Synthesis,anticancer activity,and SAR analyses of compounds containing the 5:7-fused 4,6,8-triaminoimidazo[4,5-e][1,3]diazepine ring system

Described herein are our limited structure–activity relationship (SAR) studies on a 5:7-fused heterocycle (1), containing the 4,6,8-triaminoimidazo[4,5-e][1,3]diazepine ring system, whose synthesis and potent broad-spectrum anticancer activity we reported a few years ago. Our SAR efforts in this study are mainly focused on judicial attachment of substituents at N-1 and N⁶-positions of the heterocyclic ring. Our results suggest that there is some subtle correlation between the substituents attached at the N-1 position and those attached at the N⁶-position of the heterocycle. It is likely that there is a common hydrophobic binding pocket on the target protein that is occupied by the substituents attached at the N-1 and N⁶-positions of the heterocyclic ligand. This pocket appears to be large enough to hold either a C-18 alkyl chain of N⁶ and no attachment at N-1, or a combined C-10 at N⁶ and a CH₂Ph at N-1. Any alkyl chain shorter or longer than C-10 at N⁶ with a CH₂Ph attached at N-1, would result in decrease of biological activity.     

N-Indolylglycosides bearing modifications at the glucose C6-position as sodium-dependent glucose co-transporter 2 inhibitors

Suppression of glucose reabsorption through the inhibition of sodium-dependent glucose co-transporter 2 (SGLT2) is a promising therapeutic approach for the treatment of type 2 diabetes. To investigate the effect of C6-substitution on inhibition of SGLT2 by N-indolylglucosides, a small library of 6-triazole, 6-amide, 6-urea, and 6-thiourea N-indolylglycosides were synthesized and tested. A detailed structure–activity relationship (SAR) study culminated in the identification of 6-amide derivatives 6a and 6o as potent SGLT2 inhibitors, which were further tested for inhibitory activity against SGLT1. The data obtained indicated that 6a and 6o are mildly to moderately selective for SGLT2 over SGLT1. Both compounds were also evaluated in a urinary glucose excretion test and pharmacokinetic study; 6a was found capable of inducing urinary glucose excretion in normal SD rats.     

Design,synthesis and biological evaluation of LBM-A5 derivatives as potent P-glycoprotein-mediated multidrug resistance inhibitors

A novel series of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) inhibitors with triazol-N-phenethyl-tetrahydroisoquinoline or triazol-N-ethyl-tetrahydroisoquinoline scaffold were designed and synthesized via click chemistry. Most of the synthesized compounds showed higher reversal activity than verapamil (VRP). Among them, the most potent compound 4 showed a comparable activity with the known potent P-gp inhibitor WK-X-34 with lower cytotoxicity toward K562 cells (IC₅₀ >100 μM). Compared with VRP, compound 4 exhibited more potency in increasing drug accumulation in K562/A02 MDR cells. Moreover, compound 4 could significantly reverse MDR in a dose-dependent manner and also persist longer chemo-sensitizing effect than VRP with reversibility. Further mechanism studies revealed that compound 4 could remarkably increase the intracellular accumulation of Adriamycin (ADM) in K562/A02 cells as well as inhibit rhodamine-123 (Rh123) efflux from the cells. These results suggested that compound 4 may represent a promising candidate for developing P-gp-mediated MDR inhibitors.     

Anion inhibition profiles of the complete domain of the η-carbonic anhydrase from Plasmodium falciparum

We have cloned, purified and investigated the catalytic activity and anion inhibition profiles of a full catalytic domain (358 amino acid residues) carbonic anhydrase (CA, EC 4.2.1.1) from Plasmodium falciparum, PfCAdom, an enzyme belonging to the η-CA class and identified in the genome of the malaria-producing protozoa. A truncated such enzyme, PfCA1, containing 235 residues was investigated earlier for its catalytic and inhibition profiles. The two enzymes were efficient catalysts for CO₂ hydration: PfCAdom showed a k_cat of 3.8 × 10⁵ s⁻¹ and k_cat/K_m of 7.2 × 10⁷ M⁻¹ × s⁻¹, whereas PfCA showed a lower activity compared to PfCAdom, with a k_cat of 1.4 × 10⁵ s⁻¹ and k_cat/K_m of 5.4 × 10⁶ M⁻¹ × s⁻¹. PfCAdom was generally less inhibited by most anions and small molecules compared to PfCA1. The best PfCAdom inhibitors were sulfamide, sulfamic acid, phenylboronic acid and phenylarsonic acid, which showed K_Is in the range of 9–68 μM, followed by bicarbonate, hydrogensulfide, stannate and N,N-diethyldithiocarbamate, which were submillimolar inhibitors, with K_Is in the range of 0.53–0.97 mM. Malaria parasites CA inhibition was proposed as a new strategy to develop antimalarial drugs, with a novel mechanism of action.     

