Evaluation and Optimization of the Anti-Melanogenic Activity of 1-(2-Cyclohexylmethoxy-6-hydroxy-phenyl)-3-(4-hydroxymethyl-phenyl)-propenone Derivatives.

The chemical modification and optimization of biologically active compounds are essential steps in the identification of promising lead compounds for drug development. We previously reported the anti-melanogenic activity of 1-(2-cyclohexylmethoxy-6-hydroxy-phenyl)-3-(4-hydroxymethyl-phenyl)-propenone (chalcone 21). In this study, we synthesized 21 derivatives of chalcone 21 and evaluated their anti-melanogenic activity in -MSH-induced B16F10 cells. (E)-N-(4-(3-(2-(Cyclohexylmethoxy)phenyl)-3-oxoprop-1-en-1-yl)phenyl)acetamide (chalcone 21-21) exhibited the strongest inhibition of cellular melanin production, with an IC50 value of 0.54 M. It was more potent than chalcone 21 and the known anti-melanogenic agents kojic acid and arbutin, whose IC50 values were 4.9, 38.5, and 148.4 M, respectively. Chalcone 21-21 decreased the expression and activity of tyrosinase. It also decreased the expression of TRP1, TRP2 and MITF, the phosphorylation of CREB and ERK1/2, and the transcriptional activity of MITF and CRE. Our results demonstrate that chalcone-21-21 is an effective lead compound with anti-melanogenic activity.

Diarylheptanoid Hirsutenone Attenuates Osteoclastogenesis by Suppressing IFNγ and NF-κB Signaling in Th1 and Preosteoclastic Cells.

The aim of the present study was to examine the inhibitory roles and mechanisms of hirsutenone (HTN) in the regulation of osteoclastogenesis. Gene levels were compared to assure the effects of HTN on osteoclastogenesis in mouse splenocytes/CD4+ T cells, mouse macrophage-like cell line RAW264.7 (preosteoclast), MG63 (osteoblast), and RPMI1788 (B cell) cells. The mechanism by which HTN regulates the degradation of tumor necrosis factor receptor-associated factor 6 (TRAF6) and inhibits inhibitor of kappaB (IκB) and nuclear factor-kappaB (NF-κB) signaling was examined by Western blotting and luciferase reporter assays. Our results demonstrated that HTN effectively downregulated the expression of interferon γ (IFNγ), interleukin-22 (IL-22), IL-1ß, and tartrate-resistant acid phosphatase (TRAP) in splenocyte-/CD4+-RAW264.7 co-culture system. Moreover, receptor activator of nuclear factor-κB ligand (RANKL) and CD25 expression were also significantly inhibited in MG63 and CD4+ single culture system, suggesting an additional independent effect of HTN on osteoclastogenesis. Notably, TRAF6 was markedly degraded along with a decrease in nuclear factor of activated T-cells (NFATc) and NF-κB activities in RAW264.7 cells. Finally, we concluded that HTN directly or indirectly inhibits osteoclastogenesis via the inhibition of NF-κB signaling by promoting TRAF6 degradation, and plays a crucial role in suppressing the expression of RANKL and cytokines expressed in IFNγ-producing T-helper 1 (Th1) cells. These findings suggest that HTN may be a promising therapeutic candidate for diseases resulting from bone loss.

Inhibition of tyrosinase activity and melanin production by the chalcone derivative 1-(2-cyclohexylmethoxy-6-hydroxy-phenyl)-3-(4-hydroxymethyl-phenyl)-propenone.

