conformationally restricted amino acids and dipeptides, (non)peptidomimetics and secondary structure...

Reciieil cles Trui:miu Cllimiques rlex Pays-Bus, I13/01, Jurlrrury 1994 1

Red. Trav. Chim. Pays-Bas 113, 001-019 (1994) SSDI 0 I 6 5 - 0 5 1 3( 93 )EO 1 00- 2

0 165-05 I3/94/0 I00 I - I Y$07.00

Recueil Review

Conformationally restricted amino acids and dipeptides, ( n o d peptidomimetics and secondary structure mimetics #

Rob M.J. Liskamp

Department of Organic Chemistry, Corlaeus Laboratories, University of Leiden, P. 0. Box 9502, 2300 RA Leiden, The Netherlands (Receioed August 25th, 1993)

Introduction

The rational design and synthesis of peptides and peptidomimetics with a predetermined structure and/or less flexible structure as well as de nouo protein design are among the most challenging and exciting fields in present- day peptide chemistry. Unfavorable solubility, bioavailability, biodegradation and bioselectivity properties have limited the use of unmodi- fied peptides as drugs to a largc cxtent. Conformationally restricted amino acids and dipeptides, as wcll as (non)peptide mimetics and secondary structure mimetics, can be employed to address or even remedy these disad- vantages and to improve the biological activity. In addition, they offer a means to investigate the factors that are important in determining the flexible nature of a peptide and to probe the bio-active conformation. A deeper un- derstanding of peptide structure may also shed some light on the role and function of peptide segments in a protein and perhaps on events in the folding process of a protein.

The flexibility of the pepride /protein structure

A peptide sequence as part of the large entity of a protein usually assumes a particular fold referred to as a secondary structure element. There are three classes of secondary structure elements: a-helices, P-sheets and turns or loops (Figure 1). The importance of the individual secondary structure elements in a protein is apparent from numerous examples. The a-helix is e.g. important in the recognition of a particular DNA sequence by DNA- binding proteins such as repressors and endonucleases I . The a-helix also plays an important role in ion channel proteins '. Furthermore, the G-protein-coupled receptors, which mediate the action of a large range of extracellular signals consist of transmembrane a-helices '. p-Sheets are a dominant structural motif characterizing the V,, and V, domains in antibodies 4, and p - and y-turns are often involved in diverse biochemical recognition mechanisms. In many cases recognition is the first step of a cascade of complex biochemical events leading to the biological effect. Turns are important in the recognition necessary for post-translational modification of proteins by phosphory-

' Dedicated to Professor Dr. G.I. Tesser on the occasion of his 65 birthday

lation and glycosylation '. Turns are often sites of high antigenicity ' and often the peptide antigen binds to the antibody in a p-turn conformation ', e.g. the glycoprotein gp 120 of the human immune deficiency virus (HIV) contains a turn, which is part of the so-called immun- odominant loop ". Study of the molecular basis of the role played by a particular secondary structure element in a protein by synthesizing its amino acid sequence e.g. the sequence comprising a recognition a-helix, is often hampered by the size of the sequence. Usually the sequencc is too small to assume a stable secondary structure. When an a-hclix has not reached its critical length I", it is not stable. Even if the peptide sequence is in principle long enough, the solvent may still destabilize the secondary structure. The problem of flexibility is also encountered in the development of biologically active peptides as drugs. Because of the flexibility of a peptide molecule, the desired biologically active conformation(s) are hidden in a population of many thousands of other conformers. Even within a nar- row energy window of the conformation which interacts with the receptor, there are often dozens of conformers present. It is therefore understandable that for a good interaction between the peptide ligand and the receptor, leading to an optimal biological effect, it will be energeti- cally most favorable to approach the biologically active conformation of the peptide ligand and to try to maintain it by fixation or rigidification. Combined with approaches to influence solubility and bioavailability as well as biodegradation, pharmaceutically meaningful compounds i.e. drugs may then ultimately be obtained. A major approach in the development of conformationally restricted amino acids and peptides is to decrease the flexibility of the backbone. This flexibility is caused by the rotation about the single bonds within each amino acid residue of a peptide. The torsion or dihedral angles of the backbone are the phi (41, the psi ($) and omega ( w ) angle of the amide bond. The latter angle, since it usually assumes values close to 180", i.e. a trans bond, is capable of imposing a certain rigidity on the peptide backbone 11,'2,13. The $ angle involves rotations about the N-C, bond and is defined by the dihedral angle of C,-,-N,-C,-C, (Figure 2 ) . The $ angle involves rotation about the C,-C=O bond and is defined by the dihedral angles of N,-C,-C,-N,, ,. Although many combinations, of $ and 9 angles are not allowed because of steric interactions, these angles involve rotations about single