Discovery of N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives as potential antiproliferative agents by inhibiting MEK

Mitogen activated protein kinase (MAPK) signal transduction pathway has been proved to play an important role in tumorigenesis and cancer development. MEK inhibitor has been demonstrated significant clinical benefit for blocking MAPK pathway activation and possibly could block reactivation of the MAPK pathway at the time of BRAF inhibitor resistance. Twenty N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives have been designed and synthesized as MEK inhibitors, and their biological activities were evaluated. Among these compounds, compound 7b showed the most potent inhibitory activity with IC₅₀ of 91 nM for MEK1 and GI₅₀ value of 0.26 μM for A549 cells. The SAR analysis and docking simulation were performed to provide crucial pharmacophore clues that could be used in further structure optimization.     

New imidazoquinoxaline derivatives: Synthesis,biological evaluation on melanoma,effect on tubulin polymerization and structure–activity relationships

Microtubules are considered as important targets of anticancer therapy. EAPB0503 and its structural imidazo[1,2-a]quinoxaline derivatives are major microtubule-interfering agents with potent anticancer activity. In this study, the synthesis of several new derivatives of EAPB0503 is described, and the anticancer efficacy of 13 novel derivatives on A375 human melanoma cell line is reported. All new compounds show significant antiproliferative activity with IC₅₀ in the range of 0.077–122 μM against human melanoma cell line (A375). Direct inhibition of tubulin polymerization assay in vitro is also assessed. Results show that compounds 6b, 6e, 6g, and EAPB0503 highly inhibit tubulin polymerization with percentages of inhibition of 99%, 98%, 90%, and 84% respectively. Structure–activity relationship studies within the series are also discussed in line with molecular docking studies into the colchicine-binding site of tubulin.     

裸花紫珠提取物及其主要成分抗氧化活性研究

裸花紫珠是海南一种道地药材,具有消炎止血的功效。裸花紫珠富含黄酮类和苯乙醇苷类化学成分,它们已经被证实是天然抗氧化剂的主要来源之一。为了考察裸花紫珠药材的抗氧化活性,该研究采用DPPH.自由基清除法测定裸花紫珠醇提物、4个不同极性部位(石油醚、乙酸乙酯、正丁醇、水)及其7个主要成分的抗氧化作用。结果表明：裸花紫珠醇提物、醇提物的水部位、正丁醇部位、乙酸乙酯部位和化合物木犀草素、木犀草苷、毛蕊花糖苷具有较强的抗氧化活性,而5-羟基-3,7,3′,4′-四甲氧基黄酮的抗氧化活性则较弱。该研究结果为裸花紫珠的保健功能开发提供了依据。     

淹水胁迫下江南牡丹生长及光合特性研究

以3年生江南牡丹品种‘凤丹白’为材料,利用盆栽淹水法,设置正常管理、轻度胁迫和重度胁迫3个水平,研究不同淹水胁迫水平对牡丹生长和光合特性的影响。结果表明：经过30 d胁迫后,正常管理、轻度胁迫和重度胁迫下的江南牡丹苗高生长量分别为3.6、1.1和0.73 cm,地径生长量分别为0.21、0.11和0.06 cm,植株总生物量增加量分别为7.0、3.0和2.75 g,淹水胁迫和正常生长差异显著,淹水胁迫严重影响了江南牡丹的生长。同时,在正常管理时,牡丹总叶绿素含量升高,而在淹水胁迫下呈下降趋势。淹水胁迫不同时间根系活力均呈下降趋势且随着胁迫程度的增加下降越大。正常管理下光合速率逐渐增加而胁迫条件下光合速率逐渐降低。同时胁迫条件下,牡丹蒸腾速率、气孔导度均明显下降;轻度淹水胁迫下胞间CO2浓度先升高后降低;而重度胁迫下胞间CO2浓度呈现逐渐升高的变化趋势。淹水胁迫对牡丹根系活力、茎段生长和叶片光合特性影响较大。该研究结果为江南牡丹耐涝胁迫机理研究奠定了理论基础。     