Abnormal accumulation of melanin pigments in the skin can be lead to hyperpigmentation disorders and melanoma. Melanin biosynthesis is ultimately regulated by the rate-limiting enzyme tyrosinase. In the present study, we synthesized chalcone derivatives and identified 1-(2-cyclohexylmethoxy-6-hydroxy-phenyl)-3-(4-hydroxymethyl-phenyl)-propenone (chalcone-21) as an anti-melanogenic substance in B16F10 melanoma cells. Chalcone-21 strongly inhibited cellular melanin production and tyrosinase activity in B16F10 melanoma cells stimulated with α-melanocyte stimulating hormone (α-MSH) or protoporphyrin IX. In addition, the compound suppressed not only the expression of tyrosinase, tyrosinase-related protein-1 (TRP-1), TRP-2, and microphthalmia-associated transcription factor (MITF), but also the transcriptional activity of tyrosinase and MITF. Our results demonstrated chalcone-21 to be an effective depigmenting agent.

The anti-aging properties of a human placental hydrolysate combined with dieckol isolated from Ecklonia cava.

BACKGROUNDS: In the present study, we aimed to examine the anti-aging properties of human placental hydrolysate (HPE) and dieckol (DE) from Ecklonia cava against free radical scavenging, muscle hypertrophy-related follistatin mRNA expression, amelioration of cognition-related genes and proteins, inhibition of collagenase-regulating genes, and elastinase activity. METHODS: The anti-aging effects were examined in human fibroblast (CCD986sk), mouse myoblast (C2C12), and neuroblastoma (N2a) cell models, by employing various assays such as 2,2-diphenyl-1-picrylhydrazyl hydrate (DPPH) scavenging, hydroxyl radical-mediated oxidation, quantitative real-time polymerase chain reaction, enzyme activity, and immunocytochemistry observation. RESULTS: Our results show that HPE combined with DE (HPE:DE) strongly scavenged DPPH radicals and protected proteins against degradation by hydroxyl radical attack. HPE:DE effectively inhibited matrix metalloproteinase-1 expression, protein kinase C alpha expression, and elastinase activity. Furthermore, HPE:DE improved the expression of cognition-related genes (choline acetyltransferase and vesicular acetylcholine transporter). These events may proactively contribute to retard the aging processes and the abrupt physiological changes probably induced by mitochondrial dysfunction with aging. CONCLUSIONS: Based on these findings, we conclude that the combined treatment of HPE:DE may be useful for anti-aging therapy in which the accumulation of oxidative damage is the main driving force.

Safety and efficacy of transcutaneous bone conduction implant surgery for hearing improvement in microtia patients with bilateral hearing impairment.

BACKGROUND: In microtia patients with bilateral hearing impairment, hearing improvement is crucial for language development and performance. External auditory canal reconstruction (EACR) has been performed to improve hearing, but often result in complications. We performed transcutaneous bone conduction implant (TBCI) surgery in these patients. This study aimed to evaluate the safety and efficacy of TBCI surgery. METHODS: A retrospective review was performed of five patients who underwent auricular reconstruction and TBCI surgery and 12 patients who underwent EACR between March 2007 and August 2018. Hearing improvement was measured based on the air-bone gap values using pure-tone audiometry over a 6-week postoperative period. We reviewed other studies on hearing improvement using EACR and compared the findings with our result. The surgical techniques for TBCI were reviewed through case analyses. RESULTS: Postoperative hearing outcomes showed a significant improvement, with a mean gain of 34.1 dB in the TBCI cohort and 14.1 dB in the EACR cohort. Both gains were statistically significant; however, the TBCI cohort showed much larger gains. Only three of the 12 patients who underwent EACR achieved hearing gains of more than 20 dB, which is consistent with previous studies. All patients who underwent TBCI surgery demonstrated hearing gains of more than 20 dB and experienced no device-related complications. CONCLUSIONS: TBCI is a safe and effective method of promoting hearing gains in microtia patients with bilateral hearing impairment. TBCI surgery provided better hearing outcomes than EACR and could be performed along with various auricular reconstruction techniques using virgin mastoid skin.

Anticancer Activity of Tubulosine through Suppression of Interleukin-6-Induced Janus Kinase 2/Signal Transducer and Activation of Transcription 3 Signaling.

