Synthesis and biological evaluation of aminothiazoles against Histoplasma capsulatum and Cryptococcus neoformans

The design and synthesis of a library of forty novel 2-aminoazole analogues as well as their evaluation as antifungal compounds against Histoplasma capsulatum and Cryptococcus neoformans is described. These structures were derived from N-[5-(1-naphthalenylmethyl)-2-thiazolyl]cyclohexanecarboxamide (41F5), a fungistatic agent previously identified through phenotypic screening (Antimicrob Agents Chemother. 2013;57:4349). Modifications to improve potency and water-solubility of 41F5 focused primarily on the 5-naphthalenyl group, the thiazole core, and the methylene linker between these two structural elements. In general, compounds with lipophilic [5+6] bicyclic ring systems, such as the 7-benzothiophenyl- and 4-indanyl groups, at the 5-position were 2–3 times more active against both fungal species as compared to 41F5. Also, introduction of a carbonyl group at the methylene linker of 41F5 resulted in a 2–3-fold increase in potency. These highly active compounds also showed generally low toxicities against murine P388D1 macrophages resulting in selectivity indices ranging from 63 to >200. Compounds that were highly active against fluconazole-sensitive C. neoformans strains had almost identical activity against fluconazole-resistant variants of this fungus indicating that 14α-demethylase is not their molecular target. Highly active compounds also retained activity against H. capsulatum phagocytosed into P388D1 macrophages.     

In vitro and in vivo anti-inflammatory properties of imine resveratrol analogues

Resveratrol is a natural polyphenol found mainly on red grapes and in red wine, pointed as an important anti-inflammatory/immunomodulatory molecule. However, its bioavailability problems have limited its use encouraging the search for new alternatives agents. Thus, in this study, we synthetize 12 resveratrol analogues (6 imines, 1 thioimine and 5 hydrazones) and investigated its cytotoxicity, antioxidant activity and in vitro anti-inflammatory/immunomodulatory properties. The most promising compounds were also evaluated in vivo. The results showed that imines presented less cytotoxicity, were more effective than resveratrol on DPPH scavenger and exhibited an anti-inflammatory profile. Among them, the imines with a radical in the para position, on the ring B, not engaged in an intramolecular hydrogen-interaction, showed more prominent anti-inflammatory activity modulating, in vivo, the edema formation, the inflammatory infiltration and cytokine levels. An immunomodulatory activity also was observed in these molecules. Thus, our results suggest that imines with these characteristics presents potential to control inflammatory disorders.     

模拟CO2浓度升高和降雨量变化对红砂生物量分配及碳氮特征的影响

以荒漠优势植物红砂2年生苗木为试材,采用盆栽试验和开顶式CO_2控制气室模拟CO_2浓度变化(350μmol/mol和700μmol/mol)研究了红砂生物量分配及碳氮特征对降水变化减少30%、减少15%、自然降水、增加15%和增加30%(-30%、-15%、0、15%、30%)的响应。结果表明:(1)CO_2浓度上升显著性的促进红砂地上茎叶和地下的根生物量,降雨量增加或减少也显著性的促进或抑制了这一作用;CO_2倍增时,红砂的地上生物量在降水增加30%时平均增加了61.28%(P0.05),而根生物量在降水增加或减少30%时均分别增加了84%(30%)和3.21%(-30%),这种响应导致红砂根冠比在降水减少时大于降雨量增加时,CO_2倍增显著地抑制了这一作用。(2)CO_2浓度上升显著性地促进了红砂根、茎、叶中的碳含量,显著性地抑制了红砂根、茎、叶中氮含量,降雨量增加或减少也显著性的促进或抑制了这一作用;这种响应导致红砂根、茎、叶的C/N在降雨减少30%时增加80.22%(根)、103.02%(茎)和199.88%(叶)(P0.05),在降雨增加30%时增加24.99%(根)、30.27%(茎0)和104.45%(叶)(P0.05),CO_2浓度倍增显著性地促进了这一作用。(3)以上结果表明,未来全球CO_2浓度升高时,在降雨量增加地区红砂因充足的碳源和水分而得以恢复;在降雨减少的地区,CO_2的升高对降雨减少造成的干旱胁迫有一定的补偿作用,红砂则以较高的根冠比来维持其在荒漠生态系统中地位。     

Design,synthesis, in vitro and in vivo evaluation,and structure-activity relationship (SAR) discussion of novel dipeptidyl boronic acid proteasome inhibitors as orally available anti-cancer agents for the treatment of multiple myeloma and mechanism studies

A series of novel dipeptidyl boronic acid inhibitors of 20S proteasome were designed and synthesized. Aliphatic groups at R¹ position were designed for the first time to fully understand the SAR (structure–activity relationship). Among the screened compounds, novel inhibitor 5c inhibited the CT-L (chymotrypsin-like) activity with IC₅₀ of 8.21?nM and the MM (multiple myeloma) cells RPMI8226, U266B and ARH77 proliferations with the IC₅₀ of 8.99, 6.75 and 9.10?nM, respectively, which showed similar in vitro activities compared with the compound MLN2238 (biologically active form of marketed MLN9708). To investigate the oral availability, compound 5c was esterified to its prodrug 6a with the enzymatic IC₅₀ of 6.74?nM and RPMI8226, U266B and ARH77 cell proliferations IC₅₀ of 2.59, 4.32 and 3.68?nM, respectively. Furthermore, prodrug 6a exhibited good pharmacokinetic properties with oral bioavailability of 24.9%, similar with MLN9708 (27.8%). Moreover, compound 6a showed good microsomal stabilities and displayed stronger in vivo anticancer efficacy than MLN9708 in the human ARH77 xenograft mouse model. Finally, cell cycle results showed that compound 6a had a significant inhibitory effect on CT-L and inhibited cell cycle progression at the G2M stage.     