2 R. M.J. Liskamp / Conformationally restricted amino acids and dipeptides

€3 6 P

reverse turn

type I type I' type II type It'

Fig. I .

bonds and are therefore the cause of the flexibility of a peptide. The + and $ angles are often plotted in a +,$ map or Rarnachundrun map I 2 3 I 4 , in which the approximate areas of +,$ angles of the various secondary structures can be indicated. The approximate +,$-angle combinations for the helix and sheet structures l 5 as well as the standard Q,,$ angles of reverse turns l 6 are summa- rized in Table I. There are a number of general approaches to decrease the flexibility of a peptide. By limiting the number of 4,$-angle combinations, conformationally restricted peptides can be obtained. With regard to this, the most obvious approach involves the preparation of a cyclic peptide by formation of a lactam by an intramolecular reaction of the N and C termini. Many approaches are based on linking side-chain functional groups together in such a way that e.g. disulfide bridges 17, lactam I * and metal-containing bridges are formed. In addition, cyclization of a side-chain functionality with the N or C terminus will lead to conformationally restricted peptides 20. These types of conformational restriction will only be discussed here if they concern the connection of side-chains in two adjacent amino acids. Another, more indirect method, though very important, is to constrain the Q, and $ angles by incorporation into a peptide of a,a-disubstituted amino acids which are known to induce 3,0/a-helix formation 21.

0

I I I 0 n H

Fig. 2.

The purpose of this review is to offer a representative cross-section of the synthetic methods described, mostly in the recent literature, which have been applied to restrict the conformational freedom of relatively small peptides by constraining the backbone torsion angles + and $ (uide supra). Emphasis will be placed on methods which achieve this by "short range" cyclizations 22 or other methods within an amino acid residue or (di)peptide sequence. Recently, Toniolo 22 reviewed the conformational restrictions that were achieved by short-range cyclizations. Here we will focus on the synthetic approaches for the introduction of conformational constraints in

Table I Approximate 4,JI-angle (deg) combinations for the helix and sheet structures as well as the standard 4,$ (deg) angles of reverse turns l 5 , I 6 , For a further subdiuision of the reuerse (/3) turn see Ref. 16b.

4 * a helix - 51 - 41 3,, helix - 60 - 30 parallel chain -119 +113

antiparallel chain -139 +135 P-plated sheet

/3-plated sheet extended chain +180 +I80 reverse (p)turns: 4r+l *,+I 4,+2 *t+2 type I - 60 -30 -90 0 type I' + 60 +30 +90 0 type I 1 -60 +I20 +SO 0 type 11' i 6 0 -120 -80 0 y-turn: *, 4r+l * , + I * ,+2 + 120 -65 + S O -120

a A reverse turn consists of four amino acids. These are numbered, starting from the N-terminus, I to 1 +3. The indicated 4 and JI angles refer to the dihedral angles in that particular amino-acid residue.

Reciteil des Trrtvrri~r Chiiiiiques des Pays-Bas, I13 /OI, January 1994

(dilpcptides, and consider the reasons for their introduction as well as available results. In addition, this review will discuss (non)peptidomimetics, which are often used as mimics of secondary structure elements, especially of the p turn. In these molecules the flexibility is also diminished. However, in the mimetics of nonpeptide nature it is often not possible to relate the restriction in conformational freedom to particular torsion angles of the backbone in the parent peptide.

3

Conformationally restricted amino acids and dipeptides

Restriction of the +i torsion angle

Nature has provided its own conformationally restricted amino acid uiz. proline (Figure 3). In proline the $I torsion angle is restricted in its rotation because this dihedral angle is part of a five-membered ring. As a consequence, the range of 4 angles is restricted to - 65 & 15" 22 and no regular helix in the a-helix region (4 -60") is possible because of steric hindrance 1 2 . In addition, a tertiary amide formed upon attachment of an amino acid to the proline amino functionality may undergo cis-trans isomerization ' I . It is not surprising that many efforts

Fig. 3. Proline (Pro), homoproline (pipecolic acid, Pip) and DTC.

\+ / S' S

have been directed and are still directed towards the expansion of possibilities to constrain the 4 torsion angle by preparing (1) proline derivatives containing fewer or more ring carbon atoms leading to aziridine (Azy), azeti- dine ( h e ) or homoproline (pipecolic acid, Pip, Figure 3) derivatives 22; ( 2 ) proline derivatives containing a hetero atom (Azaproline, AzaPro 23); (3) proline derivatives bearing substituents on the proline ring, which impose an additional conformational constraint (3-, 4- and 5-sub- stituted prolines 24,25926). Often the latter two approaches are combined and a well known example is a proline analog derived from penicillamine uiz. 5,5-dimethylthia- zolidine-4-carboxylic acid (DTC, Figure 3) 27.

