Sripadi Prabhakar

Mitochondrial-Targeted Curcuminoids: A Strategy to Enhance Bioavailability and Anticancer Efficacy of Curcumin

Although the anti-cancer effects of curcumin has been shown in various cancer cell types, in vitro, pre-clinical and clinical studies showed only a limited efficacy, even at high doses. This is presumably due to low bioavailability in both plasma and tissues, particularly due to poor intracellular accumulation. A variety of methods have been developed to achieve the selective targeting of drugs to cells and mitochondrion. We used a novel approach by conjugation of curcumin to lipophilic triphenylphosphonium (TPP) cation to facilitate delivery of curcumin to mitochondria. TPP is selectively taken up by mitochondria driven by the membrane potential by several hundred folds. In this study, three mitocurcuminoids (mitocurcuminoids-1, 2, and 3) were successfully synthesized by tagging TPP to curcumin at different positions. ESI-MS analysis showed significantly higher uptake of the mitocurcuminoids in mitochondria as compared to curcumin in MCF-7 breast cancer cells. All three mitocurcuminoids exhibited significant cytotoxicity to MCF-7, MDA-MB-231, SKNSH, DU-145, and HeLa cancer cells with minimal effect on normal mammary epithelial cells (MCF-10A). The IC50 was much lower for mitocurcuminoids when compared to curcumin. The mitocurcuminoids induced significant ROS generation, a drop in ΔØm, cell-cycle arrest and apoptosis. They inhibited Akt and STAT3 phosphorylation and increased ERK phosphorylation. Mitocurcuminoids also showed upregulation of pro-apoptotic BNIP3 expression. In conclusion, the results of this study indicated that mitocurcuminoids show substantial promise for further development as a potential agent for the treatment of various cancers.

Mitochondria-targeted esculetin alleviates mitochondrial dysfunction by AMPK-mediated nitric oxide and SIRT3 regulation in endothelial cells: potential implications in atherosclerosis

Mitochondria-targeted compounds are emerging as a new class of drugs that can potentially alter the pathophysiology of those diseases where mitochondrial dysfunction plays a critical role. We have synthesized a novel mitochondria-targeted esculetin (Mito-Esc) with an aim to investigate its effect during oxidative stress-induced endothelial cell death and angiotensin (Ang)-II-induced atherosclerosis in ApoE−/− mice. Mito-Esc but not natural esculetin treatment significantly inhibited H2O2- and Ang-II-induced cell death in human aortic endothelial cells by enhancing NO production via AMPK-mediated eNOS phosphorylation. While L-NAME (NOS inhibitor) significantly abrogated Mito-Esc-mediated protective effects, Compound c (inhibitor of AMPK) significantly decreased Mito-Esc-mediated increase in NO production. Notably, Mito-Esc promoted mitochondrial biogenesis by enhancing SIRT3 expression through AMPK activation; and restored H2O2-induced inhibition of mitochondrial respiration. siSIRT3 treatment not only completely reversed Mito-Esc-mediated mitochondrial biogenetic marker expressions but also caused endothelial cell death. Furthermore, Mito-Esc administration to ApoE−/− mice greatly alleviated Ang-II-induced atheromatous plaque formation, monocyte infiltration and serum pro-inflammatory cytokines levels. We conclude that Mito-Esc is preferentially taken up by the mitochondria and preserves endothelial cell survival during oxidative stress by modulating NO generation via AMPK. Also, Mito-Esc-induced SIRT3 plays a pivotal role in mediating mitochondrial biogenesis and perhaps contributes to its anti-atherogenic effects.

Diels–Alder trapping of 3-methylenequinolin-2,4-dione: a facile synthesis of pyranoquinolinones and spiroquinolinediones

3-Methylenequinolin-2,4-dione generated in situ by Knoevenagel condensation of 4-hydroxyquinoline with formaldehyde is trapped by Diels–Alder cycloaddition to provide spiroquinolinediones and pyranoquinolinones.

Cerium(IV) Ammonium Nitrate Induced Dimerization of Methoxystyrenes

4-Methoxystyrene 1 underwent dimerization to 1,4-diphenylbutane derivatives 5 and 6 in presence of CAN in methanol. But in ethanol the same reaction afforded a tetralone derivative along with 5 and 6. 3,4-Dimethoxystyrene 10 underwent dimerization in presence of CAN in methanol to afford acyclic as well as cyclic products. 3,4,5-Trimethoxystyrene 12 in presence of CAN in methanol afforded only the cyclized dimers, the tetralone 21 and the tetralin derivative 22.

