Leishmania donovani: Oral therapy with glycosyl 1,4-dihydropyridine analogue showing apoptosis like phenotypes targeting pteridine reductase 1 in intracellular amastigotes

Glycosyl 1,4-dihydropyridine analogue (2,6-dimethyl-4-(3-O-benzyl-1,2-O-isopropylidene-β-l-threo pentofuranos-4-yl)-1-phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester) synthesized in our laboratory, inhibited Leishmania donovani infection in vitro and in hamsters (Mesocricetus auratus) when administered orally. This analogue is nontoxic, cell-permeable and orally effective. This glycosyl dihydropyridine analogue functioned through arrest of cells in sub-G0/G1-phase, triggering mitochondrial membrane depolarization-mediated programmed cell death of the intracellular amastigotes.     

Enhanced death signaling in ozone-exposed ischemic-reperfused hearts

Although numerous advancements made in the field of human health have resulted in reduced deaths due to cardiovascular diseases (CVD), many patients with cardiac disease show no established risk. Therefore, other unknown factors may be responsible for the pathophysiology of CVD. Out of 350,000 sudden cardiac deaths each year in the United States, 60,000 deaths have been related to air pollution, suggesting a detrimental role of environmental pollutants in the development of CVD. The present study tested our hypothesis that chronic ozone exposure enhances the sensitivity to ischemia–reperfusion (I/R) injury in isolated perfused hearts. Sprague-Dawley rats were continuously exposed for 8 h/day for 28 and 56 days to filtered air or 0.8 ppm ozone. Isolated hearts were subjected to 30 min of global ischemia followed by 60 min of reperfusion. Cardiac function after I/R measured as left ventricular developed pressure (LVDP), +dP/dt, –dP/dt, and left ventricular end diastolic pressure (LVEDP) was significantly decreased and increased respectively in ozone-exposed I/R hearts compared to I/R hearts exposed to filtered air. The enhanced sensitivity to I/R injury upon ozone exposure was associated with increased myocardial TNF-α levels and lipid peroxidation and decreased myocardial activities of superoxidase dismutase (SOD) and IL-10. These data suggest that ozone-induced sensitivity to myocardial I/R injury may be due to promoting levels of oxidative stress as well as inflammatory mediators.     

Mutation in the lysA gene impairs the symbiotic properties of Mesorhizobium ciceri

A Tn5-induced mutant of Mesorhizobium ciceri, TL28, requiring the amino acid lysine for growth on minimal medium was isolated and characterized. The Tn5 insertion in the mutant strain TL28 was located on a 6.8-kb EcoRI fragment of the chromosomal DNA. Complementation analysis with cloned DNA indicated that 1.269 kb of DNA of the 6.8-kb EcoRI fragment restored the wild-type phenotype of the lysine-requiring mutant. This region was further characterized by DNA sequence analysis and was shown to contain a coding sequence homologous to lysA gene of different bacteria. The lys ^? mutant TL28 was unable to elicit development of effective nodules on the roots of Cicer arietinum L. There was no detectable level of lysine in the root exudates of chickpea. However, addition of lysine to the plant growth medium restored the ability of the mutant to produce effective nodules with nitrogen fixation ability on the roots of C. arietinum.     

Single primer amplification reaction (SPAR) reveals intra-specific natural variation in Prosopis cineraria (L.) Druce

Prosopis cineraria, an important multipurpose tree and vital component of the otherwise fragile ecosystem of arid and semiarid regions of India. It is highly drought tolerant and sprouts profusely during the extreme dry summer months when most other trees are leafless. P. cineraria is known to exhibit comparable genetic variations at intra-specific and inter-population levels reflected through morphological and cytogenetical diversity in regions, where this plant grows naturally. In the present study, single primer amplification reaction (SPAR) methods have been used for determination of diversity at DNA level in 30 accessions of P. cineraria collected from different districts of Rajasthan. The analyses include the use of six minisatellite core sequence primers for direct amplification of minisatellite DNA (DAMD), eight inter simple sequence repeats (ISSR) and 20 arbitrary primed decamer sequences for random amplification (RAPD) reactions. Upon analysis of the data generated, all the three SPAR methods, either independently and/or in combination, revealed wide range of genetic variation among accessions. Comparison of matrix of individual SPAR method using MxComp component of NTSYS-pc 2.02 K software proving that analysis of natural genetic variation using combination of SPAR methods particularly ISSR and DAMD, rather than an isolated approach, is very effective. Such an approach also yields better information and reflection of the relatedness and affinities at intra-species and inter-population levels. Therefore, it is opined that in order to reveal the intrinsic intra-specific variation, SPAR approaches involving more than one DNA marker may reveal more authentic genetic variation in tropical tree species like P. cineraria.     

A new benzil derivative from Derris scandens: Structure-insecticidal activity study

Bioactivity-directed investigation of root extract of Derris scandens has led to the isolation and characterization of a new benzil derivative (11), along with ten known compounds (1–10). Their structures were determined on the basis of extensive spectroscopic (IR, MS, 1D and 2D NMR) data analysis and by comparison with the literature data. The insect antifeedant activity and growth inhibitory studies of these compounds were investigated against castor semilooper pest, Achaea janata using a no-choice laboratory bioassay. Several of the isolates displayed potent feeding deterrence and were also toxic or caused developmental abnormalities following topical administration. The new compound, derrisdione A was moderately active with an antifeedant index of 58.6 ± 1.7% at 10 μg/cm³ against A. janata.     

Non-aromatic A-ring replacement in the triaryl bis-sulfone CB2 receptor inhibitors

The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inhibition is described.     

Discovery and SAR of hydantoin TACE inhibitors

We disclose inhibitors of TNF-α converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.     

Synthesis and anti breast cancer activity of biphenyl based chalcones

A series of (2E,2′E)-1,1′-(3-hydroxy-5-methylbiphenyl-2,6-diyl)-bis(3-pheylprop-2-ene-1-ones (5–33) were prepared by the reaction of 1,3-diacetyl biphenyls (1–4) with different aldehydes in presence of catalytic amount of solid KOH in ethanol in excellent yields. The compounds were evaluated for anticancer activity against human breast cancer MCF-7 (estrogen responsive proliferative breast cancer model) and MDA-MB-231 (estrogen independent aggressive breast cancer model) cell lines, HeLa (cervical cancer) cell line, and human embryonic kidney (HEK-293) cells. Most of the compounds preferentially inhibited the growth of the aggressive human breast cancer cell lines, MDA-MB-231 in the range of 4.4–30 μM. The two compounds 9 and 29 proved to be better anticancer agents than the standard drug tamoxifen against the MDA-MB-231 cell lines. Mode of action of these compounds was established to be apoptosis, cell cycle arrest and loss of mitochondrial membrane potential.