Restriction of the t,!Ji torsion angle

Freidinger et al. 28 have prepared peptides containing a lactam as a conformational constraint. As a consequence, the torsion angle was restricted in its rotation and the poor conformational freedom of the w i torsion angle of the amide bond was further reduced. The preparation of the y-lactam featured the cyclization of a sulfonium salt (Scheme 1). This conformationally restricted dipeptide was used in the synthesis of a luteinizing hormone-releasing hormone analog in order to freeze the presumed bioactive conformation having a p-turn. Using the dis- placement of dimethyl sulfide from a sulfonium salt, Ede et al. 29 prepared a lactam-bridged dipeptide, which was incorporated into a peptide (Scheme l), which is analogous to the N terminus of the human growth hormone. The lactam is isomeric with the lactam prepared by Frei- dinger et al. (uide supra) and comprises in fact a p-amino acid.

0

Scheme I . Synthesis of a luteinizing hormone-releasing hormone analog containing a y -1actam and the isomeric lactam incorporated into a human growth hormone sequence.

H,/Pd/CI MeOH, H,O, HOAc,

c

H+H 0

Bocy H

H O

fLJOH

Scheme 2. Preparation of 6- and c-lactams and PLG structures containing y - and S-lactarns to mimic the turn in native PLG.

4 R.M.J. Liskamp / Conformariotially restricled amino acids and dipeprides

Starting from an ornithine or lysine derivative, 6- and E-lactams were accessible by cyclization (Scheme 2) 2xh. Alternative syntheses for the y-, 6- and E-lactams were developed 3",3' for the preparation of conformationally restricted inhibitors of angiotensin-converting enzyme (ACE inhibitors). Based on the methodology of Freidinger et al. 28b, peptidomimetics were prepared in which the y- and &lactam p-turn mimetics (Scheme 2) were introduced into the PLG (Pro-Leu-Gly-NH,) structure 32. Re- cently 33, the p- and E-lactams were added to this series. PLG is an endogenous tripeptide, which has a direct modulatory effect on dopamine receptors in the central nervous system. NMR and X-ray indicate that this tripeptide can adopt a type-I1 p-turn. The method of Freidinger et al. 2Xb turned out to be unsuccessful for the synthesis of a lactam necessary for the preparation of a conformationally restricted cy- closporine analog. Fortunately, the cyclization using a dipeptide containing a tosylated hydroxy amino acid gave the desired product (Scheme 3) 34. Finally Wb, a sulfur- containing 6-lactam was prepared from Pht-Cys(Acm1-OH as is shown in Scheme 4. 7- And 6-lactam-containing conformationally restricted dipeptide analogs were synthesized (Scheme 5 ) of the dipeptide sequence of Phe-His to obtain compounds that have a stabilized Phe-His bond with respect to proteolytic cleavage by chymotrypsin) 35. Molecular modeling suggested that the Phe-His conformation was important for the maintenance of good binding potency. In the examples of Freidinger et al. 28b the side-chain of the amino acid was used to the prepare the lactam-containing pep-

Scheme 3.

tide (uide supra), whereas, in order to maintain the in- tegrity of the side-chain on the a-position Zydowsky et al. 35 introduced a second a-substituent, which was used for the preparation of the y- and 6-lactam (Scheme 5 ) containing dipeptide isostere. It was also possible to employ the amino-acid side-chain itself in the preparation of a y-lactam in such a way that the side chain functionality or characteristics are main- tained to a certain degree. This is apparent from examples of Garuey et al. 36, who prepared y-lactam constrained peptides still containing the side-chain carboxylic acid moiety of the aspartic acid derivative used for its synthesis (Scheme 6) as well as in examples of Wolf and Rupoport 37, who prepared conformationally constrained y-lactam-containing dipeptide analogs of Val-Ala, Ile-Ala and p-MeLeu-Ala (Figure 4). In addition, Flynn et al. 3X

synthesized Phe-Gly dipeptide mimetics in which the phenyl substituent is present as part of the lactsm ring constraining this dipeptide, using an elegant intramolecular acyliminium cyclization (Scheme 7).

0 s o H C I ' H 2 N J ~ ~ e DMF, Et3N,

d N $ H NAOMe TsOH, (CH20)n + d N q N J o M e DCC, HOB1 CHC12CH2CI ' 0

0 0 0

Scheme 4.

