Rupesh L. Gawade

Carboxamide versus Sulfonamide in Peptide Backbone Folding: A Case Study with a Hetero Foldamer

Strikingly dissimilar hydrogen-bonding patterns have been observed for two sets of closely similar hetero foldamers containing carboxamide and sulfonamides at regular intervals. Although both foldamers maintain conformational ordering, the hydrogen-bonding pattern and backbone helical handedness differ diametrically.

Sugar furanoid trans-vicinal diacid as a γ-turn inducer: synthesis and conformational study

A simple method for the synthesis of a sugar furanoid trans vicinal diacid and its incorporation into the N-terminal tetrapeptide sequence (H-Phe-Trp-Lys-Thr-OH) to get glycopeptide has been described. 2D NMR and MD simulation studies of clearly show that the sugar diacid adopts a γ-turn conformation towards the N-terminus.

Nucleophilic Ring-Opening of Benzoxazinones by DBU: Some Observations

Abstract This communication demonstrates the formation of an unusual nucleophilic ring opening of benzoxazinones by 1,8-diazabicycloundec-7-ene (DBU). This observation contradicts the intrinsic feature of a hindered nonnucleophilic base like DBU. Confirmation of the product was achieved via single-crystal X-ray diffraction studies. GRAPHICAL ABSTRACT

Comparative study of dG affinity vs. DNA methylation modulating properties of side chain derivatives of procainamide: insight into its DNA hypomethylating effect

Procainamide derivatives have been synthesized to investigate the role of side chains in modulating the DNA methylation level in cancer cells and gain insight into its mechanism of action. The synthesized derivatives comprised of flexible (dimethyl), constrained (pyrrolidine, piperidine, morpholine) and planar aromatic (pyridine, phenyl) side chain motifs. The affinity of procainamide and its derivatives towards the deoxyguanosine (dG) base in neutral form has been assessed by performing Differential Pulse Voltammetry (DPV) under physiological conditions. Further, molecular docking with hemimethylated CpG rich DNA acquired from an active mDNMT-1-DNA (PDB ID-4DA4) crystal structure, reveals their preferential non-covalent interaction with dG nucleobase in the intercalation cavity of the minor groove. Differential affinity of the derivatives to dG base in neutral and bound forms (DNA) is correlated with their DNA methylation modulating properties at sub-lethal concentrations. Among all the derivatives, a compound with an aromatic phenyl side chain (1) has shown a highest binding affinity for dG nucleobase in neutral form as well as for partially denatured CpG rich DNA which is attributed to the formation of π⋯π stacking interaction in addition to N–H⋯O hydrogen bonding with the pyrimidine ring of dG base. It also shows the highest cytotoxicity and global hypomethylation at a sub-lethal level in the MCF-7 cancer cell line compared to other derivatives and procainamide. A docking study has also illustrated the plausible structural basis of DNA methylation modulating a property of procainamide. Strong association of procainamide with dG bases of partially denatured CpG rich DNA via H-bonding and other non-covalent interactions may alter the active topology of DNA required by the DNA-binding regulatory proteins (e.g. DNMT-1) which is validated by a DNMT-1 inhibition assay. This systematic investigation leads to a new potent alternative to procainamide being found and gives a plausible insight into the DNA hypomethylating effect of procainamide.

3-Aminothiophenecarboxylic acid (3-Atc)-induced folding in peptides

This paper describes the consequences of incorporating a constrained heterocyclic aromatic β-amino acid 3-aminothiophenecarboxylic acid (3-Atc) into peptides containing β-turn forming elements such as Pro-Gly motif and the effect on the secondary structural architecture of the entire peptide backbone. Conformational investigations of oligomers comprising an α,β,α peptide sequence were carried out by single-crystal X-ray diffraction, solution-state NMR, nOe-restrained MD simulation and circular dichroism studies. The results suggested that these peptide sequences assume helical architecture. The helical folding in the oligomers was found to be devoid of inter-residual H-bonding, instead found to be stabilized by a co-operative effect of 6-membered H-bonding within the 3-Atc unit and conformational restrictions of individual amino acids in the peptide backbone.

