GORGILE AMOL T.M.S.(MEDICHEM)

REG. NO.-MC/2014/08

NIPER, HYDERABAD.

Peptides Containing β-Amino Acid Patterns:

Challenges and

Successes in Medicinal Chemistry

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CONTENT

Introduction.

Classification β- Amino acid.

Method of Synthesis of β- amino acid.

Membrane-Targeting Peptide.

Mimicry Of Protein Function.

Receptor Ligand.

Conclusion.

References.

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A peptide is a chain of amino acids linked together by -CO-NH- bonds known as amidebonds(peptide).

These are strong bonds they can be hydrolysed by either strong acid or strong base.

β-Amino acids are key structural elements of peptides and peptidomimetics.

β-peptides consist of β-amino acids, which have their amino group bonded to the

β- carbon rather than the α- carbon .

These are not proteinogenic amino acids.

β-peptides in general do not appear in nature, except only

β-alanine.

Only glycine lacks a β-carbon.

β- amino acid are precursors for β-lactum ,class of antibiotics.

INTRODUCTION

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The synthesis of β amino acids have various substitution pattern.

distribution functional group (ligand) bonded to the β-carbon atom, for effective intraction.

The necessity of maintaining chirality.

Physicochemical properties.

β-amino acid-containing peptides have greater stability than regular peptides, because usual

protease type, (resistance the proteolysis).

The development of effective drug is based on α- peptide is limited. So molecular size of such

peptide higher than typical non peptide.

β- peptide show amphipathic property

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CONFORMATIONAL PROPERTY OF β-AMINO ACID

The appropriate conformation of peptide required for development of bioactive molecule.

In the case of β-residues the number of torsional variables is three (Φ, Ψ, θ)

β-Amino acids, with a specific side chain, can exist as the R or S isomers at either the α(C2) carbon or the β(C3) carbon.

Folded helical or turn like conformation of peptide requird GAUCH conformation about

torsion angle ϴ C2 –C3

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ø

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Classification β- Amino acid:

Classification is based on the position of the side chain attached.

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SYNTHESIS OF β-AMINO

ACID:

It is of two type:

METAL CATALYSIS

Hydrogenation

Mannichreaction

Conjugate addition

ORGANOCATALYSIS

Mannichreaction

Conjugate addition

Miscellaneous

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Synthesis of β-amino acids before their installation into natural analogue. In fact, there are various enzyme mediated mechanisms to construct β-amino acids in nature.

Most of β-amino acids are derived from L-amino acids via intramolecular rearrangement of the α-amino acid to the β-position, C–C-bond rearrangement of glutamate, decarboxylation, and Michael addition to dehydroalanine.

German chemists Fritz Arndt (1885–1969) and Bernd Eistert (1902–1978), Arndt–Eistert

synthesis is a popular method of producing β-amino acids from α-amino acids.

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METAL CATALYSIS:

Various transition metals and chiral ligands have been used for synthesis of β-amino acid. such as nickel, palladium or platinum

1. Hydrogenation-

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2 .Mannich reaction-

• Diethylzinc and bridged-Binol form in situ the active catalyst that has been used

in the anti-selective Mannich reaction of

hydroxyketone.

• The anti-Mannich products are

obtained with high diastereomeric ratio

and high enantiomeric excess from

imines with aromatic, heteroaromatic,

cyclopropyl and cinnamyl.

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3. Conjugate addition:

The catalytic asymmetric conjugate addition, when applied in the synthesis of b-amino acids, can be achieved in two ways:

(1) Addition of carbon nucleophiles, such as organometallic reagents, cyanide or Michae

donors. The conjugate addition of carbon nucleophiles to α, β-unsaturated compounds is

an important C–C bond formation reaction.

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(2) Addition of nitrogen nucleophiles, such as aromatic amines, hydroxylamines, and carbamates.

The enantioselective addition of primary aromatic amines to α, β-unsaturated oxazolidinones.

It investigated cationic palladium–BINAP complex Using aniline derivatives and

crotonyloxazolidinone, the adducts were obtained in very good yield with ee’s up to 93%.

However, when the substrate incorporated longer aliphatic chains than methyl, i.e. ethyl and

propyl, a significantly lower ee was observed.

