Gangadhar J. Sanjayan

Sequence-Specific Unusual (1→2)-Type Helical Turns in α/β-Hybrid Peptides

This article describes novel conformationally ordered alpha/beta-hybrid peptides consisting of repeating l-proline-anthranilic acid building blocks. These oligomers adopt a compact, right-handed helical architecture determined by the intrinsic conformational preferences of the individual amino acid residues. The striking feature of these oligomers is their ability to display an unusual periodic pseudo beta-turn network of nine-membered hydrogen-bonded rings formed in the forward direction of the sequence by 1-->2 amino acid interactions both in solid-state and in solution. Conformational investigations of several of these oligomers by single-crystal X-ray diffraction, solution-state NMR, and ab initio MO theory suggest that the characteristic steric and dihedral angle restraints exerted by proline are essential for stabilizing the unusual pseudo beta-turn network found in these oligomers. Replacing proline by the conformationally flexible analogue alanine (Ala) or by the conformationally more constrained alpha-amino isobutyric acid (Aib) had an adverse effect on the stabilization of this structural architecture. These findings increase the potential to design novel secondary structure elements profiting from the steric and dihedral angle constraints of the amino acid constituents and help to augment the conformational space available for synthetic oligomer design with diverse backbone structures.

Foldamers: They’re Not Just for Biomedical Applications Anymore

Conformationally ordered synthetic oligomers, called foldamers, are a class of compounds that have ushered into prominence, and interest in these systems continues unabated, primarily as a result of the fact that they hold considerable promise for potential applications in biomedical sciences. These synthetic oligomers may provide excellent starting points for the elaboration of peptide mimics that could only be designed with difficulty on the basis of small-molecule scaffolds. By means of diverse synthetic tools, the “bottomup” foldamer approach is also highly useful in engineering new frameworks that can be successfully molded to mimic the structure and functions of biopolymers. The scope and feasibility of this concept is reflected in the exponential growth from its foundation in the early 21st century to the present stage. The recent launch of the heterofoldamer concept has further fuelled activity in this area, essentially because the conformational space that is available for foldamer design can be enormously augmented by developing oligomers that feature a variety of building blocks in the backbone. Despite offering considerable promise because of the enormous structural diversity, a breakthrough in applications of the foldamers in material science, in particular in molecular machines, is yet to be realized. The technique of using foldamers as dynamic receptors for rod-like guest molecules was first described by Moore and coworkers. In their interesting study, it was demonstrated that m-phenylene ethynylene oligomers fold into macromolecular receptors and adopt a helical architecture that binds to hydrophobic guests. In the helical conformation, these oligomers bind nonpolar ligands within the tubular hydrophobic cavity. Along this line, Huc and co-workers recently reported a fascinating finding that conveys clear indications that the time has come to scan the wide repertoire of foldamers for the purpose of developing molecular machines and nanodevices. This idea is valid because foldamers of any desired shape/architecture can be engineered by using delicate and flexible noncovalent interactions, among which the highly directional hydrogen-bonding interaction assumes prime importance. In their classic paper, Huc and coworkers demonstrated that double helical foldamers that are coiled around rod-shaped guest molecules can perform a screw-type motion, which is an unusual phenomenon that is not observed in other molecular machines (Figure 1a). The heterofoldamers described by Huc and co-workers, called

A Synthetic Zipper Peptide Motif Orchestrated via Co-operative Interplay of Hydrogen Bonding, Aromatic Stacking, and Backbone Chirality

Here, we report on a new class of synthetic zipper peptide which assumes its three-dimensional zipper-like structure via a co-operative interplay of hydrogen bonding, aromatic stacking, and backbone chirality. Structural studies carried out in both solid- and solution-state confirmed the zipper-like structural architecture assumed by the synthetic peptide which makes use of unusually remote inter-residual hydrogen-bonding and aromatic stacking interactions to attain its shape. The effect of chirality modulation and the extent of noncovalent forces in the structure stabilization have also been comprehensively explored via single-crystal X-ray diffraction and solution-state NMR studies. The results highlight the utility of noncovalent forces in engineering complex synthetic molecules with intriguing structural architectures.

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.

Sheet-forming abiotic hetero foldamers

Abiotic hetero oligomers, adopting a well-defined extended self-assembled sheet-like structure, derived from conformationally constrained aliphatic and aromatic amino acid residues repeating at regular intervals are reported.

Correlation of hydrogen-bonding propensity and anticancer profile of tetrazole-tethered combretastatin analogues.

A series of 1,5-disubstituted tetrazole-tethered combretastatin analogues with extended hydrogen-bond donors at the ortho-positions of the aryl A and B rings were developed and evaluated for their antitubulin and antiproliferative activity. We wanted to test whether intramolecular hydrogen-bonding used as a conformational locking element in these analogues would improve their activity. The correlation of crystal structures with the antitubulin and antiproliferative profiles of the modified analogues suggested that hydrogen-bond-mediated conformational control of the A ring is deleterious to the bioactivity. In contrast, although there was no clear evidence that intramolecular hydrogen bonding to the B ring enhanced activity, we found that increased substitution on the B ring had a positive effect on antitubulin and antiproliferative activity. Among the various analogues synthesized, compounds 5d and 5e, having hydrogen-bonding donor groups at the ortho and meta-positions on the 4-methoxy phenyl B ring, are strong inhibitors of tubulin polymerization and antiproliferative agents having IC50 value in micromolar concentrations.

Isotactic N-alkyl acrylamide oligomers assume self-assembled sheet structure: first unequivocal evidence from crystal structures

Herein we present the first unequivocal evidence of the ability of isotactic N-alkyl acrylamide oligomers to assume self-assembled sheet-like structures that are reminiscent of protein beta-sheets.

Novel hybrid nocodazole analogues as tubulin polymerization inhibitors and their antiproliferative activity.

We describe the design, synthesis and SAR profiling of a series of novel combretastatin-nocodazole conjugates as potential anticancer agents. The thiophene ring in the nocodazole moiety was replaced by a substituted phenyl ring from the combretastatin moiety to design novel hybrid analogues. The hydroxyl group at the ortho position in compounds 2, 3 and 4 was used as the conformationally locking tool by anticipated six-membered hydrogen bonding. The bioactivity profiles of all compounds as tubulin polymerization inhibitors and as antiproliferative agents against the A-549 human lung cancer cell line were investigated Compounds 1 and 4 showed μM IC50 values in both assays.

The role of N-terminal proline in stabilizing the Ant–Pro zipper motif

Hetero-chiral hybrid peptides of the general sequence LαβnDαβn featuring proline (Pro, a constrained α-amino acid) and anthranilic acid (Ant, a constrained β-amino acid) as building blocks, where n = 2, 4 etc., form a three-dimensional zipper-like architecture. These zipper peptides attain stable conformation by balancing the co-operative contribution of two competing non-covalent forces, namely hydrogen bonding and aromatic stacking. However, the selection of the N-terminal residue also stands to be one of the key contributors in stabilising the unusually long-range intramolecular hydrogen bond, featuring 26 atoms in the H-bonded ring observed at the termini. This article deals with the substitution alterations at the N-terminus of the zipper motif and their consequent influences on its structure and stability. In this study, the N-terminal Pro residue of the zipper motif was substituted with a flexible amino acid, alanine, and a constrained acyclic amino acid, 2-aminoisobutyric acid, to investigate the role of N-terminal proline in stabilizing the Ant–Pro zipper motif, and its stabilities were assessed by employing solution-state NMR and restrained MD simulation studies.

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