1. 9-BBN, THF HC1.H-His-OMe,

a. KHMDS, (CHzO), C b z N p o -70", THF

cbz'flOH TsOH, - b. ally1 bromide Ph NaCNBH3, MeOH

Ph 0 Ph PhMe

H

H N

CPrNH,, MeOH, AT * Cbz$N$ie

Ph Ph

N V OMe NH

Scheme 5.

NMe,

Y O a. t-BuO--( NMe, t BOCNJ y o -SiMe, H-Phe-OMe, ~ Boc:JNCOMe

BocN ,,ko-SiMe, : o cyclohexane, b. 5 N HCI, MeOH, 40" Oo f i O B n

NaCNBH,, rt - 4 0 " EtOH, Bnoc 0

Y O B n 0 OH 0

Scheme 6.

Recucil cles Traoalw Chimicpes des Pays-Bas, 113 / 01, January 1994 5

Fig. 4. Conformarionally constrained y-laclam-containing dipeptide anulogs of Val-Ah, Ile-Ah and p-Meleu-Ala

PhtN eH 0

1. CIZCHOCH,, 60"

Na2C03, H@,

- 2. H-Gly-OH,

acetone

Scllellle 7.

J$-- -o 0 MeS0,H or

TFMSA or TMSTf

c

0

Fig. 5. General stntcfures har;ing constrained w , and 4, + , angles; the two right-hand structures are present in cylotoxic peptides

yy N, p PhsP, DEAD

H X BOC!

R H X A

HO R

X = 0, S; R = H. Me

Scheme 8.

Restriction of the wi and &;+, torsion angles

Systems in which w i and 4,+, , torsion angles are constrained can be represented by the general structures 39 depicted in Figure 5. This type of peptide mimetics in which X = S or 0 is present in naturally cyclic peptides such as the cytotoxic peptides ascidiacyclamide and ulithi- acyclamide 40-4'. Depending on the five-membered ring system, some remnant of a side-chain may be present in amino acid i + 1 . In the synthesis of oxazoline- and thiazoline-containing peptide mimetics employing the Mitsunobu reaction 42, it was possible to obtain a few constrained dipeptide mimetics (Scheme 8), in which a side-chain in amino acid i + 1 can be distinguished. Using a 1,3-dipolar cycloaddition a

2-isoxazoline-containing peptide mimetic was obtained 43.

The possibilities for having a side-chain in amino acid i + 1 are much more limited in this case (Scheme 9). Thiazole-, imidazole- and oxazole-containing dipeptide mimetics were prepared by coupling of Boc- or Z-amino acids and a-amino- P-keto esters followed by cyclization to introduce the azole moiety (Scheme 10) 44. Imidazoline and oxazoline peptide mimetics were earlier prepared by Jones and Ward 45 employing the imidate salt of an amino acid derivative (Scheme 11).

Restriction of the 4i, +i and wi torsion angles

In restricticting +,, 4, and w, torsion angles, approaches for the restriction of the 4, and $, angles (uide supra) were in fact combined. Thus, starting from a (homo)proline derivative, in which the 4, angle is constrained, an additional side-chain was introduced, leading to an &,a- disubstituted amino acid. This side-chain was transformed in such a way that a y-lactam could be formed via a Mitsunobu reaction, leading to spirolactam system (Scheme 12) 46*47. This method is similar to the method of Zydowski et al. 35 (uide supra, Scheme 9, although the lactam ring was formed by a different reaction sequence (Scheme 12).

Boc 0

H 0

Boc N

Scheme 9.

6 R.M.J. Liskamp / Conformarionally restricted amino acids and dipeplides

R2NH2, HOAc, xylenes, AT

R / R

&'*OMe CC14, PPh3, pyr, DBU MeCN 9 P y \ N g O M e H

R i -BuOCOCI, NMM, THF - PN

O O R l R'

PN A 0 &OH + H c ' ' H 2 N d O M e 0 H

P = Cbz, BOC R = Ph. 3-indolyl R'= Me, i-Pr, Ph, cyclohexyl,

2-naphthy1, 3-pyridyl R2= H, Me

Scheme 10.

C b ~ A @ ~ h k R l

R 0 NR'

R'= Leu-OMe, Phe-Leu-OMe H,N R=H.Bn

R2= H, Phe 0

Scheme 11.