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Cont…

ORGANOCATALYSIS:

Asymmetric transformation promoted by small chiral organic molecule have become very

useful mehod for synthesis of β- amino acid.

Important catalysts used for this purpose are proline, proline- derived amines, chiral Bronstedacids, (thio)urea, and Cinchona alkaloids

1. Mannich reaction.

2. Conjugate addition.

3. Miscellaneous.

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MEMBRANE TARGETING PEPTIDE:

β-amino acid containing peptides focused on their interaction

with biological membranes, for desired bioactivity.

The mechanism of cell penetration is dependent on the sequence

and conformation of the peptide and cell type.

The structural requirements of β-amino acid is usually lower than proteins or DNA

For membrane target.

Because interaction of such molecule on amphiphilic character of cell Membranes.

E.g. the N-terminal part of the p53 protein forms an α-helix that has three key amino acids that makes up most of the interaction with a hydrophobic groove .

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Peptides containing the β3-hVal/hLeu-β3-hLys-β3-hLeu motif. These peptides showed antibacterial activity in the micromolarrange;show hemolytic activity.

If improved it by changing the sequence to β3-hAla-β3-hLys-β3-hLeu repeats, thus lowering the lipophilic character of the peptides.

peptides having (β3-hAla-β3-hLys-β3-hPhe)n sequences showed a poor profile with moderate antibacterial activity and high hemolytic activity.

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peptide 2 containing (3R,4S)-trans-4-aminopyrrolidine-3-carboxylic acid (APC) and (1R,2S)-trans-2-aminocyclopentanecarboxylic acid (ACPC) which also exhibited little hemolytic activity at the minimal inhibitory concentration (MIC) against various bacterial strains.

It was proven that the net charge of the peptide is highly important: negatively charged C-terminal carboxylates substantially decrease the activity.

proteolytic stability of α,β-peptides is high, it14/15 helix was resistant to cleavage by trypsin or chymotrypsin show in fig.

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MIMICRY OF PROTEIN SURFACE:

Structure-based design of synthetic peptide that mimic the functional site of natural proteins, plays an important role in drug discovery.

Application- antiviral, antifertility, or antitumor antimicrobial agents to therapeutic agents that are able to mimic or disrupt protein–protein interactions.

A structural mimics exist for α-helices,β-turns or hairpins, and β-sheets. topologies, like four-helix bundles, are often needed to mimic protein function.

Mimicry Secondary Structures- Many protein−protein interactions occur through an α-helical interface, which is accommodated by a shallow cleft on the

binding partner.

To design the proper structure is an ideal template of mimicking helix−peptide

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MDM2−p53 - It is an important negative regulator of the p53 tumor suppressor inhibitor of p53 transcriptional activation.

hDM2−p53AD Interaction Inhibitors-(human oncogene double minute2)

It is recognized by a short helix motif of the p53 activation domain (p53AD), making

it a potential target for cancer therapy.

γ- secretase inhibiter : aspartic protease, that processes amyloid precursor protein (APP) to obtain Aβ peptides

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o Protein gp41 Inhibitors- Targeting ,mimicking the components of helices derived from the gp41 N & C-terminal 7A A domain has been investigated and applied as an anti-HIV.

Profound rearrangement of gp-41 is to form antiparrel six helix .

o Intrleukin-8receptor: IL-8 is a pro-inflammatory chemokine it acts on neutrophil granulocytes.

IL-8 contains a central β-sheet motif, which is stabilized by an amphiphilic C-terminal helix through hydrophobic interactions.

o Fibrinogen receptor: (PLATLET INTEGRIN α2bβ3)

Approach for that first entry into the membrane and scaffold have active site for attachment.

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PROTEIN LIGAND RECEPTOR :

The formation and dissociation of specific noncovalent interactions between a variety of macromolecules play a crucial role in the function of biological systems.

o GnRH Receptor Ligands :The agonistic potency of the hormone (pIC50 of

7.7 for β-analogue vs 8 for parental GnRH) however, the β-analogue is 100-fold less

potent than buserelin that contains (R)-Ser(tBu) at position 6 .

