Amino acids derived benzoxazepines: Design,synthesis and antitumor activity

Two series of new benzoxazepines substituted with different alkyl amino ethyl chains were synthesized comprising synthetic steps of inter and intramolecular Mitsunobu reaction, lithium aluminium hydride (LAH) reduction, debenzylation, bimolecular nucleophilic substitution (S_N2) reaction. The present study investigates the effect of a tyrosine-based benzoxazepine derivative in human breast cancer cells MCF-7 and MDA-MB-231 and in breast cancer animal model. The anti-proliferative effect of 15a on MCF-7 cells was associated with G1 cell-cycle arrest. This G1 growth arrest was followed by apoptosis as 15a dose dependently increased phosphatidylserine exposure, PARP cleavage and DNA fragmentation that are hallmarks of apoptotic cell death. Interestingly, 15a activated components of both intrinsic and extrinsic pathways of apoptosis characterized by activation of caspase-8 and -9, mitochondrial membrane depolarization and increase in Bax/Bcl2 ratio. However, use of selective caspase inhibitors revealed that the caspase-8-dependent pathway is the major contributor to 15a-induced apoptosis. Compound 15a also significantly reduced the growth of MCF-7 xenograft tumors in athymic nude mice. Together, 15a could serve as a base for the development of a new group of effective breast cancer therapeutics.     

Does the position of the electron-donating nitrogen atom in the ring system influence the efficiency of a dye-sensitized solar cell? A computational study

Electronic structure of the XeOF₂ molecule and its two complexes with HX (X= F, Cl, Br, I) molecules have been studied in the gas phase using quantum chemical topology methods: topological analysis of electron localization function (ELF), electron density, ρ(r), reduced gradient of electron density |RDG(r)| in real space, and symmetry adapted perturbation theory (SAPT) in the Hilbert space. The wave function has been approximated by the MP2 and DFT methods, using APF-D, B3LYP, M062X, and B2PLYP functionals, with the dispersion correction as proposed by Grimme (GD3). For the Xe-F and Xe=O bonds in the isolated XeOF₂ molecule, the bonding ELF-localization basins have not been observed. According to the ELF results, these interactions are not of covalent nature with shared electron density. There are two stable F₂OXe^…HF complexes. The first one is stabilized by the F-H^…F and Xe^…F interactions (type I) and the second by the F-H^…O hydrogen bond (type II). The SAPT analysis confirms the electrostatic term, E_elst ⁽¹⁾ and the induction energy, E_ind ⁽²⁾ to be the major contributors to stabilizing both types of complexes.

     

Sporadic Retinoblastoma and Parental Smoking and Alcohol Consumption before and after Conception: A Report from the Children’s Oncology Group

Background

Retinoblastoma is the most frequent tumor of the eye in children and very little is known about the etiology of non-familial (sporadic) retinoblastoma. In this study we examined whether parental tobacco smoking or alcohol consumption (pre- or post-conception) contribute to the two phenotypes (bilateral or unilateral) of sporadic retinoblastoma.

Methods

Two large multicenter case-control studies identified 488 cases through eye referral centers in the United States and Canada or through the Children’s Oncology Group. Controls (n = 424) were selected from among friends and relatives of cases and matched by age. Risk factor information was obtained via telephone interview. We employed multivariable logistic regression to estimate the effects of parental tobacco smoking and alcohol consumption on retinoblastoma.

Findings

Maternal smoking before and during pregnancy contributed to unilateral retinoblastoma risk in the child: year before pregnancy conditional Odds Ratio (OR), 8.9; 95% confidence interval (CI) 1.5–51, and unconditional OR, 2.4; 95% CI, 1.3–4.7; month before or during pregnancy, conditional OR, 3.3; 95% CI, 0.5–20.8, and unconditional OR, 2.8; 95% CI, 1.1–7.0. No association was found for maternal or paternal alcohol consumption.

Conclusion

The results of this study indicate that maternal active smoking during pregnancy may be a risk factor for sporadic retinoblastoma. Our study supports a role for tobacco exposures in embryonal tumors.     

Leishmania donovani: dyskinetoplastid cells survive and proliferate in the presence of pyruvate and uridine but do not undergo apoptosis after treatment with camptothecin

We have shown that treatment with luteolin in leishmanial cells causes loss of mt-DNA and induces apoptosis through mitochondria dependent pathway [Sen, N., Das, B.B., Ganguly, A., Banerjee, B., Sen, T., Majumder, H.K., 2006. Leishmania donovani: intracellular ATP level regulates apoptosis-like death in luteolin induced dyskinetoplastid cells. Experimental Parasitology, in press]. Here, we report that mitochondrial DNA depleted leishmanial cells require exogenous sources of pyruvate and uridine to survive and proliferate. The presence of pyruvate and uridine in a growing media help them to produce sufficient amount of glycolytic ATP to maintain the mitochondrial membrane potential in the absence of their functional ETC. Treatment of wild type cells with CPT causes generation of ROS that leads to apoptosis. But unlike the normal cells ROS was not generated in these mt-DNA depleted cells after treatment with CPT. Taken together we have shown for the first time that dyskinetoplastid cells are auxotrophic for pyruvate and uridine and apoptosis cannot be induced in these cells in the presence of CPT. Therefore, the presence of mitochondrial DNA is absolutely necessary for the cytotoxicity of CPT in kinetoplastid parasites.     

Impact of metal accumulation pattern on the annual rhythmicity of antioxidants and their interrelationship to maintain the oxidative balance in mollusc

A chronological relationship between the annual profiles of oxidative stress markers, the key regulator of stress physiology has been sought in a terrestrial mollusc (Nerita articulata) under natural photothermal conditions. The hemolymph samples were collected at two different times in each month (from January to December) and the same was repeated for two consecutive years throughout an annual cycle. The fluctuations in the concentrations of certain heavy and trace metals (zinc, copper, cadmium, mercury, lead, and nickel) in both soil and hemolymph of Nerita are also estimated accordingly. Therefore, the present study aims to explore the rhythmic responses of oxidative stress marker to assess the impact of different trace and heavy metals on selected mollusc species. We tries to develop a realistic conceptual idea to analyze and predict the effect of changing environmental pollution on the possible shift in the rhythmicity of aforesaid antioxidants in terrestrial mollusc and their adaptive responses to thrive in such environment. Our results indicates that the amplitude of circannual rhythms of all the selected stress markers varied accordingly but the pattern of annual fluctuation is noted to be similar, and correlated with the metal accumulation. Therefore current information might help to frame the adaptive strategies for invertebrate species under similar toxic circumstances.