presentation...

1. 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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2. 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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3.  A peptide is a chain of amino acids linked together by -CO-NH- bonds known as amide
bonds(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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4.  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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5.  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
ῳ
ø
Ө
ᴪ
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6. Classification β- Amino acid:
 Classification is based on the position of the side chain attached.
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7. SYNTHESIS OF β-AMINO
ACID:
It is of two type:
METAL
CATALYSIS
Hydrogenati
on
Mannich
reaction
Conjugate
addition
ORGANOCATALYSIS
Mannich
reaction
Conjugate
addition
Miscellaneou
s
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8.  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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9.  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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10. 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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11. 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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12. (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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13. 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 Bronsted
acids, (thio)urea, and Cinchona alkaloids
1. Mannich reaction.
2. Conjugate addition.
3. Miscellaneous.
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14. 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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15.  Peptides containing the β3-hVal/hLeu-β3-hLys-
β3-hLeu motif. These peptides showed
antibacterial activity in the micromolar
range;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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16.  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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17. 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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18.  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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19. 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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20. 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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21. 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 subnanomolar
affinity at BRS-3
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22. 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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23.  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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24.  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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25. 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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26. 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 roten
surface 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 Diastereoselective
Aminomethylation 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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