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o Angiotensin receptor ligand-GPCR:-

The AT-II analogues show different proteolytic stability in rat plasma, depending on the

position of the β3-residue; in particular, [β3-hIle5]-AT-II is found to be much more stable than [β3-hTyr4]-AT-II.

o Orphan receptor-.It plays a key role in development and body physiology.

Recently developed new orphan receptor-mediated signaling is benzoate x receptor(BXR ), constitutive androstate receptor(CAR), pregnan x receptor(PXR)

In 14-helix orphan receptor does not bind, its C-terminal fragment containing four

substitutions, including, [(R)-Tyr6, β-Ala11, Phe13, Nle14]-(6−14), shows subnanomolaraffinity at BRS-3

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o Opioid receptor ligand: Morphiceptin is a tetrapeptide

(H-Tyr-Pro-Phe-Pro-NH2) with submicromolar potency at the μ-opioid receptor. Analogues containing (1R,2S)-β-ACPC in the place of Pro-2 have been reported that show better activity than morphiceptin at the μ-opioid receptor.2

o Somatostatin Receptor Ligands:- It is secreted by ∂ cell of pancrease, also regulate the secretion of growth hormone, glucagon, insulin, and gastrin.

The biologically active conformation of SST consists of a β-turn residues

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GLP-1 Receptor ligand : GLP-1R plays a relevant role in the development of drugs for the treatment of diabetes mellitus type 2

The N-terminal region of GLP-1/exendin-4 is essential for receptor activation, whereas

the well-defined C-terminal α-helix is likely to have a role in receptor binding.

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Integrin receptor ligand: Important targets are the fibrinogen-specific GPIIb/IIIa integrin, which mediates platelet aggregation and is a target for anti-thrombotic agents

β-Residues have been used to replace the (R)-configured residue.

ACC containing cyclic analogue shows higher potency than the 1s 2s 3s configration.

Neuroeptide Y receptor ligand:The approach used to develop receptor ligands has been

based on the replacement of the native α-amino-acid residue at position 34 and 32 with β-amino-acid residues.

α,β-peptide analogues of the C-terminal NPY fragment 25−36 containing (1R,2R,3R)-β-ACC at position 34 or at both positions 32 and 34 have been found to be Y1R have low nanomolar affinity, in contrast to the micromolar affinity .

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CONCLUSION:

The synthesis of β-amino acids remains a challenging target for organic chemists due to the importance of the peptidomimetics.

Metal catalyzed hydrogenation is the method of choice, due to very low catalyst loadings (0.1 mol%), high selectivities (90% ee).

The formation of products that do not require a multi step synthesis to β-amino acids.

β-Peptides form secondary structures with greater stability (against enzymatic degradation) than α-peptides.

Asymmetric catalysis should provide inexpensive and quick access to novel β-amino acid.

Resistance to protolyais and maintain chirality.

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References

Chiara Cabrele, Tamas A. Martinek, Oliver R. and Lukasz B., Peptide Containg β–amino Acid Patterns: Challenges and Successes in Medicinal Chemistry, J. MED. Chem,XXXX American Chemical Society, ACS Publication, July 2014, A-V.

Barbara Weiner, Wiktor S. Dick B.Janssen, Recent advances in catalytic asymmetric synthesis of β-amino acid, J. of R.S.C., Chem. Soc. Rev., 2010, 1656-1691.

W. Seth H, Lisa M. Johnson, Thomas J. Ketas, Structural and biological mimicry of rotensurface recognition by α / β-peptide foldamers, PNAS, sept-2009, vol. 106, no.35, 14751-14756.

Richard P.Cheng, Samue H. Gellman, and Willam F. DeGrado, β-Peptide : From Structure to Function J. of American Chemical Society, Chem. Rev. 2001, 101, 3219-3232.

Yonggui Chi, Emily P. English, William C. Pomerantz, Practical Synthesis of Enantiomerically Pure β2-Amino Acids via Proline-Catalyzed DiastereoselectiveAminomethylation ofAldehydes, J. AM. CHEM. SOC. 2007, 129, 6050-6055.

Ilker Avan,a C. Dennis Hallb and Alan R. Katritzky, Peptidomimetics via modifications of amino acids and peptide bonds, Chem. Soc. Rev., 2014, 43, 3575.

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