Tetrahydroisoquinoline
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Tetrahydroisoquinoline -based peptidomimetics mimicking reverse turn secondary structures Nicola Landoni , Giordano Lesma , Alessandro Sacchetti and Alessandra Silvani

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Synthesis

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Synthesis

Tetrahydroisoquinoline-based peptidomimetics mimicking reverse turn secondary structures

Nicola Landoni, Giordano Lesma, Alessandro Sacchetti and Alessandra Silvani

Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, via Venezian 21 – 20133 Milano, Italy E-mail: [email protected]

The Tic heterocyclic frame (Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) is present in many biologically active natural alkaloids and in a great number of pharmaceutical compounds. Particularly, the presence of the Tic nucleus, which is a conformationally constrained Phe analogue, seems to be essential in many synthetic peptidomimetics showing agonistic and antagonistic activity towards many G protein-coupled receptors.

This project is aimed to identify new Tic-based privileged structures having the capability to mimic reverse turn secondary motifs.

2

3

1

Peptidomimetics design through computational chemistry:

- Conformational analysis (MM / MC);- Analysis of geometrical parameters of low energy conformers.

Conformational analysis (intramolecolar hydrogen bond evaluation):

- 1H NMR;- IR;- CD.

Peptidomimetics synthesis:

- Control of stereochemistry .

Pyrrolo-tetrahydroisoquinoline (AHPIC)(AHPIC = 2-amino-8,9-dimethoxy-3-oxo-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline-5-carboxylic acid)

Synthesis

1

2

1

2

  • NMR and IR spectroscopical data. a

The presence of a reverse turn was observed in both the structures, with the C1 stereochemistry playing a central role in determining stable conformations. In particular, all the analyses led to the conclusion that a type II’ b-turn is mostly stabilized in tetrapeptide mimic 1, while a typical inverse γ-turn geometry is revealed for the diastereoisomer 2.

Similarity analysis of Ac-AHPIC-NHMe 1 and 2 with standard type β-turns.

1

2

aAll analyses were performed on 3.0 mM CDCl3 solutions. b At 298 K. c Determined between 298 and 328 K.

Conformational analysis of the structures AHPIC (Spartan ‘06, MC search, MMFF94 force field):

1

2

G. Lesma, E. Meschini, T. Recca, A. Sacchetti, A. Silvani, Tetrahedron 2007, 63, 5567-5578;

N. Landoni, G. Lesma, A. Sacchetti,A. Silvani, J. Org. Chem. 2007, 72, 9765-9768.

The score is defined as [(1-R2)/N], where R2 is the r.m.s. of the distances between points of similarity of structures and N is the number of centres.

Results expressed as % of the conformers that meet the requirement. In parentheses, the number of conformers.

Spyro-pyrrolo-tetrahydroisoquinoline (SIPP)(SIPP = 2-(2'-oxo-2,4-dihydro-1H-spiro[isoquinoline-3,3'-pyrrolidine]-1'-yl)propanoic acid)

Synthesis

% of conformers which meet the requirements.

3

1

3

  • Analysis of geometrical parameters of 3.

X-Ray Structure (from isopropanol)

  • NMR e IR spectroscopical data. a

Titration with DMSO-d6

aAll analyses were performed on 3.0 mM CDCl3 solutions. b At 298 K. c Determined between 298 and 328 K.

Bradikinin (Bk):

H-Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9-OH

Applicationof the SIPP scaffoldtomimic a bioactive peptide

HOE 140: A powerful antagonist for the bradykinin B2 receptor

Synthesis of a II’b-turn mimic fragment of HOE 140.

b-turn (type II’)

Type II’ b-turn with D-Tic in the i+1 position.

  • Bradikinin (Bk):an endogenous ligand for G protein-coupled receptors (GPCRs):

  • GPCRs: membrane receptors involved in signal transduction;

  • Control of different aspects of cell function, through the mediation of the response to different extracellular stimuli;

  • Adjust many biological processes, including sensory (smell, taste, sight) and not sensory (appetite, digestion, blood pressure, reproduction, inflammation) activities;

  • Approximately 50% of drugs on the market today exerts its therapeutic function through interaction with the GPCRs.

Type II’ b-turn

CD (MeOH 0.2 mM)

4

Synthesis

  • NMR and IR spectroscopical data.

4

Biochemistry, 1978, 17, 4951.


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