation, as well as expression of TP53 and DR5 more effectively than curcumin. In a mouse model, GO-Y078 presented 1.4 fold more survival elongation that was not achieved by curcumin and GO-Y030. CONCLUSIONS: The 1,5-diaryl-3-oxo-1,4-pentadiene analogs can yield good lead compounds for cancer chemotherapy, to overcome low bioavailability of curcumin.

A novel inhibitor of Smad-dependent transcriptional activation suppresses tissue fibrosis in mouse models of systemic sclerosis.

OBJECTIVE: Tissue fibrosis is a major cause of morbidity and mortality in systemic sclerosis (SSc), and an increasing number of promising molecular targets for antifibrotic therapies have been described recently. Transforming growth factor beta (TGFbeta) is well known to be the principal factor that leads to tissue fibrosis. The present study was undertaken to investigate the ability of HSc025, a novel small compound that antagonizes TGFbeta/Smad signaling through the activation of nuclear translocation of Y-box binding protein 1, to prevent tissue fibrosis in vitro or in mouse models of SSc. METHODS: Human dermal fibroblasts were exposed to HSc025 at various concentrations in the presence of TGFbeta, and levels of collagen or fibronectin expression were determined. HSc025 (15 mg/kg/day for 14 days) was administered orally to tight skin mice and to mice with bleomycin-induced pulmonary fibrosis. Improvement of tissue fibrosis was evaluated by histologic or biochemical examination in each model. RESULTS: Pretreatment with HSc025 prevented Smad-dependent promoter activation, in a dose-dependent manner; however, HSc025 had no effect on TGFbeta-induced phosphorylation of Smad3. The inhibitory effects of HSc025 on TGFbeta-induced collagen or fibronectin expression were also confirmed in vitro. Orally administered HSc025 significantly reduced hypodermal thickness and hydroxyproline content in tight skin mice, and markedly decreased the histologic score and hydroxyproline content in the lungs of bleomycin-treated mice. CONCLUSION: These results demonstrate that HSc025 is a novel inhibitor of TGFbeta/Smad signaling, resulting in the improvement of skin and pulmonary fibrosis. Orally available HSc025 might therefore be useful in the treatment of SSc.

1,5-diaryl-3-oxo-1,4-pentadienes: a case for antineoplastics with multiple targets.

A number of organic molecules which contain the 1,5-diaryl-3-oxo-1,4-pentadienyl group, referred to hereafter as the dienone moiety, have antineoplastic properties. Emphasis is made on the attachment of this structural moiety to several molecular scaffolds, namely piperidines, N-acylpiperidines, cycloalkanes and 3,4-dihydro-1H-napthalenes. Many of these compounds are potent cytotoxins having micromolar and nanomolar IC(50) values towards a wide range of neoplastic and transformed cells. On occasions, greater toxicity towards neoplasms than normal cells has been demonstrated. A number of these compounds have in vivo anticancer properties and in general excellent tolerability in rodents is demonstrated. The way in which a number of physicochemical properties such as redox potentials, torsion angles, atomic charges and logP values govern cytotoxic potencies are presented. The importance of the shapes of different compounds as determined by molecular modeling in contributing to antineoplastic properties is outlined. Arguments are presented in favour of designing antineoplastics which have multiple sites of action in contrast to those bioactive molecules which have only one molecular target. A number of compounds which possess the dienone group have different modes of action some of which are chronicled in this review, such as inducing apoptosis, affecting respiration in mitochondria, inhibiting macromolecular biosynthesis and both inhibiting and stimulating certain enzymes. Other important properties of these compounds are discussed including their anti-angiogenic, MDR-revertant and antioxidant properties. It is hoped that this eulogy of the importance of the dienone group will encourage researchers to consider incorporating this structural unit into candidate cytotoxins in the future.