Dipolar cycloaddition of carbonyl ylides to 2-oxoindolinylidenes: a facile approach towards the synthesis of functionalized spiroindolenins

Oxoindolinylidenes undergo regiospecific dipolar cycloaddition with carbonyl ylides affording highly functionalized spiroindolenin systems in high yield.

Chiral discrimination of α-amino acids by the DNA triplet GCA

The DNA triplet GCA is successfully used for the first time as a chiral selector for the chiral discrimination and optical purity measurement of some α-amino acids by investigating the collision-induced dissociation spectra of the sodiated ternary complex ion formed by electrospray ionization.

[4+2] Cycloaddition reactions of o-thioquinones with pentafulvenes: efficient synthesis of benzoxathiins

o-Thioquinones undergo [4+2] cycloaddition reactions with pentafulvenes leading to 1,4-benzoxathiins. Reactions of 6-styrenylfulvene with o-thioquinones also afforded similar products.

Exploration of mononucleotides as fixed ligands towards chiral discrimination of hexose monosaccharides by the kinetic method

The most recent version of the kinetic method, i.e. fixed ligand method, is applied towards chiral discrimination of three pairs of enantiomeric hexose monosaccharides under mass spectral conditions. Naturally occurring mononucleotides are used as fixed ligands (FL) and the amino acids are selected as the chiral references (ref) to discriminate the analyte (A), the enantiomers of glucose, mannose and galactose. Chiral discrimination is achieved by investigating the collision-induced dissociation spectra of trimeric complex ion, [NiII(FL)(ref)(A)–H]+ generated by electrospraying the solution mixture of d- or l-analyte (A), FL, amino acid (ref) and NiCl2. The relative abundance of product ions resulting from the competitive loss of reference amino acid and analyte are considered for measuring the degree of chiral discrimination by applying the kinetic method. l-Asp, l-Thr, l-Glu, l-Trp and l-Ser are found as suitable reference compounds. Among the tested mononucleotides (5′AMP, 5′GMP, 5′CMP, 5′UMP and 5′TMP), 5′GMP is found to be the best for the studied analytes. Chiral discrimination is found to depend on the nature of the monosaccharide, the functional groups present in the side chain of reference amino acids and the configuration of reference amino acids.

Hetero Diels–Alder reactions of o-thioquinones with cyclic dienes: an efficient synthesis of novel heterocyclic compounds

o-Thioquinones undergo facile hetero Diels–Alder reactions with cyclic dienes leading to novel heterocyclic compounds.

Estimation of gas-phase acidities of deoxyribonucleosides: An experimental and theoretical study

We determined the gas-phase acidities (ΔHacid) of four deoxyribonucleosides, i.e., 2′-deoxyadenosine (dA), 2′-deoxyguanosine (dG), 2′-deoxycytidine (dC), and 2′-deoxythymidine (dT) by applying the extended kinetic method. The negatively charged proton-bound hetero-dimeric anions, [A-H-B]− of the deoxyribonucleosides (A) and reference compounds (B) were generated under electrospray ionization conditions. Collision-induced dissociation spectra of [A-H-B]− were recorded at four different collision energies using a triple quadrupole mass spectrometer. The abundance ratios of the individual monomeric product ions were used to determine the ΔHacid of the deoxyribonucleosides. The obtained ΔHacid value follows the order dA7>dC7>dT7>dG. The ΔGacid (298 K) values were determined by using ΔGacid=ΔHacid-TΔSacid where the ΔHacid and ΔSacid values were determined directly from the kinetic method plots. The ΔHacid values were also predicted for the deoxyribonucleosides at the B3LYP/6-311+G**//B3LYP/6-311G** level of theory. The acidity trend obtained from the computational investigation shows good agreement with that obtained experimentally by the extended kinetic method. Theoretical calculations provided the most preferred deprotonation site as C5′-OH from sugar moiety in case of dA, and as −NH2 (dC and dG) or -NH- (dT) from nitrogenous base moiety in the case of other deoxyribonucleosides.