Naiem Ahmad Wani

Inhibition of Invasion in Pancreatic Cancer Cells by Conjugate of EPA with β(3,3)-Pip-OH via PI3K/Akt/NF-kB Pathway.

The present work describes the anti-invasive effect of conjugate BC06, a novel conjugate of EPA, (2E,4E)-4-(benzo[d][1,3]dioxol-5-ylmethylene) hex-2-enoic acid with β,β-disubstituted-β-amino acid, β(3,3)-Pip-OH (2-(4-aminopiperidin-4-yl)acetic acid), in human pancreatic carcinoma. The conjugate BC06 inhibited invasion and migration of PANC-1 cells in wound healing, matrigel invasion, and gelatin degradation assays. Apart from suppressing PI3K/Akt/NF-kB signaling, which is involved in the up-regulation of matrix metalloproteinases, our study also demonstrated that dose-dependent treatment of BC06 results in the upregulation of TIMP-1 and E-cadherin expression. Further, BC06 was found to be inhibiting the metastatic ability of PANC-1 cells by reducing MMP-2 and MMP-9 expression. These findings suggest that EPA conjugate with β(3,3)-Pip-OH, BC06, may be used as an anti-invasive agent against human pancreatic carcinoma.

2-(1-Amino-4-tert-butyl-cyclo-hex-yl)acetic acid (tBu-β(3,3)-Ac6c) hemihydrate.

The title compound, C12H23NO2·0.5H2O, crystallized with two 2-(1-amino-4-tert-butylcyclohexyl)acetic acid molecules, which are present as zwitterions, and one water molecule in the asymmetric unit. The molecular structure of each zwitterion is stabilized by an intramolecular six-membered (C 6 ) N—H⋯O hydrogen bond. In the crystal, the two independent zwitterions are linked head-to-head by N—H⋯O hydrogen bonds. Further O—H⋯O and N—H⋯O hydrogen bonds link the zwitterions and the water molecules, forming sandwich-like layers, with a hydrophilic filling and a hydrophobic exterior, lying parallel to the ab plane.

C11/C9 Helical Folding in αβ Hybrid Peptides Containing 1-Amino-cyclohexane acetic acid (β3, 3-Ac6c)

The present study describes the solid-state conformation of αβ hybrid peptides, Boc-Leu-β3, 3 -Ac6 c-OH, P1; Boc-Leu-β3, 3 -Ac6 c-Leu-β3, 3 -Ac6 c-OMe, P2; and Boc-Leu-β3, 3 -Ac6 c-Leu-β3, 3 -Ac6 c-Leu-OMe, P3. The dipeptide P1 adopts extended conformations, whereas tetrapeptide P2 and pentapeptide P3 favor a helical conformation stabilized by mixed types of C11 /C9 intramolecular hydrogen bonds. In peptide P3, the amino group of β3, 3 -Ac6 c(2) and β3, 3 -Ac6 c(4) residues occupies axial orientation, whereas in P2 it occupies axial and equatorial orientations for residues β3, 3 -Ac6 c(2) and β3, 3 -Ac6 c(4), respectively. The self-assembly of P3 forms channels filled with solvent molecules that present interesting patterns.

Ribbon structure stabilized by C10 and C12 turns in αγ hybrid peptide

The present study describes the synthesis and crystallographic analysis of αγ hybrid peptides, Boc‐Gpn‐L‐Pro‐NHMe (1), Boc‐Aib‐Gpn‐L‐Pro‐NHMe (2), and Boc‐L‐Pro‐Aib‐Gpn‐L‐Pro‐NHMe (3). Peptides 1 and 2 adopt expanded 12‐membered (C12) helical turn over γα segment. Peptide 3 promotes the ribbon structure stabilized by type II β‐turn (C10) followed by the expanded C12 helical γα turn. Both right‐handed and left‐handed helical conformations for Aib residue are observed in peptides 2 and 3, respectively Copyright

Bioinspired Functionalized Melanin Nanovariants with a Range of Properties Provide Effective Color Matched Photoprotection in Skin.

Melanin and related polydopamine hold great promise; however, restricted fine-tunabilility limits their usefulness in biocompatible applications. In the present study, by taking a biomimetic approach, we synthesize peptide-derived melanin with a range of physicochemical properties. Characterization of these melanin polymers indicates that they exist as nanorange materials with distinct size distribution, shapes, and surface charges. These variants demonstrate similar absorption spectra but have different optical properties that correlate with particle size. Our approach enables incorporation of chemical groups to create functionalized polyvalent organic nanomaterials and enables customization of melanin. Further, we establish that these synthetic variants are efficiently taken up by the skin keratinocytes, display appreciable photoprotection with minimal cytotoxicity, and thereby function as effective color matched photoprotective agents. In effect we demonstrate that an array of functionalized melanins with distinct properties could be synthesized using bioinspired green chemistry, and these are of immense utility in generating customized melanin/polydopamine like materials.

Amino acid amides of piperic acid (PA) and 4-ethylpiperic acid (EPA) as NorA efflux pump inhibitors of Staphylococcus aureus.