PURPOSE: The chemical structure of tubulosine has been known since the mid-1960s. However, little is known about its biological and pharmacological functions. The aim of this study was to investigate the novel functions of tubulosine in cancer treatment, specifically in breast cancer. METHODS: An Unpaired (Upd)-induced Drosophila cell line and interleukin (IL)-6-stimulated human breast cancer cell lines were used to investigate the biological and pharmacological activities of tubulosine in vitro. To investigate the activities of tubulosine, we performed molecular and cellular experiments such as Western blot and reverse transcription polymerase chain reaction analyses, immunoprecipitation and terminal deoxynucleotidyl transferase dUTP nick end labeling assays, and immunofluorescence staining using breast cancer cell lines. RESULTS: Tubulosine exhibited anticancer activity in IL-6-stimulated human breast cancer cells. Moreover, tubulosine reduced the tyrosine phosphorylation level and transcriptional activity of signal transducer and activator of transcription (STAT) protein at 92E in Upd-induced Drosophila cells. Additionally, tubulosine suppressed IL-6-induced Janus kinase 2 (JAK2)/STAT3 signaling, resulting in decreased viability and induction of apoptotic cell death in breast cancer cells. Interestingly, inhibition of IL-6-induced JAK2/STAT3 signaling by tubulosine was associated with the blocking of IL-6 receptor (IL-6R) and glycoprotein 130 (gp130) binding. CONCLUSION: Tubulosine exhibits anticancer activity through functional inhibition of IL-6-induced JAK2/STAT3 signaling by targeting IL-6Rα/gp130 binding in breast cancer cells. These findings suggest that tubulosine may hold promise for the treatment of inflammation-associated cancers, including breast cancer.

Streptopyrrolidine, an angiogenesis inhibitor from a marine-derived Streptomyces sp. KORDI-3973.

Streptopyrrolidine, a benzyl pyrrolidine derivative, was isolated as an angiogenesis inhibitor from the fermentation broth of a marine Streptomyces sp. isolated from the deep sea sediment. Its structure was elucidated by extensive 2D NMR and mass spectroscopic analyses. Streptopyrrolidine exhibited significant anti-angiogenesis activity.

Microtia Reconstruction in Hemifacial Microsomia Patients: Three Framework Coverage Techniques.

BACKGROUND: Microtia with hemifacial microsomia is difficult to treat because of skin volume deficiency. To provide further information for coverage techniques in microtia reconstruction, the authors have reviewed and analyzed patients who underwent surgery at their center. METHODS: A total 52 patients with microtia with hemifacial microsomia who underwent reconstruction between 2006 and 2016 were involved. Patients were reviewed retrospectively by examining medical records and photographic data. RESULTS: All reconstructed cases were followed for 6 months to 10 years (median, 33 months). The average (median) surgeon's satisfaction score was 8.2 (median, 9) for the embedded and elevation technique (n = 23); 7.89 (median, 8) for the temporoparietal fascia flap technique (n = 10); and 6.30 (median, 7) for the subfascial expansion technique (n = 19). The median score difference between the embedding and subfascial expansion techniques was statistically significant (p = 0.03). Major factors that deteriorated aesthetic outcomes were large reconstructed ears (11 cases), cartilage framework resorption (11 cases), mismatched skin color (eight cases), different axis (seven cases), and different shapes (five cases). Mismatched skin color was significant in cases treated with the fascia flap technique (p < 0.0001), whereas cartilage framework resorption was significant in cases treated with the tissue expansion technique (p = 0.004). CONCLUSIONS: To obtain better aesthetic outcomes, the embedding technique should be used when the patient shows a mild to moderate degree of low hairline and usable remnant vestiges. In cases showing severe degrees of associated anomalies, the temporoparietal fascia flap technique should be used. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Reconstruction of Microtias with Constricted Ear Features: A 22-Year Experience.

