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Evidence of diketopiperazine and oxazolone structures for HA b2+ ion.

ABSTRACT: Peptide fragmentation can lead to an oxazolone or diketopiperazine b(2)(+) ion structure. IRMPD spectroscopy combined with computational modeling and gas-phase H/D exchange was used to study the structure of the b(2)(+) ion from protonated HAAAA. The experimental spectrum of the b(2)(+) ion matches both the experimental spectrum for the protonated cyclic dipeptide HA (a commercial diketopiperazine) and the theoretical spectrum for a diketopiperazine protonated at the imidazole pi nitrogen. A characteristic band at 1875 cm(-1) and increased abundance of the peaks at 1619 and 1683 cm(-1) indicate a second population corresponding to an oxazolone species. H/D exchange also shows a mixture of two populations consistent with a mixture of b(2)(+) ion diketopiperazine and oxazolone structures.

SUBMITTER: Perkins BR

PROVIDER: S-EPMC3477237 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Evidence of diketopiperazine and oxazolone structures for HA b2+ ion.

Perkins Brittany R BR Chamot-Rooke Julia J Yoon Sung Hwan SH Gucinski Ashley C AC Somogyi Arpád A Wysocki Vicki H VH

Journal of the American Chemical Society 20091201 48

Peptide fragmentation can lead to an oxazolone or diketopiperazine b(2)(+) ion structure. IRMPD spectroscopy combined with computational modeling and gas-phase H/D exchange was used to study the structure of the b(2)(+) ion from protonated HAAAA. The experimental spectrum of the b(2)(+) ion matches both the experimental spectrum for the protonated cyclic dipeptide HA (a commercial diketopiperazine) and the theoretical spectrum for a diketopiperazine protonated at the imidazole pi nitrogen. A cha ...[more]

PMID: 19904982

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Project description:Phosphodiesterase 5 (PDE5) is one of the most extensively studied phosphodiesterases that is highly specific for cyclic-GMP hydrolysis. PDE5 became a target for drug development based on its efficacy for treatment of erectile dysfunction. In the present study, we synthesized four novel analogues of the phosphodiesterase type 5 (PDE5) inhibitor-tadalafil, which differs in (i) ligand flexibility (rigid structure of tadalafil vs. conformational flexibility of newly synthesized compounds), (ii) stereochemistry associated with applied amino acid building blocks, and (iii) substitution with bromine atom in the piperonyl moiety. For both the intermediate and final compounds as well as for the parent molecule, we have established the crystal structures and performed a detailed analysis of their structural features. The initial screening of the cytotoxic effect on 16 different human cancer and non-cancer derived cell lines revealed that in most cases, the parent compound exhibited a stronger cytotoxic effect than new derivatives, except for two cell lines: HEK 293T (derived from a normal embryonic kidney, that expresses a mutant version of SV40 large T antigen) and MCF7 (breast adenocarcinoma). Two independent studies on the inhibition of PDE5 activity, based on both pure enzyme assay and modulation of the release of nitric oxide from platelets under the influence of tadalafil and its analogues revealed that, unlike a reference compound that showed strong PDE5 inhibitory activity, the newly obtained compounds did not have a noticeable effect on PDE5 activity in the range of concentrations tested. Finally, we performed an investigation of the toxicological effect of synthesized compounds on Caenorhabditis elegans in the highest applied concentration of 6a,b and 7a,b (160 ?M) and did not find any effect that would suggest disturbance to the life cycle of Caenorhabditis elegans. The lack of toxicity observed in Caenorhabditis elegans and enhanced, strengthened selectivity and activity toward the MCF7 cell line made 7a,b good leading structures for further structure activity optimization and makes 7a,b a reasonable starting point for the search of new, selective cytotoxic agents.

Dataset Information

Evidence of diketopiperazine and oxazolone structures for HA b2+ ion.

Publications

Evidence of diketopiperazine and oxazolone structures for HA b2+ ion.

Similar Datasets

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