Kolupula Srinivas

Synthesis and evaluation of novel 2-pyridone derivatives as inhibitors of phosphodiesterase3 (PDE3): a target for heart failure and platelet aggregation.

Twenty-six 2-pyridone derivatives (8a-8z), which are structurally analogous to amrinone and milrinone two important cardiotonic drugs, are synthesized and characterized. The synthesis of 2-pyridone derivatives involves addition, followed by cyclization between Baylis-Hillman acetates (7a-7k) and enamino esters or nitriles (3a-3e). Thus synthesized pyridones were subjected to PDE3 inhibitory activity, 14 pyridones were found to be hits out of 26 pyridones synthesized and out of 14 hits, there are 5 pyridones found to be lead compounds having excellent PDE3 inhibitory activity. Further we have carried out computational analysis to understand protein/enzyme and 2-pyridone derivative interactions to identify amino acid residues involved in the vicinity of binding and compared with milrinone drug.

Synthesis and biological evaluation of new epalrestat analogues as aldose reductase inhibitors (ARIs).

Baylis-Hillman chemistry derived four series of new epalrestat analogues were synthesized. Three structural changes are introduced in these 39 new epalrestat analogues synthesized. All compounds were evaluated for their in vitro aldose reductase inhibitory (ALR) activity. Biological activity data indicates that compounds 6, 16, 19, 28 and 29 are potent and the activity is in the range of reference drug, epalrestat. Molecular modelling studies were performed to understand the binding interactions of these active molecules with the ALR protein. Molecular docking data indicates the key interactions of epalrestat were retained in some of the active compounds whereas some new interactions were noticed for other molecules. The modifications introduced on epalrestat have impact for developing a new-type of ALR inhibitor.

Remote Substituent Effects and Regioselective Enhancement of Electrophilic Substitutions in Helical Aromatic Oligoamides

The bromination of helically folded oligoamides of 8-amino-4-isobutoxy-2-quinolinecarboxylic acid by N-bromosuccinimide has been investigated. Bromination occurs preferentially if not exclusively at one position in the sequence despite the presence of multiple, up to seven, a priori comparable, reaction sites. Reactions are up to 2 orders of magnitude faster in a folded octamer than in a short nonhelical dimer, despite the steric hindrance that is expected in a compact folded conformation. The presence of substituents remote from the reaction site have considerable influence, resulting in the loss of regioselectivity, or in the slowing down of the reaction by several orders of magnitude.

Anticancer siRNA delivery by new anticancer molecule: a novel combination strategy for cancer cell killing.

The present report describes development of a novel, bifunctional molecule possessing both selective antiproliferative activity and siRNA transfection ability. We synthesized a series of cationic lipo-benzamides and screened for in vitro anticancer activities against a panel of cancer and non-cancer cells. The molecule with a ten carbon chain-length (C10M) significantly inhibited proliferation of cancer cells via arresting the cell cycle predominantly in the G1 phase; but did not affect non-cancerous cells. C10M effectively mediated siRNA delivery in vitro. The combined anticancer effect of the delivery of C10M together with its survivin-targeting siRNA cargo was significantly (p < 0.05) superior to that of agent alone. To our knowledge, this is the first report of a dual-purpose molecule with intrinsic anticancer activity and suitability for use in siRNA delivery.

Synthesis and Multibromination of Nanosized Helical Aromatic Amide Foldamers via Segment-Doubling Condensation

The synthesis of very long helical aromatic amide foldamers was thought to be limited by steric hindrance associated with stable folded conformations. This difficulty may be overcome by using pure reagents, relatively high concentrations, and long reaction times. Bromine substituents and careful identification and elimination of anhydride byproducts both greatly improve chromatographic purification, giving access to pure products amenable to a segment-doubling synthesis of sequences composed of up to 96 monomers. An efficient one-pot multibromination of helical oligomers is also reported.

Ionic Photodissociation in Arylallyl Acetates

Abstract We have synthesized several 3-arylallyl acetates 1, 2, 3, 5 and 6, and E-3-(1-naphthyl)-2-propene-1-ol 4 for studying ionic photodissociation. Compounds 1, 2 and 3 underwent an efficient ionic photodissociation in polar solvents like acetonitrile and methanol leading to the formation of rearranged acetate and methyl ether products, as well as undergoing an E–Z isomerization. The arylallyl alcohol 4 and the two arylallyl acetates 5 and 6 did not undergo ionic photodissociation. Quantum yields of product formation, quantum yields of fluorescence, solvent polarity effects and triplet-sensitization studies indicated that a highly polarized excited singlet state is responsible for the ionic photodissociation. Both the singlet- and triplet-excited states are effective in displaying E–Z isomerization in 1, 2, 3 and 4. Compounds 5 and 6 are highly fluorescent, and the fluorescence may be the excited state deactivation pathway along with internal conversion.

Erratum to: Synthesis and characterization of new s-triazine bearing benzimidazole and benzothiazole derivatives as anticancer agents

Erratum to: Med Chem Res (2015) 24:3991–4001DOI 10.1007/s00044-015-1430-9

Unusual regioselective electrophilic substitutions in quinoline foldamers: conceptual DFT and frontier molecular orbital analysis reveal the crucial role of folding and substituents.

We carried out a detailed computational investigation of an earlier experimentally observed, unusual, regioselective, electrophilic halogenation in helically folded quinoline oligoamides. In the experimental studies, halogenation occurred selectively at a given monomer of a foldamer substituted with electron-withdrawing groups at the N terminus, although apparently identical reactive sites were available to react with the incoming electrophile. On the other hand, the selectivity was lost with weakly electron-donating groups. To gain an insight into the regioselective preference of bromination in quinoline foldamers, conceptual DFT was used to calculate the local nucleophilicity index of various foldamers of different sizes and with different substituents, and it was found that the predicted reaction centers were in line with the experimental results. Frontier molecular orbital analysis was used to understand this behavior. A detailed study of the hypothetical linear conformation of the tetramer for comparison with the folded conformation was carried out. In the case of a linear conformer, the HOMO is localized on specific monomers irrespective of substitution, but upon folding delocalization is observed, which is larger for the weakly electron-donating groups when compared with the electron-withdrawing groups. In the case of strongly donating groups there is no delocalization, even upon folding. The behavior remains the same when the size of the helix is increased (octamer). Thus, it is clearly seen in this work that the combined effects of conformations and substituents dictate the regioselectivity in the folded oligoamides; this knowledge will have a profound effect on the field of foldamer chemistry.

Conformational analysis of 2-anthryl-ethylene derivatives: Photochemical and computational investigation

Abstract2-Anthrylethylene derivatives 1E–5E and 1Z are synthesized to study the cis-trans photoisomerization. Interestingly, unlike 9-anthrylethylene derivatives, 2-anthrylethylene derivatives 1E to 5E do not exhibit E(trans) to Z (cis) photoisomerization upon direct and triplet sensitization. One-way Z (cis) to E (trans) photoisomerization of 1Z is found to be very efficient under direct and triplet sensitization conditions, demonstrating the involvement of both singlet and triplet states. 1E–5E exhibits excitation wavelength dependent fluorescence indicating the existence of conformers (rotamers) at room temperature, which is confirmed by fluorescence lifetimes measurements of compounds 1E and 2E. Theoretical studies are carried out at DFT and ab initio methodology and the calculated relative energy difference of the conformers is very small; it ranges between 2.9 kJ·mol−1 to 6.3 kJ·mol−1 for both ground and excited states.