BACKGROUND: The surgical correction of microtias with constricted ear features has remained a challenge because of the variable shape and large volume of the remnant cartilage and skin involved. To clarify how this remnant cartilage and skin should be treated, the authors have reviewed and analyzed cases operated on at their center. METHODS: A total of 167 cases of microtia with constricted ear features, operated on from 1992 to 2014, were included in the study. They were reviewed through medical records and photographs, analysis of surgical methods, and postoperative outcomes. RESULTS: A total of 141 cases (84 percent) were followed for 2 months to 13 years (average, 28 months). The average score given for the aesthetic outcomes, rated on a four-point Likert scale (i.e., 1 = poor, 2 = fair, 3 = good, and 4 = excellent), was 3.1. For framework construction, the authors used remnant cartilage-saving methods (n = 37) or remnant cartilage-replacement methods (n = 104). The average scores for the aesthetic outcome for these methods were 2.56 (median, 3) and 3.36 (median, 4), respectively. The difference in these scores was statistically significant (p < 0.001). For the coverage of new frameworks, various flap techniques were used. CONCLUSION: To correct microtias with constricted ear features with consistent postoperative results, the deformed cartilage remnant should be completely replaced with a costal cartilage framework, and the remnant skin should be maximally saved.

Impact of hormonal therapy and other adjuvant therapies on contralateral breast volume change after implant-based breast reconstruction.

BACKGROUND: Adjuvant therapy after breast surgery, including tamoxifen or aromatase inhibitors, improves the postoperative outcomes and long-term survival of breast cancer patients. The aim of this study was to determine whether volume changes occurred in the contralateral breast during hormonal or other adjuvant therapies. METHODS: This study reviewed 90 patients who underwent unilateral breast reconstruction between September 2012 and April 2018 using tissue expanders and a permanent implant after the surgical removal of breast cancer. The volume of the contralateral breast was measured using a cast before the first (tissue expander insertion) and second (permanent implant change) stages of surgery. Changes in breast volume were evaluated to determine whether adjuvant therapy such as hormonal therapy, chemotherapy, and radiation therapy influenced the volume of the contralateral breast. RESULTS: The group receiving tamoxifen therapy demonstrated a significant decrease in volume compared with the group without tamoxifen (-7.8% vs. 1.0%; P=0.028). The aromatase inhibitor-treated group showed a significant increase in volume compared with those who did not receive therapy (-6.2% vs. 4.5%; P=0.023). There were no significant differences between groups treated with other hormonal therapy, chemotherapy, or radiation therapy. CONCLUSIONS: Patients who received tamoxifen therapy showed a significant decrease in volume in the contralateral breast, while no significant change in weight or body mass index was found. Our findings suggest that we should choose smaller implants for premenopausal patients, who have a high likelihood of receiving tamoxifen therapy.

In vitro histoculture drug response assay and in vivo blood chemistry of a novel Pt(IV) compound, K104.

BACKGROUND: The newly synthesized octahedral Pt(IV) complex series showed potent antitumor activities, both in vitro and in vivo. Carboplatin, possessing a soluble leaving ligand, is known to be less toxic than cisplatin. The synthesized K104 is a Pt(IV) complex with a malonato leaving group and seven-membered ring structure between the central platinum and amine carrier ligands. In this study, the histoculture drug response assay (HDRA) of K104 on human cancer tissues was investigated in vitro and nephrotoxicity was examined in vivo. MATERIALS AND METHODS: Cytotoxicity was tested in various cancer cell lines, and the HDRA of K104 was evaluated by MTT assay in vitro using colorectal and breast cancer tissues from patients. In order to compare the nephrotoxicity of K104 with cisplatin and carboplatin, blood serum levels of BUN, creatinine and uric acid in ICR mice were measured. RESULTS: K104 showed more effective anticancer activities than carboplatin in most cancer cell lines. In HDRA, K104 showed a 50.0-66.7% efficacy rate compared with 33.3% of cisplatin and 58.3% of carboplatin against colorectal cancer patient tissues. In breast cancer tissues, K104 only showed an efficacy rate above 50%. The serum levels of BUN, creatinine and uric acid did not change after a single intraperitoneal administration of K104 (90 mg/kg) in ICR mice. CONCLUSION: K104 showed more effective anticancer activities than carboplatin. Cisplatin was associated with nephrotoxic effects, but K104 did not change the serum levels of BUN, creatinine and uric acid in vivo. These results suggest that K104 is a promising anticancer agent in view of its high efficacy against human solid cancer and lower toxicity in vivo.

