Antitumor Effects of Vitamin D Analogs on Hamster and Mouse Melanoma Cell Lines in Relation to Melanin Pigmentation

Deregulated melanogenesis is involved in melanomagenesis and melanoma progression and resistance to therapy. Vitamin D analogs have anti-melanoma activity. While the hypercalcaemic effect of the active form of Vitamin D (1,25(OH)₂D₃) limits its therapeutic use, novel Vitamin D analogs with a modified side chain demonstrate low calcaemic activity. We therefore examined the effect of secosteroidal analogs, both classic (1,25(OH)₂D₃ and 25(OH)D₃), and novel relatively non-calcemic ones (20(OH)D₃, calcipotriol, 21(OH)pD, pD and 20(OH)pL), on proliferation, colony formation in monolayer and soft-agar, and mRNA and protein expression by melanoma cells. Murine B16-F10 and hamster Bomirski Ab cell lines were shown to be effective models to study how melanogenesis affects anti-melanoma treatment. Novel Vitamin D analogs with a short side-chain and lumisterol-like 20(OH)pL efficiently inhibited rodent melanoma growth. Moderate pigmentation sensitized rodent melanoma cells towards Vitamin D analogs, and altered expression of key genes involved in Vitamin D signaling, which was opposite to the effect on heavily pigmented cells. Interestingly, melanogenesis inhibited ligand-induced Vitamin D receptor translocation and ligand-induced expression of VDR and CYP24A1 genes. These findings indicate that melanogenesis can affect the anti-melanoma activity of Vitamin D analogs in a complex manner.     

Behavioral and electroantennogram responses of periplanone analogs

The biological activities of synthetic periplanone analogs, including four candidates of periplanone-A (P-A), were evaluated by behavioral and electroantennogram (EAG) assays. Among 16 periplanone analogs, six compounds evoked pheromonal activity from the male American cockroaches. The threshold dosages of these biological active analogs were 10–10⁵ times lower than that of the known periplanone mimic, germacrene-D. The conformation required for eliciting the pheromonal activity is discussed in terms of the structure-activity relationship of these analogs. Hauptmann's P-A elicited the strongest pheromonal activity among four candidates of P-A in our bioassay, suggesting that Hauptmann's P-A is a natural P-A produced from female cockroaches.     

3-取代-6β-乙酰氧基莨菪烷的合成及其生物活性研究

以3α-羟基-6β-乙酰氧基莨菪烷(5)为起始原料，合成4个新3-取代-6β-乙酰氧基莨菪烷。药理筛选结果表明3α-苯磺酰氧基-6β-乙酰氧基莨菪烷(6d)对大鼠回肠肌具有强激动活性；经M受体阻断剂阿托品的拮抗试验，提示6d是潜在的M胆碱能受体激动剂。     

一类核苷类似物关键中间体的合成

对一类核苷类似物的关键中间体———(4R,5R) 4 (N 甲基羟氨基) 5 [(叔丁基二苯基硅烷基)氧甲基] 3,4 二氢 2(5H) 呋喃酮的合成进行了研究。以L 抗坏血酸为原料,经Pd/C催化加氢和缩酮保护,生成5,6 O 异亚丙基 L 古洛糖酸 1,4 内酯,产率74 3%。该内酯经NaIO4氧化、Wittig反应、水解成环和柱色谱分离,得(R) (+) 5 羟甲基 2 (5H) 呋喃酮,产率43 0%。最后该呋喃酮再经硅烷保护和羟胺Michael加成,即得到目标化合物。这7步反应的总产率27 9%。     

Nutlins类似物诱导TCA-8113细胞凋亡的研究

目的:研究新型小分子化合物Nutlins类似物在体外对舌癌TCA-8113细胞的凋亡作用.方法:采用MTT法检测新型小分子化合物Nutlins类似物对TCA-8113细胞增殖的影响;用流式细胞仪(FCM)检测Nutlins类似物诱导TCA-8113细胞凋亡情况和周期阻滞情况;用DAPI染色法观察细胞核变化.结果:Nutlins类似物NL-11和NL19以浓度依赖的方式抑制TCA-8113细胞增殖并诱导其凋亡,而且能引起TCA-8113细胞发生G2期周期阻滞.结论:NL-11和NL-19化合物能够有效地在体外抑制TCA-8113细胞增殖,并诱导细胞凋亡.     

Pre-Protonated Vanadium Hexacyanoferrate for High Energy-Power and Anti-Freezing Proton Batteries

Proton batteries have been considered as an innovative energy storage technology owing to their high safety and cost-effectiveness. However, the development of fast-charging proton batteries with high energy/power density is greatly limited by feasible material selection. Here, the pre-protonated vanadium hexacyanoferrate (H-VHCF) is developed as a proton cathode material to alleviate the capacity loss of proton-free electrode materials during electrochemical tests. The pre-protonation process realizes fast and long-distance transport of protons by shortening diffusion path and reducing migration barriers. Benefitting from the enhanced hydrogen bonding network combined with dual redox reactions of V and Fe in protonated H-VHCF cathode, a high energy density of 74 Wh kg⁻¹ at 1.1 kW kg⁻¹, and a maximum power density of 54 kW kg⁻¹ at 65 Wh kg⁻¹ is achieved for the asymmetric proton batteries coupling with MoO₃/MXene anode. Proton transport and double oxidation-reduction center are verified by theoretical calculations and ex situ experimental measurements. Considering the anti-freezing availability of proton batteries, 82.5% of its initial capacity is maintained after 10000 cycles under −40 °C at 0.5 A g⁻¹. As a proof-of-concept, flexible device fabricated by optimized electrodes and hydrogel electrolytes can power up a light-emitting diode even under a bent state.     