The (R)-spiro[4.4]lactam prepared in Scheme 12 was shown to be a good mimic of the type-I1 p-turn 4m. According to calculations 48, the 4; and +hi angles are constrained to values of - 75 f 20" and + 140 f lo", respectively. It was suggested that the corresponding (S)- spiro[4.4]lactam in which the c$~ and +hi angles are constrained to values of +75 f 20" and - 140 & lo", respectively, would be a good mimic of the type-11' p-turn conformation. Therefore these spirolactams were incorporated into a substance-P-related sequence 48 culminating in a competitive antagonist, GR71251 (Figure 6), with high affinity and selectivity for NK-1 receptors. The ( R ) - and (S)spiro[5.4]lactams were also designed and synthesized as /?-turn mimetics by Genin et al. 47a. In-

H h N 2 O M e

R'

deed, X-ray crystallography revealed that the ( R ) - and the (S)-spiro[5.4]lactam systems are capable of constraining the peptides into a type-I1 and type-11' p-turn, respectively (Figure 7). In a recent approach by Smith and Hirschmann et al. 49,

the carbonyl of the amide bond was replaced by a normal carbonyl and the amino functionality was made part of a pyrrolinone ring. In this way, the dihedral angles +hi and wi in the parent peptide were fixed; the presence of an cup-disubstituted carbon atom constrained rotation corresponding to 4; in the parent peptide (Scheme 13). X-ray analysis showed that in the unit cell the pyrrolinone-based peptidomimetic adopts an antiparallel p-pleated-sheet or- ganization in the crystal, demonstrating that the pyrrolinone N-H's serve as interstrand hydrogen bond donors.

H-Arg-Pro-Lys-Pro-GIn-Gln-N H O / n \ w

GR7125 1

Fig. 6

(-$$JoMe Ph3Ph, DEAD WNJ - incorporation into peptide

I I Wi OMe Boc 0 Boc 0

Scheme 12

Recueil des Trauuux Chimiques 1Ie.s Pays-Bus, I13/01, Junuary 1994 7

Fig. 7. Fig. 8

Restriction of the

In the examples discussed above torsion angles within one amino acid were constrained. At the most the adjacent amide bond was also restricted in its rotation. In this section, restriction of rotation of three adjoining torsion- angles comprising two amino acid residues is discussed, namely restriction of the $;, w, and + i + , torsion angles. One of the earliest peptide mimetics having these constraints was described by Kemp et al. ''. NMR showed that the peptide mimetic can adopt a P-turn-like shape '(Ib (Figure 8). Continuing along these lines, a @-turn mimetic was prepared in three steps starting from Cbz-Gln-D-Glu-OH '' (Scheme 14). In this peptide mimetic the torsion angles are part of a much larger bislactam ring than the &lactam mimetic of Figure 8.

w i and 4;+, torsion angles Other examples in which conformational restriction was or can be achieved by connecting the side-chains of adjacent amino acids include the formation of a lactam ring in Glu-Lys or Lys-Glu '2 or the connection of the aromatic residues in two modified adjacent tyrosin residues as is present in an antitumor peptide '3 (Figure 9). Although to our knowledge, they have not been used for the preparation of conformationally restricted peptides, pyrazolo[l,2-a]pyrazolones and pyrazolo[l,2-a]pyrazinones (Figure 10) can be considered as dipeptides in which the $,, w , and 4,+, torsion angles are constrained by the bicyclic system. As such these systems may offer interesting possibilities for the preparation of conformationally restricted peptides 54, especially as structural analogs have been used with success in the design and synthesis of ACE inhibitors (uide mfra, Figure 16).

I 0

U 0 0 \ ;- I

repetition of the previous steps

Scheme 13.

H 01

Scheine 14.

8 R.M.J. Liskamp / Conformationally restricted amino acids and dipeptides

H OMe

Fig. 9.

Nagai and Sato " have synthesized a type-11' p-turn mimetic starting from glutamic acid and cysteine (Scheme 15). This p-turn mimetic (+hi+, = - 161", 4i+2 = -69") was incorporated into gramicidin S in place of the D-Phe- Pro sequences, which form the p-turns. The thus obtained analog showed an equal antibacterial activity to gramicidin S and a closely related CD spectrum 56. This was confirmed by NMR conformational analysis " which showed that the peptide portion of this analog assumes a solution structure which is equivalent to that of native gramicidin S. The analog was also incorporated in the N-terminal 29-residue fragment of human-growth- hormone-releasing factor (hGRF) at positions 7-8, 8-9, 9-10, because secondary structure predictions by the Chou and Fasman procedure suggested that the hGRF might assume a p-turn in the region of positions 6-11. Although the three derivatives containing the p-turn mimetic

O Y S P h

R = C(O)Me, C(0)OMe

Fig. 10.