Classification and Algorithmic Management of Constricted Ears: A 22-Year Experience.

BACKGROUND: The classification and corrective methods for the constricted ears continue to be controversial. To clarify them, the authors have reviewed and analyzed cases operated on at their Center from January of 1992 to January of 2014. METHODS: A total of 164 ear cases (involving 139 patients), showing features of lidded helix, compression of scapha and fossa triangularis, and/or cup-like protrusions, were included in their study (microtias with constricted ear features were excluded) and reviewed through medical records, photographs, analysis of surgical methods, and postoperative outcomes. RESULTS: The deformed ears were classified into four graded types by means of the antihelical tubing test and the scapha-helix push test as follows: type I (n = 21), type II (n = 63), type III (n = 38), and type IV (n = 42). Throughout this series, the authors have continued the improvement and performance of consistent operative techniques. Antihelical tubing, concha cartilage grafting, tumbling concha-cartilage flap, antihelical wrapping, and helical expansion were the preferred techniques. A total of 144 ear cases (88 percent) were followed for 1 month to 14 years (average, 13.2 months). The average score of aesthetic outcomes, rated on a four-point Likert scale (i.e., 1 = poor, 2 = fair, 3 = good, and 4 = excellent), was 3.3. Corrective methods and aesthetic outcomes for patients with each graded type of deformity were described. CONCLUSIONS: Constricted ears were effectively corrected by a graded surgical approach. All corrections were performed in one stage, without removal of deformed auricular cartilage. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Pharmacological advantages of melatonin in immunosenescence by improving activity of T lymphocytes.

Melatonin plays a critical role in regulating photoperiodic signals and has recently been shown to decrease immunosenescence with age. In this study, we examined whether melatonin activates T lymphocytes as major adaptive immune cells in in vitro and in vivo models. Splenocytes, CD4(+), and naïve CD4 T lymphocytes were isolated from the spleen of BALB/c mice and the cell population patterns and mRNA profiles associated with T cell activation (CD28 and p21) and the melatonin receptor (MT1A and MT1B) were assessed. The T cell activation-related proteins Ki67 and Bcl2 were also evaluated to confirm the relationship between gene and protein levels. Our data clearly revealed that CD28, p21, MT1A, and MT1B mRNA were highly expressed in the presence of melatonin. Co-culture of CD4(+) T lymphocyte and peritoneal macrophage 7 days after melatonin administration to young and aged mice significantly increased APRIL mRNA, suggesting induction or maintenance of T lymphocyte responses. We also found that the intracellular amount of Ki67 and Bcl2 proteins were significantly upregulated in aged CD4(+) T lymphocytes, suggesting enhancing T cell proliferation and ling-term maintenance of memory T cells. Taken together, we conclude that melatonin supplementation may enhance immunity in aged individuals by upregulating immunosenescence indices in association with T lymphocytes and may be an attractive pharmacological candidate for aged and immunocompromised individuals.

Decoction and Fermentation of Selected Medicinal Herbs Promote Hair Regrowth by Inducing Hair Follicle Growth in Conjunction with Wnts Signaling.

It is well recognized that regulating the hair follicle cycle in association with Wnt signaling is one of the most interesting targets for promoting hair regrowth. In this study, we examined whether selected herbal medicines processed by decoction and fermentation promote hair growth by upregulating the number and size of hair follicles and Wnt signaling, including activation of ß-catenin and Akt in telogen-synchronized C57BL/6N mice. The results revealed that the fermented extract after decoction (FDE) more effectively promoted hair growth than that of a nonfermented extract (DE). Notably, FDE effectively enhanced formation of hair follicles with clearer differentiation between the inner and outer root sheath, which is observed during the anagen phase. Mechanistic evidence was found for increased ß-catenin and Akt phosphorylation levels in dorsal skin tissue along with elevated expression of hair regrowth-related genes, such as Wnt3/10a/10b, Lef1, and fibroblast growth factor 7. In conclusion, our findings suggest that FDE plays an important role in regulating the hair cycle by increasing expression of hair regrowth-related genes and activating downstream Wnt signaling targets.