Synthesis and Biological Activity of New Brassinosteroid Analogs of Type 24-Nor-5β-Cholane and 23-Benzoate Function in the Side Chain

Brassinosteroids are polyhydroxysteroids that are involved in different plants’ biological functions, such as growth, development and resistance to biotic and external stresses. Because of its low abundance in plants, much effort has been dedicated to the synthesis and characterization of brassinosteroids analogs. Herein, we report the synthesis of brassinosteroid 24-nor-5β-cholane type analogs with 23-benzoate function and 22,23-benzoate groups. The synthesis was accomplished with high reaction yields in a four-step synthesis route and using hyodeoxycholic acid as starting material. All synthesized analogs were tested using the rice lamina inclination test to assess their growth-promoting activity and compare it with those obtained for brassinolide, which was used as a positive control. The results indicate that the diasteroisomeric mixture of monobenzoylated derivatives exhibit the highest activity at the lowest tested concentrations (1 × 10⁻⁸ and 1 × 10⁻⁷ M), being even more active than brassinolide. Therefore, a simple synthetic procedure with high reaction yields that use a very accessible starting material provides brassinosteroid synthetic analogs with promising effects on plant growth. This exploratory study suggests that brassinosteroid analogs with similar chemical structures could be a good alternative to natural brassinosteroids.     

[2.2]Paracyclophane-Based TCN-201 Analogs as GluN2A-Selective NMDA Receptor Antagonists

Recent studies have shown the involvement of GluN2A subunit-containing NMDA receptors in various neurological and pathological disorders. In the X-ray crystal structure, TCN-201 ( 1 ) and analogous pyrazine derivatives 2 and 3 adopt a U-shape (hairpin) conformation within the binding site formed by the ligand binding domains of the GluN1 and GluN2A subunits. In order to mimic the resulting π/π-interactions of two aromatic rings in the binding site, a [2.2]paracyclophane system was designed to lock these aromatic rings in a parallel orientation. Acylation of [2.2]paracyclophane ( 5 ) with oxalyl chloride and chloroacetyl chloride and subsequent transformations led to the oxalamide 7 , triazole 10 and benzamides 12 . The GluN2A inhibitory activities of the paracyclophane derivatives were tested with two-electrode voltage clamp electrophysiology using Xenopus laevis oocytes expressing selectively functional NMDA receptors with GluN2A subunit. The o-iodobenzamide 12 b with the highest similarity to TCN-201 showed the highest GuN2A inhibitory activity of this series of compounds. At a concentration of 10 μM, 12 b reached 36 % of the inhibitory activity of TCN-201 ( 1 ). This result indicates that the [2.2]paracyclophane system is well accepted by the TCN-201 binding site.     

Extracellular Nucleotides Affect the Proangiogenic Behavior of Fibroblasts,Keratinocytes, and Endothelial Cells

Chronic wound healing is currently a severe problem due to its incidence and associated complications. Intensive research is underway on substances that retain their biological activity in the wound microenvironment and stimulate the formation of new blood vessels critical for tissue regeneration. This group includes synthetic compounds with proangiogenic activity. Previously, we identified phosphorothioate analogs of nucleoside 5′-O-monophosphates as multifunctional ligands of P2Y6 and P2Y14 receptors. The effects of a series of unmodified and phosphorothioate nucleotide analogs on the secretion of VEGF from keratinocytes and fibroblasts, as well as their influence on the viability and proliferation of keratinocytes, fibroblasts, and endothelial cells were analyzed. In addition, the expression profiles of genes encoding nucleotide receptors in tested cell models were also investigated. In this study, we defined thymidine 5′-O-monophosphorothioate (TMPS) as a positive regulator of angiogenesis. Preliminary analyses confirmed the proangiogenic potency of TMPS in vivo.     

Somatostatin Receptor Splicing Variant sst5TMD4 Overexpression in Glioblastoma Is Associated with Poor Survival,Increased Aggressiveness Features,and Somatostatin Analogs Resistance

Glioblastoma (GBM) is the most malignant and lethal brain tumor. Current standard treatment consists of surgery followed by radiotherapy/chemotherapy; however, this is only a palliative approach with a mean post-operative survival of scarcely ~12–15 months. Thus, the identification of novel therapeutic targets to treat this devastating pathology is urgently needed. In this context, the truncated splicing variant of the somatostatin receptor subtype 5 (sst5TMD4), which is produced by aberrant alternative splicing, has been demonstrated to be overexpressed and associated with increased aggressiveness features in several tumors. However, the presence, functional role, and associated molecular mechanisms of sst5TMD4 in GBM have not been yet explored. Therefore, we performed a comprehensive analysis to characterize the expression and pathophysiological role of sst5TMD4 in human GBM. sst5TMD4 was significantly overexpressed (at mRNA and protein levels) in human GBM tissue compared to non-tumor (control) brain tissue. Remarkably, sst5TMD4 expression was significantly associated with poor overall survival and recurrent tumors in GBM patients. Moreover, in vitro sst5TMD4 overexpression (by specific plasmid) increased, whereas sst5TMD4 silencing (by specific siRNA) decreased, key malignant features (i.e., proliferation and migration capacity) of GBM cells (U-87 MG/U-118 MG models). Furthermore, sst5TMD4 overexpression in GBM cells altered the activity of multiple key signaling pathways associated with tumor aggressiveness/progression (AKT/JAK-STAT/NF-κB/TGF-β), and its silencing sensitized GBM cells to the antitumor effect of pasireotide (a somatostatin analog). Altogether, these results demonstrate that sst5TMD4 is overexpressed and associated with enhanced malignancy features in human GBMs and reveal its potential utility as a novel diagnostic/prognostic biomarker and putative therapeutic target in GBMs.