showed the same maximal growth-hormone secretion, their relative potencies were more than 106 times lower ' 8 than hGRF. Based on the studies of Nagai et al. 55, Baldwin et al. '' envisaged that the bicyclic lactam shown in Scheme 16 had a good potential for serving as a p-turn-inducing peptide mimetic. A synthesis was designed featuring an acid-catalyzed bicyclization which provided access to four diastereomeric bicyclic lactams (Scheme 16). A bicyclization approach had also been used by Gonza'fez-Muiiiz et al. 6o to obtain closely related systems (Scheme 17). In the design of ACE inhibitors, the approach of Ffyn et al. 6' was to mimic closely the three carboxy-terminus amino acids of the natural substrate, angiotensin I (Phe- His-Leu, Figure 11). A conformationally restricted mimic of this tripeptide (Figure 11) was therefore designed in which the 4,+, torsion angle is restrained, being part of a homoproline ring. The +hi as well as the w , torsion angle are constrained because this homoproline ring is con- nected to the side-chain of amino acid i uiz. the aromatic

OH -

HC1.H-CyS-OH NaOAc, HzO, EtOH, 4 OMe 0

OMe A T PhtN

1. Raney-Ni, EtOH, AT - C O M e 2. PCC PhtN

1. PhSH, DCHA 2. CHzN2 PhtN

0 0 PhtN

0

PhtN OH

Scheme I S .

0 H H # c q H H

TFA (cat), CbzN .(I CHzCIz, AT Cbzv

0 H OBn CbzN

osO4, Na104-

0 0 OBn 0 OBn

CbzN CbzN U OBn

Scheme 16.

H I

CbzN CbzN COOMe

BocN Lc, ""C>e 'c BoLcooMe PdIC'Hz_ ;;:Me,- 6 ; O O M e

H 0 COOMe H. N Boc H. NBoc H O

R = Bn, CH,ln. CHzCOOEt Scheme 17.

Reciteil cles T~OGOLLV Chimiques cles Pays-Bas, I13 / 01, January 1994 9

Fig. 11. Chz-Phe-His-Leu and its conformarionally restricted mimetic.

ring of phenylalanine (Figure 11) using an acyliminium-ion cyclization (Scheme 18). The thus designed and synthesized mimic was a very potent in-uitro ACE inhibitor. Similarily, the corresponding hetero-atom-containing homoproline derivatives were synthesized by an efficient synthesis in which the key s tep was also an intramolecular acyliminium ion cyclization 62 (Scheme 19). T h e derivative thus obtained was also a potent A C E inhibitor similar to the carbocyclic derivative synthesized in Scheme 18 (uide supra 1.

Restriction of the 41, $,, w , and 4, + , torsion angles

T h e approach of Nagai et al. 5s (Scheme 15) and an approach to prepare a spirolactam 47 (Scheme 12) were elegantly combined by Genin and Johnson 63 in the preparation of a highly constrained type-I1 @urn mimetic, in which the $,, $,, w , and c$,+~ torsion angles were restricted in their rotation (Figure 12). Temperature-de- pendent N M R measurements in CDCl, suggested that the amide proton was involved in an intramolecular hydrogen bond. For the global minimum obtained from

Fig. 12.

R = Me, CBu

modeling studies, the calculated $[, $,, 41+1 and torsion angles were approximately - 40", + log , + 78" and - 17", respectively, which was in good agreement with those of the type-I1 p- turn (Table I). Superimposition of this cqnformer on the type-I1 p-turn gave an RMS of 0.161 A. An alternative, relatively straightforward method to restrict the required torsion angles was achieved by bridging the nitrogens in a dipeptide (Figure 12) 64. Until this point it has been possible to indicate which torsion angles in the mimicked peptide were restricted in their rotation. In addition, it was still possible to distin- guish a peptide-like structure in the peptide mimetic. In many of the following examples of peptide mimetics and secondary structure mimetics it will be much harder to indicate exactly which torsion angles have been constrained and to what extent. Mdreover, in many examples it will be difficult to identify amino acid or peptide parts at all. If one defines a peptide mimetic as a compound which imitates the structure and/or action of a peptide, it is understandable that the class of peptide mimetics will

EEDQ PhtN 2. 1. TFA, a. b. 03, MeSMe. CH2CI2, MeOH pyr A T ~ PhtN f$ 2. 1 . r Y A h2 "2 ~ PhtN 8 0 2 C H p h 2 H N m

COOMe 0 0 CI 0 0

Sclieme IS.

1. a. 03, MeOH -- Lu2Me =l,X Co2Me b. MeSMe, pyr 1 ,=lbx 1.TFMSA

0 0-

x = 0,s

Scheme 19

10 R, M.J. Liskanlp / Conformationally restricted amino acids and dipeptides

CN

N? 0 U . .