饲料中添加溶菌酶对吉富罗非鱼生长、免疫-抗氧化功能及血清抗菌性能的影响

为研究在饲料中添加不同水平的溶菌酶制品对吉富罗非鱼(GIFT, Oreochromis niloticus)生长性能、免疫-抗氧化功能和血清抗菌性能的影响, 选用平均体重为(11.350.08)g的吉富罗非鱼960尾, 随机分为6组(每组4个重复, 每个重复40尾), 分别投喂基础饲料(对照组)和5种添加水平分别为18、36、54、72和90 mg/kg溶菌酶制品的试验饲料, 养殖周期为60d。结果表明: (1) 54 mg/kg溶菌酶添加组鱼的生长性能和饲料利用情况最优, 增重率和蛋白质效率均显著高于对照组, 饲料系数显著低于对照组(P0.05); 肝体比随溶菌酶添加水平的增加呈现下降趋势, 90 mg/kg添加组显著低于对照组(P0.05); 脾脏指数在36和54mg/kg添加组显著低于对照组(P0.05); 全鱼粗蛋白和粗灰分含量在54 mg/kg添加组均呈现较高水平, 显著高于对照组(P0.05)。(2)溶菌酶添加水平对罗非鱼的免疫-抗氧化能力产生影响, 54和72 mg/kg添加水平能显著提高鱼体血清和肝脏的超氧化物歧化酶、过氧化氢酶活性, 降低丙二醛含量(P0.05); 肝脏溶菌酶活性在54和72 mg/kg添加组均显著高于对照组(P0.05), 而血清溶菌酶活性随溶菌酶添加水平的增加呈现下降趋势(L90组除外), 显著低于对照组(P0.05)。(3)血清抗菌试验显示, 54和72 mg/kg溶菌酶添加组罗非鱼对大肠杆菌、金黄色葡萄球菌、嗜水气单胞菌和溶藻弧菌的抑制能力显著高于对照组(P0.05), 而对枯草芽孢杆菌的抵抗能力最低, 比对照组分别低34.71%和42.21% (P0.05)。结果表明, 在本试验条件下, 在吉富罗非鱼饲料中添加54 mg/kg溶菌酶制品可以改善其生长性能; 当添加水平为54和72 mg/kg时, 罗非鱼的免疫-抗氧化能力和血清抗菌性能均得到了显著提高。     

干旱胁迫对枇杷生理特性及生长的影响

以3年生‘大五星’枇杷嫁接苗为试验材料,通过盆栽控水试验设置4个水分处理梯度:对照(CK)、轻度胁迫(LS)、中度胁迫(MS)和重度胁迫(SS),研究不同程度土壤干旱对枇杷幼树的生长和生理特性的影响。结果显示:(1)枇杷的株高、地上和地下生物量随干旱胁迫的增强呈下降趋势。(2)在轻度和中度胁迫下叶片叶绿素含量增加,随着土壤水分的减少,叶绿素含量和叶片相对含水量(LRWC)均显著下降。(3)叶片净光合速率(Pn)、蒸腾速率(Tr)和气孔导度(Gs)随着干旱胁迫的加剧均显著下降,其中Gs下降幅度最大,而胞间CO2浓度(Ci)则表现为先下降后上升,重度胁迫时叶片的水分利用率(WUE)最低。(4)干旱的加重使叶片超氧化物歧化酶(SOD)和过氧化物酶(POD)的活性呈现先增加后降低的趋势,过氧化氢酶(CAT)活性在轻度胁迫下最为活跃但在重度胁迫时显著降低,丙二醛(MDA)含量在中度胁迫第10天开始显著升高。(5)随干旱胁迫的加剧游离脯氨酸(Pro)含量增加且在重度胁迫第10天达到最大值,而可溶性蛋白(SP)含量在胁迫后期与对照无显著差异,可溶性糖(SS)含量在重度胁迫后期达到峰值且与对照差异显著。研究表明,在轻度和中度干旱胁迫下,枇杷叶片光合作用受到抑制,但能够积极调控抗氧化酶的活性和渗透调节物质的含量等来增强耐受性,而重度胁迫下,叶片膜系统和光合系统受到损伤,枇杷生长受到严重抑制。