Xanthone derivatives as phosphoglycerate mutase 1 inhibitors: Design,synthesis, and biological evaluation

Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that dynamically converts 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG), which was upregulated to coordinate glycolysis, pentose phosphate pathway (PPP) and serine biosynthesis to promote cancer cell proliferation and tumor growth in a variety of cancers. However, only a few inhibitors of PGAM1 have been reported with poor molecular or cellular efficacy. In this paper, a series of xanthone derivatives were discovered as novel PGAM1 inhibitors through scaffold hopping and sulfonamide reversal strategy based on the lead compound PGMI-004A. Most xanthone derivatives showed higher potency against PGAM1 than PGMI-004A and exhibited moderate anti-proliferation activity on different cancer cell lines.     

Discovery and evaluation of nNav1.5 sodium channel blockers with potent cell invasion inhibitory activity in breast cancer cells

Voltage-gated sodium channels (VGSC) are a well-established drug target for anti-epileptic, anti-arrhythmic and pain medications due to their presence and the important roles that they play in excitable cells. Recently, their presence has been recognized in non-excitable cells such as cancer cells and their overexpression has been shown to be associated with metastatic behavior in a variety of human cancers. The neonatal isoform of the VGSC subtype, Na_v1.5 (nNa_v1.5) is overexpressed in the highly aggressive human breast cancer cell line, MDA-MB-231. The activity of nNa_v1.5 is known to promote the breast cancer cell invasion in vitro and metastasis in vivo, and its expression in primary mammary tumors has been associated with metastasis and patient death. Metastasis development is responsible for the high mortality of breast cancer and currently there is no treatment available to specifically prevent or inhibit breast cancer metastasis. In the present study, a 3D-QSAR model is used to assist the development of low micromolar small molecule VGSC blockers. Using this model, we have designed, synthesized and evaluated five small molecule compounds as blockers of nNa_v1.5-dependent inward currents in whole-cell patch-clamp experiments in MDA-MB-231 cells. The most active compound identified from these studies blocked sodium currents by 34.9?±?6.6% at 1?μM. This compound also inhibited the invasion of MDA-MB-231 cells by 30.3?±?4.5% at 1?μM concentration without affecting the cell viability. The potent small molecule compounds presented here have the potential to be developed as drugs for breast cancer metastasis treatment.     

亚热带米老排和杉木细根分解过程中养分与微生物群落组成的变化

对福建南平峡阳林场19年生米老排和杉木人工林的细根进行为期12个月的分解试验,研究不同树种分解过程中养分和微生物群落组成的动态变化,为理解亚热带不同人工林树种地下养分循环过程提供科学依据.结果表明: 米老排细根养分磷(P)、钾(K)初始含量显著高于杉木.分解过程中,两个树种细根P、K含量均显著降低,而细根氮(N)含量显著增加,且杉木细根N含量变化滞后于米老排.在分解过程中,杉木细根镁(Mg)含量无显著变化;米老排细根Mg含量变化显著,且在分解8个月时显著小于杉木.在分解过程中,真菌与细菌比值均显著表现为先升高后降低,且分解12个月时米老排细根真菌/细菌显著高于杉木.冗余分析表明,N(解释37.2%)、K(解释14.5%)含量和C/N(解释14.8%)是影响杉木细根分解过程中微生物群落组成变化的主要养分因子,而Mg(解释35.9%)和K(解释17.6%)含量则是米老排细根分解时影响微生物群落组成的主要养分因子.研究表明,在不同树种中,除了N之外,Mg等其他养分元素也可能是影响根系分解的重要因子.     

甘草提取物对四种牙周常见致病菌的抑菌作用

目的体外评价甘草提取物对牙龈卟啉单胞菌、中间普氏菌、具核梭杆菌和伴放线放线杆菌四种牙周常见致病菌的抑制效果。方法以牙龈卟啉单胞菌、中间普氏菌、具核梭杆菌和伴放线放线杆菌四种牙周常见致病菌作为供试菌,采用液体稀释法,考察甘草提取物对这四种细菌的最小抑菌浓度(MIC)和最小杀菌浓度(MBC);并采用不同浓度的甘草提取物溶液,绘制甘草提取物对四种牙周致病菌的时间-杀菌曲线。结果甘草提取物对牙龈卟啉单胞菌、中间普氏菌、具核梭杆菌和伴放线放线杆菌的MIC值分别为1.50、1.50、0.75和1.50mg/mL,MBC值分别为6、3、3和3mg/mL。当甘草提取物达到对四种细菌的MBC值时,对于牙龈卟啉单胞菌、中间普氏菌、伴放线放线杆菌可在2h后可达到杀菌效果,对于具核梭杆菌可在4h后达到杀菌效果。结论甘草提取物对以上四种牙周常见致病菌具有良好的抑菌及杀菌作用。