A total of eighteen piperic acid (PA) and 4-ethylpiperic acid (EPA) amides (C1-C18) with α-, β- and γ-amino acids were synthesized, characterized and evaluated for their efflux pump inhibitory activity against ciprofloxacin resistant Staphylococcus aureus. The amides were screened against NorA overexpressing S. aureus SA-1199B and wild type S. aureus SA-1199 using ethidium bromide as NorA efflux pump substrate. EPI C6 was found to be most potent and reduced the MIC of ciprofloxacin by 16 fold followed by C18 which showed 4 fold reduction of MIC. Ethidium bromide efflux inhibition and accumulation assay proved these compounds as NorA inhibitors.

C5 and C7 intramolecular hydrogen bonds stabilize the structure of N-pyrazinoyl-gabapentin (Pyr-Gpn-OH).

2-{1-[(Pyrazin-2-ylformamido)methyl]cyclohexyl}acetic acid (Pyr-Gpn-OH), C14H19N3O3, is an N-protected derivative of gabapentin (Gpn). The compound crystallizes in the triclinic space group P1 and the molecular conformation is stabilized by intramolecular five- (C5) and seven-membered (C7) hydrogen-bonded rings. The packing of the molecules reveals intermolecular O-H···O and C-H···N hydrogen bonds, together with π-π interactions.

Short hybrid peptides incorporating β- and γ-amino acids as antimicrobial agents

HIGHLIGHTSThe hybrid peptides containing &bgr;‐ and &ggr;‐amino acids were synthesized, characterized and evaluated as antimicrobial agents.&agr;&ggr; hybrid peptide, LA‐Lys(Z)‐Gpn‐PEA, P4 was found more active against P. aeruginosa and S. aureus.Peptide P4 exhibited lowest haemolytic activity and negligible cytotoxicity against human cancer cell lines A549, PC‐3 and HCT‐116 at its MIC concentration. ABSTRACT The peptides containing &bgr;‐ and &ggr;‐amino acids, LA‐Lys(Z)‐PEA, P1; LA‐Lys(Z)‐&bgr;3,3‐Ac6c‐PEA, P2; LA‐Orn(Z)‐&bgr;3,3‐Ac6c‐PEA, P3; LA‐Lys(Z)‐Gpn‐PEA, P4; LA‐Orn(Z)‐Gpn‐PEA, P5; LA‐Lys(Z)‐&ggr;4‐Phe‐PEA, P6, LA‐&ggr;4‐Leu‐Lys(Z)‐PEA, P7 and LA‐&bgr;3,3‐Pip(Ac)‐Lys(Z)‐PEA, P8 were synthesized, characterized and evaluated against Gram‐positive and Gram‐negative bacteria. Among all, peptides P2, P3, P4 and P5 exhibited potent activity (MIC 6.25 &mgr;M) against S. aureus MTCC 737 and P. aeruginosa MTCC 424. In order to understand the efficacy of peptides and mechanism of action, time kill kinetics and fluorescence microscopic studies were performed against S. aureus and P. aeruginosa for the peptides P2, P3, P4 and P5. P4 took half time to show the bactericidal effect on P. aeruginosa and S. aureus in comparison to P2 at their 2x MICs. Fluorescence microscopic studies suggested that peptides P2 and P4 both killed the bacteria via membrane disruption. Further, P4 exhibited lowest haemolytic activity among active peptides and negligible cytotoxic activity against human cancer cell lines A‐549, PC‐3 and HCT‐116 at its MIC.

Cyclodipeptide c(Orn-Pro) Conjugate with 4-Ethylpiperic Acid Abrogates Cancer Cell Metastasis through Modulating MDM2

The present work describes the synthesis, characterization, and anticancer properties of c(Lys-Pro), P1; c(Orn-Pro), P2; and conjugates PA-c(Lys-Pro), C1; PA-c(Orn-Pro), C2; EPA-c(Lys-Pro), C3; and EPA-c(Orn-Pro), C4. Among all, conjugate C4 displays potent anticancer activity with IC50 1.3 μM in MDA-MB-231, 3.5 μM in PC-3, 8.9 μM in MCF-7, and 9.6 μM in Miapaca-2 cancer cells. In addition, C4 downregulates the expression of MDM2 and abrogates the cancer cell invasion/metastasis. Through knock-down of MDM2, we demonstrate that this abrogation of metastasis by C4 is primarily MDM2 dependent. Furthermore, the animal studies underscore the antitumor as well as antimetastatic potential of C4 in vivo in breast cancer model at a safe and tolerable dose of 20 mg/kg.

Conformation of a terminally protected βγ hybrid dipeptide Boc-Ant-Gpn-OMe stabilized by C6/C7 hydrogen bonds.

The hybrid βγ dipeptide, methyl 2-[1-({2-[(tert-butoxycarbonyl)amino]benzamido}methyl)cyclohexyl]acetate (Boc-Ant-Gpn-OMe), C22H32N2O5, adopts a folded conformation stabilized by intramolecular six- (C6) and seven-membered (C7) hydrogen-bonded rings, together with weak C-H...O and C-H...π interactions, resulting in a ribbon-like structure.