STAT3 Potentiates SIAH-1 Mediated Proteasomal Degradation of ß-Catenin in Human Embryonic Kidney Cells.

The ß-catenin functions as an adhesion molecule and a component of the Wnt signaling pathway. In the absence of the Wnt ligand, ß-catenin is constantly phosphorylated, which designates it for degradation by the APC complex. This process is one of the key regulatory mechanisms of ß-catenin. The level of ß-catenin is also controlled by the E3 ubiquitin protein ligase SIAH-1 via a phosphorylation-independent degradation pathway. Similar to ß-catenin, STAT3 is responsible for various cellular processes, such as survival, proliferation, and differentiation. However, little is known about how these molecules work together to regulate diverse cellular processes. In this study, we investigated the regulatory relationship between STAT3 and ß-catenin in HEK293T cells. To our knowledge, this is the first study to report that ß-catenin-TCF-4 transcriptional activity was suppressed by phosphorylated STAT3; furthermore, STAT3 inactivation abolished this effect and elevated activated ß-catenin levels. STAT3 also showed a strong interaction with SIAH-1, a regulator of active ß-catenin via degradation, which stabilized SIAH-1 and increased its interaction with ß-catenin. These results suggest that activated STAT3 regulates active ß-catenin protein levels via stabilization of SIAH-1 and the subsequent ubiquitin-dependent proteasomal degradation of ß-catenin in HEK293T cells.

Photoprotective Potential of Penta-O-Galloyl-ß-DGlucose by Targeting NF-κB and MAPK Signaling in UVB Radiation-Induced Human Dermal Fibroblasts and Mouse Skin.

Exposure of the skin to ultraviolet radiation can cause skin damage with various pathological changes including inflammation. In the present study, we identified the skin-protective activity of 1,2,3,4,6-penta-O-galloyl-ß-D-glucose (pentagalloyl glucose, PGG) in ultraviolet B (UVB) radiation-induced human dermal fibroblasts and mouse skin. PGG exhibited antioxidant activity with regard to intracellular reactive oxygen species (ROS) generation as well as ROS and reactive nitrogen species (RNS) scavenging. Furthermore, PGG exhibited anti-inflammatory activity, inhibiting the activation of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling, resulting in inhibition of the expression of pro-inflammatory mediators. Topical application of PGG followed by chronic exposure to UVB radiation in the dorsal skin of hairless mice resulted in a significant decrease in the progression of inflammatory skin damages, leading to inhibited activation of NF-κB signaling and expression of pro-inflammatory mediators. The present study demonstrated that PGG protected from skin damage induced by UVB radiation, and thus, may be a potential candidate for the prevention of environmental stimuli-induced inflammatory skin damage.

Diastereo- and Enantioselective Synthesis of beta-Amino Cyclic Ethers via the Intramolecular Reaction of gamma-Alkoxyallylstannane with Imine.

The intramolecular Lewis acid mediated cyclization of gamma-alkoxyallylstannanes 1, 2, and 14, bearing a hydrazone group at the terminus of the carbon chain, afforded exclusively the corresponding trans beta-amino cyclic ethers 3a, 4a, and 15, respectively. The Lewis acid mediated cyclization of gamma-alkoxyallylstannane 5, having (R)-(+)-1-phenylethylamine as a chiral auxiliary, afforded exclusively trans beta-amino cyclic ether 6a with very high diastereomeric excess (de) in very high chemical yields. The asymmetric cyclization of gamma-alkoxyallylstannane with imine 7 in the presence of chiral titanium-BINOL complex 9, afforded predominantly cis beta-amino cyclic ether 8b with high enantiomeric excess (ee). The chiral Lewis acid mediated cyclization of racemic compound 38 containing phenyl as a substituent afforded cis isomer 39 with very high enantiomeric excess (ee).

