Synthesis, in vitro and structural aspects of cap substituted Suberoylanilide hydroxamic acid analogs as potential inducers of apoptosis in Glioblastoma cancer cells via HDAC /microRNA regulation.

Glioblastoma multiforme (GBM) is a heterogeneous, aggressive brain cancer characterized by chemo-resistance and cancer stemness. Histone deacetylases (HDACs) are a group of enzymes that regulate chromatin epigenetics which were in turn found to be controlled by microRNAs (miRs). The drug employed in chemotherapy for the treatment of GBM is Temozolomide (TMZ). Unfortunately, many GBM patients exhibit chemo-resistance to this drug. Here we have synthesized various Suberoyl anilide hydroxamic acid (SAHA) analogs with many substitutions at the cap site majority of which not yet studied. These SAHA analogs have exhibited profound cytotoxicity at 2 µM, and 4 µM concentrations in GBM cancer cell line U87MG, and 1 µM, and 2 µM concentrations in breast cancer cell line MCF-7. Surprisingly, these analogs have exhibited cytotoxic effects in chronic lymphoid leukemia cells (Raji) at 64 µM, and 128 µM concentrations due to mutated p53. Among all the synthesized analogs 3-Chloro-SAHA, 3-Chloro-4-fluoro SAHA have exhibited effective cytotoxicity in all cancer cells. These potent analogs inhibited HDAC-8 enzyme activity by 2-folds in U87MG, and MCF-7 cell lines and 7-folds decrease in HDAC-8 activity was observed in Raji cell line. These analogs decreased the expression of HDAC-2, HDAC-3 genes and enhanced the expression of p53 tumor suppressor. Interestingly, these compounds decreased the expression of Rictor, the main component of the mTORC2 complex involved cancer cell metabolism. Furthermore, these molecules have decreased oncogenic microRNA expression such as miR-21 and enhanced the expression of tumor suppressor microRNAs such as miR-143. The HDAC binding ability of these molecules was highly significant and have exhibited the ability to cross blood-brain barrier (BBB), and followed the Lipinski rule of five. Thus, these molecules need to be taken up further to clinics for better therapy against GBM either singly or combination therapy.

Synthesis, in vitro and structural aspects of benzothiazole analogs as anti-oxidants and potential neuroprotective agents.

Catalase, an important antioxidant enzyme, is known to have a neuroprotective role against neurodegenerative disorder. Earlier study has focussed on benzothiazole-triazole hybrid molecules that are larger in size and molecular weight and inhibit the amyloid ß (Aß)-catalase interaction thus aid in neuroprotection. Here we have synthesized the novel benzothiazole molecules with low molecular weight using One-pot methodology and assayed the neuroprotective effects of the synthesized compounds in the U87 MG cell line under H2O2 induced stressed condition and compared with other cell lines such as breast cancer (MCF-7) and macrophage (RAW-264.7) using cell viability assay. These analogs were found to enhance the neuronal cell viability and protect neuronal cells from the ROS mediated neuronal damage induced by H2O2. Furthermore, compounds 6a, 6b, 6c, 6d, and 7a modulate catalase and enhanced the catalase activity up to 90 % during the H2O2 exposure in the U87MG cell line. These analogs (6a, 6b, 6c and 6d) have exhibited strong binding energies of -7.39, -7.52, -6.5 and -7.1 as observed by molecular modeling studies using AutoDockTool-1.5.6. Lig Plot + program using potent analogs 6b and 6c and catalase enzyme indicated the presence of hydrophobic interactions in the catalytic site of catalase enzyme. Furthermore, a simulation study was conducted between ligand and catalase protein by DESMOND software that further strengthens these ligand and enzyme interactions. In silico ADMET study was conducted by the Swiss ADME program revealed the drug-likeliness of these analogs. The present study has identified benzothiazole analogs such as 6b, 6c and 6d have potential catalase modulating activity and is comparable with that of known drug Valproic acid, thus help in neuroprotection. This study can be further taken up for the in vivo animal model study for the possible therapy.

Thiamine hydrochloride as a recyclable organocatalyst for the synthesis of bis(indolyl)methanes, tris(indolyl)methanes, 3,3-di(indol-3-yl)indolin-2-ones and biscoumarins.

Thiamine hydrochloride was identified as an eco-friendly organocatalyst for the synthesis of a broad range of bis(indolyl)methanes in good to excellent yields. Green chemistry matrix calculations showed high atom economy and a small E-factor for the reaction. Moreover, the simple and easy operational protocol using a small amount of thiamine hydrochloride (1 mol%) makes this procedure an alternative approach for this transformation industrially. This protocol was also extended to the synthesis of naturally occurring alkaloids such as tris(indolyl)methane, arundine, vibrindole A, 3,3-di(indol-3-yl)indolin-2-ones and biscoumarin derivatives.

Seasonal dynamics of dissolved metals in surface coastal waters of southwest India.

Spatial and temporal variations in concentration of dissolved metals viz. Copper (Cu), Lead (Pb), Chromium (Cr), Nickel (Ni), Zinc (Zn), Cadmium (Cd) and Mercury (Hg) in surface waters of southwest coast of India were studied. Concentrations of metals showed an aberration both temporally and spatially. Seasonal average concentrations of the analyzed metals followed the order Zn > Ni > Cu > Pb > Cd > Cr > Hg. The degree of contamination due to metal was determined by comparison with coastal water quality criteria. It established enrichment of Cu, Zn, Ni and Hg due to anthropogenic influence along southwest coast of India.