2. 1 . 0 3 Emmons -$ 2. 1. RhIAI2OJH2 Pd/C/H2 -$ CN

NH2 Scheme 20.

span the whole range of compounds varying from modified peptides and peptide isosteres 65 to compounds with- out an identifiable amino acid or peptide moiety. The latter compounds are often referred to as nonpeptide mimetics or nonpeptidomirnetics. Although the peptide backbone can no longer be identified in nonpeptidomimetics, the side-chains from the parent peptide are still present.

(Nod peptide mimetics and secondary structure mimetics

Nonpeptidomimetics of the p-turn

Kahn was one of the pioneers in the development of nonpeptide mimetics of reverse turns. In an elegant synthesis a nonpeptide mimetic of the immunosuppressant tripeptide Lys-Pro-Arg was designed and synthesized (Scheme 20) 66. This tripeptide is part of the tetrapeptide tufsin (Thr-Lys-Pro-Arg) and there is evidence that tufsin

OH

Fig. 13.

OH

exists as a turn or a hairpin. The same sequence of reactions could be applied to the synthesis of a nonpeptide mimic of a conserved region (Asp-Phe-Arg-Gly) of erabutoxin, which is contained within a p-turn region 67. Jaspamide is a cyclodepsipeptide (Figure 131, that has been reported to exhibit both insecticidal and antifungal activity. Three nonpeptide mimetics (Figure 14) containing a nine-membered ring were designed and synthesized. The mimetics were investigated using molecular modeling in combination with spectroscopic and crystallographic methods. The data indicated that the position of the functional groups corresponds closely to that observed in jaspamide and that the flexibility of the nine-membered saturated lactam mimetic as well as the biological profile approached that of jaspamide 68*69. These nine-membered ring peptide mimetics can be considered as dipeptide mimetics of the p-turn (Figure 15). A system similar to the jaspamide lactam mimetics (Figure 14) was prepared (Scheme 21). In this mimetic the amide linkage was trans, as shown by NMR and X-ray and the groups at positions adjacent to the lactam amide bond occupy positions closely related to the side-chain positions of residues i + 1 and i + 2 in type-I1 p-turn '". A tetrapeptide mimetic was also designed and synthesized. The low-energy conformers of this mimetic closely match those of model tetrapeptide p-turns of types I and 11'. Although the bicyclic peptide mimetic of which the synthesis is depicted in Scheme 22 was designated as a nonpeptide mimetic of a type-I p-turn, ( p ) amino acid moieties can be distinguished in its structure. However, as is apparent from the synthesis, the molecule was composed of strictly non-amino acid starting materials 7'. Em- ploying a similar intramolecular reaction a nonpeptide p-turn of enkephalin (Scheme 22) was recently synthesized 72. Interestingly, similar bicyclic systems have been used with success in the design and synthesis of ACE inhibitors 73,74 (Figure 16).

OH OH

Fig. 14. Br Br Br

Recueil des Trauauw Chitniques des Pays-Bas, 113 /01, January 1994 11

Fig. 15. Reuerse turn, general structure of a tetrapeptide mimetic, a dipeptide mimetic and a synthesized tetrapeptide mimetic (lower-middle). *p...,/ LDA NH,OH.HCI, NaOAc, MeOH ' . I

'0

1. TsCl

Scheme 21.

\ Ph 1. CISOzNCO EtO& 71Ph 18-Crown-6 Bn

2. KOH, BnBr Et02C-

Meo2C) H-N

0 0

NZH4

HNBn 0

HN

0 Bn 0

HN

0 OH

Scheme 22. Synthesis of nonpeptide mimetic of the p-turn; a nonpeptide p-turn of enkephalin (lower right)


An important application was the design and synthesis of a mimetic 75 from an antibody complementary-determining region (CDR). Antibodies use the CDRs of their hypervariable domains to bind antigens with high affinity and specificity. Synthetic peptides derived from these CDR sequences have properties similar to the intact antibody. However, these peptides are unsuitable for use as possible drugs because they will be readily degraded, they are too water-soluble to pass the blood-brain barrier and can adopt many conformations. Therefore a nonpeptide mimetic was designed and synthesized (Scheme 23) comprising the supposedly relevant contact residues from

HZN 0

Fig. 16.

the second CDR of monoclonal antibody (MAb) 87.92.6. The compound structurally mimicked the 87.92.6 second CDR and was functionally analogous to this MAb 75. The

TBDMS I

TBDMSO N

CbzN- N

UNkO I "-OBn H

OH

PdCIH, t

TBDMS TBDMSO NH I 0 '7 Fan \,#,...< 1 ... 1 1 1

1 .b BuOCOCI, NMM, Cbz-Tyr-OH

2. PdCIH2

H

Scheme 23.