Parkinsonism-hyperpyrexia syndrome after deep brain stimulation surgery: case report.

OBJECTIVE: Deep brain stimulation is an alternative treatment for advanced Parkinson's disease. Levodopa medications are usually discontinued the night before surgery to localize the optimal response site to intraoperative macrostimulation. However, abrupt withdrawal of medication may result in side effects. We report a case of parkinsonism-hyperpyrexia syndrome (PHS), a rare complication resulting from discontinuation of antiparkinsonian medication, after a deep brain stimulation (DBS) procedure for bilateral subthalamic-nucleus (STN). CLINICAL PRESENTATION: A 66-year-old woman with an 11-year history of idiopathic Parkinson's disease was admitted for DBS. She had experienced wearing-off symptoms, severe peak-dose dyskinesia, and medication-induced side effects. Antiparkinsonian medication was discontinued 2 days before surgery because of severe drug-related complications. DBS for bilateral STN was performed uneventfully, but the patient was unconscious with fever, tachycardia, and hypertension after surgery. INTERVENTION: Levodopa and dopamine agonist replacement by nasogastric tube and hydration were immediately administered with conservative treatment for the hypertension, tachycardia, and fever. The patient's serum creatine kinase level increased to 786 U/L 3 days after the surgery and then decreased gradually as the patient's consciousness improved. CONCLUSION: Physicians should be aware of the possibility of PHS after a deep brain stimulation procedure. If the patient shows unexplained changes in consciousness with hyperpyrexia after surgery, PHS should be considered and adequate treatment should be given immediately to prevent death.

General preparation and controlled cyclization of acyclic terpenoids.

A general preparation method of the all-(E)-polyprenols 12 has been developed from readily available geranyl sulfone by the chain-extension process utilizing the C5 unit 5 and the chain-termination process utilizing the C5 unit 10 together with the chemoselective reductive desulfonylation. The polyprenols 12 were converted to compounds 3 containing two consecutive prenyl sulfone moieties at the tail end, which underwent the controlled electrophilic cyclization only at the carbon-carbon double bonds that were remote from the flat and rigid benzenesulfonyl groups.

Synthesis, in vitro assay, and molecular modeling of new piperidine derivatives having dual inhibitory potency against acetylcholinesterase and Abeta1-42 aggregation for Alzheimer's disease therapeutics.

With the goal of developing Alzheimer's disease therapeutics, we have designed and synthesized new piperidine derivatives having dual action of acetylcholinesterase (AChE) and beta-amyloid peptide (Abeta) aggregation inhibition. For binding with the catalytic site of AChE, an ester with aromatic group was designed, and for the peripheral site, another aromatic group was considered. And for intercalating amyloid-beta oligomerization, long and linear conformation with a lipophilic group was considered. The synthetic methods employed for the structure with dual action depended on alcohols with an aromatic ring and the substituted benzoic acids, which are esterificated in the last step of the synthetic pathway. We screened these new derivatives through inhibition tests of acetylcholinesterase, butyrylcholinesterase (BChE), and Abeta(1-42) peptide aggregation, AChE-induced Abeta(1-42) aggregation. Our results displayed that compound 12 showed the best inhibitory potency and selectivity of AChE, and 29 showed the highest selectivity of BChE inhibition. Compounds 15 and 12 had inhibitory activities against Abeta(1-42) aggregation and AChE-induced Abeta aggregation. In the docking model, we confirmed that 4-chlorobenzene of 12 plays the parallel pi-pi stacking against the indole ring of Trp84 in the bottom gorge of AChE. Because the benzyhydryl moiety of 12 covered the peripheral site of AChE in a funnel-like shape, 12 showed good inhibitory potency against AChE and could inhibit AChE-induced Abeta(1-42) peptide aggregation.