Synthesis of a new class of 2-anilino substituted nicotinyl arylsulfonylhydrazides as potential anticancer and antibacterial agents

A series of N'-1-[2-anilino-3-pyridyl]carbonyl-1-benzenesulfonohydrazide derivatives (7a-i) was synthesized and five of them were selected by the National Cancer Institute (NCI) and evaluated for their in vitro anticancer activity. Three of the investigated compounds 7d, 7f and 7g exhibited significant anticancer activity in the primary assay and further tested against a panel of 60 human tumour cell lines. Compound 7g showed 50% growth inhibitory activity in leukaemia, melanoma, lung cancer, colon cancer, renal cancer and breast cancer cells with GI(50) value of 3.2-9.6 microM. The synthesized compounds (7a-i) were also evaluated for their antibacterial activity against various Gram-positive and Gram-negative strains of bacteria. Most of these compounds showed better inhibitory activity in comparison to the standard drugs.     

Corn (Zea mays L.) growth, leaf pigment concentration, photosynthesis and leaf hyperspectral reflectance properties as affected by nitrogen supply

Plant nitrogen (N)deficiency often limits crop productivity. Early detection of plant N deficiency is important for improving fertilizer N-use efficiency and crop yield. An experiment was conducted in sunlit, controlled environment chambers in the 2001 growing season to determine responses of corn (Zea mays L. cv. 33A14) growth and leaf hyperspectral reflectance properties to varying N supply. Four N treatments were: (1) half-strength Hoagland's nutrient solution applied throughout the experiment (control); (2) 20% of control N starting 15 days after emergence (DAE); (3) 0% N starting 15 DAE; and (4) 0% N starting 23 DAE (0% NL). Plant height, the number of leaves, and leaf lengths were examined for nine plants per treatment every 3–4 days. Leaf hyperspectral reflectance, concentrations of chlorophyll a, chlorophyll b,and carotenoids, leaf and canopy photosynthesis, leaf area, and leaf N concentration were also determined during the experiment. The various N treatments led to a wide range of N concentrations (11 – 48 g kg^–1 DW) in uppermost fully expanded leaves. Nitrogen deficiency suppressed plant growth rate and leaf photosynthesis. At final harvest (42 DAE), plant height, leaf area and shoot biomass were 64–66% of control values for the 20% N treatment, and 46-56% of control values for the 0% N treatment. Nitrogen deficit treatments of 20% N and 0% N (Treatment 3) could be distinguished by changes in leaf spectral reflectance in wavelengths of 552 and 710 nm 7 days after treatment. Leaf reflectance at these two wavebands was negatively correlated with either leaf N (r = –0.72 and –0.75^**) or chlorophyll (r = –0.60 and –0.72^**) concentrations. In addition, higher correlations were found between leaf N concentration and reflectance ratios. The identified N-specific spectral algorithms may be used for image interpretation and diagnosis of corn N status for site-specific N management.     

Leaf mass area determines water use efficiency through its influence on carbon gain in rice mutants

Saving water and enhancing rice productivity are consensually the most important research goals globally. While increasing canopy cover would enhance growth rates by higher photosynthetic carbon gain, an accompanied increase in transpiration would have a negative impact on saving water as well as for sustainability under water-limited conditions. Increased water use efficiency (WUE) by virtue of higher carbon assimilatory capacity can significantly circumvent this trade-off. Here, we report leaf mass area (LMA) has an important canopy architecture trait which when combined with superior carboxylation efficiency (CE) would achieve higher water productivity in rice. A set of 130 ethyl methanesulfonate induced mutants of an upland cultivar Nagina-22 (N22), was screened for leaf morphological traits leading to the identification of mutants differing in LMA. The wild-type, N22, along with a selected low-LMA (380–4-3) and two high-LMA mutants (392–9-1 and 457–1-3), all with comparable total leaf area, were raised under well-watered (100% Field Capacity (FC)) and water-limited (60% FC) conditions. Low Δ¹³C and a higher RuBisCO content in high-LMA mutants indicated higher carboxylation efficiency, leading to increased carbon gain. Single parent backcross populations developed by crossing high and the low-LMA mutants with N22, separately, were screened for LMA, Δ¹³C and growth traits. Comparison of dry matter accumulation per unit leaf area among the progenies differing in LMA and Δ¹³C reiterated the association of LMA with CE. Results illustrated that high-LMA when combined with higher CE (low Δ¹³C) lead to increased WUE and growth rates.     

Inhibitory effects of Mannich bases of heterocyclic chalcones on NO production by activated RAW 264.7 macrophages and superoxide anion generation and elastase release by activated human neutrophils

Some chalcones exert potent anti-inflammatory activities. Mannich bases of heterocyclic chalcones inhibited nitric oxide (NO) production in lipopolysaccharide and interferon-γ stimulated RAW 264.7 macrophages. Also Formyl-Met-Leu-Phe and cytochalasin B induced superoxide anion generation (O2·-) and elastase release in human neutrophils. Mannich bases of heterocyclic chalcone analogs exhibited potent inhibitory effects on NO production with IC(50) values ranges between 10.5 and 0.018 μM, O2·- generation (IC(50) 39.87-0.68 μM) and elastase release (IC(50) 39.74-0.95 μM). Compound 29 (IC(50) 0.055 μM) and 34 (IC(50) 0.018 μM) were showed excellent inhibition on NO production. On the other hand, compounds 2 and 8 showed potent inhibition on O2·- generation and elastase release. Therefore, these four compounds may be new leads for development of anti-inflammatory activities. The structure-activity relationships are also discussed.     

Glutathione S-transferases as antioxidant enzymes: small cell lung cancer (H69) cells transfected with hGSTA1 resist doxorubicin-induced apoptosis

It has been suggested that the alpha-class glutathione S-transferases (GSTs) protect various cell types from oxidative stress and lipid peroxidation (LPO). In order to examine the protective role of alpha-class GST isozyme hGSTA1-1 against doxorubicin (DOX)-induced lipid peroxidation, cytotoxicity, and apoptosis, human small cell lung cancer (SCLC) H69 cells were stably transfected with hGSTA1. Immunological and biochemical characterization of hGSTA1-transfected cells revealed the expression of functionally active hGSTA1-1 localized near the cellular plasma membranes. hGSTA1-transfected cells acquired significantly increased resistance to the DOX-induced cytotoxicity by suppressing lipid peroxidation levels in these cells. Overexpression of hGSTA1-1 in cells inhibited DOX-mediated depletion of GSH and higher GSH levels were found in DOX-treated hGSTA1-transfected cells as compared with empty vector-transfected controls. hGSTA1-1 overexpression also provided protection to cells from DOX-induced apoptosis by inhibiting phosphorylation of c-Jun-N-terminal kinases (JNK), caspase-3 activation, and by preserving the levels of anti-apoptotic protein Bcl-2. These results are consistent with the idea that the alpha-class GSTs provide protection against oxidative stress by attenuating lipid peroxidation and these enzymes can modulate signaling for apoptosis.     

From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part I: the discovery of CCR3 antagonist development candidate BMS-639623 with picomolar inhibition potency against eosinophil chemotaxis

Conformational analysis of trans-1,2-disubstituted cyclohexane CCR3 antagonist 2 revealed that the cyclohexane linker could be replaced by an acyclic syn-alpha-methyl-beta-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the alpha-methyl group to the urea lowered protein binding and that the beta-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the alpha-methyl group governs the spatial orientation of three key functionalities within the molecule. alpha-Methyl-beta-hydroxypropyl urea 31 with a chemotaxis IC(50)=38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.