Design, synthesis and cytotoxicity of novel N-benzylpiperidin-4-one oximes on human cervical cancer cells

AbstractA series of fifteen diversified N-benzylpiperidin-4-one oximes were synthesized and characterized by their NMR spectral data. Additionally, single-crystal XRD analysis was performed for the representative symmetrically and unsymmetrically substituted molecules. All the synthesized oximes from unsymmetrical ketones existed as E-isomer as witnessed by their NMR and XRD data. Among the synthesized target compounds that evaluated for their in vitro cytotoxicity against human cervical carcinoma (HeLa) cells, five compounds were potent with IC50 < 17 μM. 1-Benzyl-2,6-bis(4-isopropylphenyl)-3-methylpiperidin-4-one oxime 3c with an IC50 of 13.88 μM was found to be the best active compound as depicted by the microscopic analysis. Graphical AbstractA series of fifteen diversified N-benzylpiperidin-4-one oximes were synthesized and characterized by their NMR spectral data. Single-crystal XRD analysis was performed for the representative symmetrically and unsymmetrically substituted molecules. All the synthesized oximes from unsymmetrical ketones existed as Eisomer. Among the synthesized target compounds that were evaluated for in vitro cytotoxicity against human cervical carcinoma (HeLa) cells, 1-benzyl-2,6- bis(4-isopropylphenyl)-3-methylpiperidin-4-one oxime with an IC50 of 13.88 μM was most potent.

1-Benzoyl-3-[(2-benzylsulfanyl)phenyl]thiourea.

In the title compound, C(21)H(18)N(2)OS(2), a strong intramolecular N-H...O hydrogen bond [N...O = 2.642 (3) Å] between the amide N atom and the benzoyl O atom forms an almost planar six-membered ring in the central part of the molecule. In the crystal, molecules are packed through weak N-H...S interactions. Intra- and intermolecular hydrogen bonds and van der Waals interactions are the stabilizing forces for the crystal structure.

Additive-induced capture of elusive polymorphs of conformationally flexible sulfonamides/sulfoesters

Understanding the process of prenucleation clustering (PNC) during crystal growth is of significant importance in envisaging the polymorphism. Structural investigation of stable and metastable polymorphs reveals that supramolecular synthons share a close relationship with PNCs which subsequently helps in understanding of nucleation phenomena.[1] Preferential crystallization of a thermodynamically stable crystal during nucleation suggests self-assembly of molecules through energetically favoured supramolecular synthons. However, slight change in the crystallization conditions like, solvent, temperature, impurity, etc. can lead to metastable polymorphs. To gain more insight into the nucleation dynamics, the polymorphic behaviour of conformationally flexible sulfonamide/sulfoester derivatives during crystallization was investigated with and without additive.[2] Absence of additive during crystallization at various conditions exclusively produced thermodynamically stable crystals wherein molecule acquired syn conformation facilitated by energetically favoured intra and intermolecular p-stacking interactions. Surprisingly, exploitation of pyrazinamide as an additive in different stoichiometric ratios during crystallization produced elusive metastable polymorphs. The melt crystallization and lattice matching studies revealed that pyrazinamide played a pivotal role in providing an alternate nucleation pathway (epitaxial growth) thereby defying natural process of crystal growth. This suggests that it is possible to envisage the selective polymorphic form using tailor-made auxiliaries, although it is critical to design such additives in more general way to control its inhibition or promotion.

Probing the folding induction ability of orthanilic acid in peptides: some observations

This paper describes the ability of orthanilic acid (2-aminobenzenesulfonic acid, SAnt) to promote folding when introduced in a peptide sequence. Three peptide sequences, containing orthanilic acid (SAnt) with a sulfonamide moiety in the turn segment, have been synthesized in the solution phase using suitable coupling agents, and their structural aspects investigated using NMR and X-ray crystallographic studies. Solid- and solution-state conformational analyses reveal that the peptide sequences containing orthanilic acid in their backbone exist in a folded conformation featuring long-range 15-membered ring H-bonding.