Fig. 17.

Reciieil rles Travriiu- Chirniques d e . ~ Pays-Bas, 113 /01, January 1994 13

H

Scheme 24.

synthesis featured coupling of a hydrazine amino acid using a N-carboxyanhydride derivative (NCA), a method which is becoming increasingly popular in peptide chemistry 7 6 , as well as ring opening of a p-lactam to form the ten-membered ring, which mimics the pseudocyclic ten- membered ring of the turn (Scheme 23). Using a similar synthetic strategy, which is readily amenable to solid phase peptide synthesis (SPPS), conformationally constrained nonpeptide @urn mimetics of enkephalin were synthesized 7’. In order to approach the design of a protein p-turn in a more systematic way Ripka et al. 7x transformed the pseudocyclic ten-membered ring system of the p-turn via a ten-membered ring system in which the amide bonds were replaced by double bonds, to a bicyclic ten-atom system (Figure 17). Because of anticipated synthetic and stability problems, this bicyclic system was further transformed to a bicyclic system reminiscent of the benzodiazopines. The thus designed benzodiazopine (Figure 17) showed a re- markable f i t with p-turns present in the X-ray structures of several proteins available from the Brookhaven Protein Data Bank. The benzodiazepine in which R’=R4=H,

R2=Ph and R3=Bn was synthesized and incorporated into a cyclic octapeptide similar to the naturally occurring cyclic decapeptide antibiotic gramicidin S in place of the four amino acid residues that make up one of the p-turns (Figure 17). The double p-turn conformation in the re- sulting “octapeptide” was retained, showing that the benzodiazepine is an effective p-turn mimetic. Using computer-assisted molecular modeling we have designed nonpeptide reverse-turn type-I and type-XI mimetics based on minimized structures of the reverse turns. The mimetics comprise amino acid i + 1 and i + 2 of the turn (Scheme 24). A [2,3]-Wittig rearrangement 79 is being used to approach these mimetics synthetically (Scheme 25) ‘O.

Nonpeptidomimetics of the y-turn

Whereas the p-turn comprises four amino acids, the y- turn only contains three amino acids (Figure 18). The y-turn forms a pseudocyclic seven-membered system held together by a hydrogen bond. Huffman et al. ’’ have designed and synthesized nonpeptide mimetics in which

0

[2,3]-Wittig

Scheme 25.

14 R.M.J. Liskamp / Conformationally restricted amino acids and dipeptides

Fig. 18. y -Turn and nonpeptide mimetics of the y -turn comprising the Arg-Gly-Asp fRGD) sequence.

OMe OMe

I - NaCNBH, --.-___,. imidazole

OTBDPS OH

Scheme 26.

the intramolecular hydrogen bond was fixed by replacing the carbonyl-oxygen and the hydrogen by an ethylene unit (Scheme 26). These nonpeptide mimetics were used to prepare enkephalin analogs. The obtained mimetics were devoid of any affinity for an opiate receptor. In contrast, mimetics containing a p-turn exhibited significant in uiuo analgesic activity 72 (Scheme 22, vide supra). The same y-turn mimetic could be employed for the design and synthesis of peptide mimetics, mimicking the C-terminal region of an RGD (Arg-Gly-Asp) antagonist, leading to a potent inhibitor of in uitro platelet aggregation (Figure 18) 82. Starting from (S)-4-hydroxyproline Kemp et al. 83 have prepared a y-turn template (Scheme 27).

Mimetics of the a-helix

Although the a-helix is a common secondary structure element, only a few mimetics are known to date. A classical a-helix has C$ and 4 angles of -57" and -47", respectively (Table I). The pyrrolidine ring of a proline residue constrains the C$ angle to approximately -60". Therefore, if there is a way to constrain the + torsion angle to the desired value of an a-helix, an a-helix template could be obtained. By introducing a two-atom bridge between position 4 of proline-1 and position 5 of proline-2 Kemp et al. 84 obtained a potential helical template (Scheme 28). The proposed template provided three amide carbonyls that can assume helical pitch and spacing. In the crystal and in CDCI, solution this template - as the free acid - was shown to exist as the cs conformation (Figure 19), in which the acetamido function had the cis conformation. If a peptide sequence is attached to the template, the template conformation cannot accomodate an intramolecular

H-T yr-G I y-G I y- N. H

hydrogen bond to the acetamido carbonyl and therefore the conjugate is expected to be nonhelical. In solution in other solvents the acid exists as a mixture of cis (cs) and trans (ts) isomers. Molecular mechanics calculations also suggested that the te conformation, in which the thiomethylene group has also reoriented, was only slightly less stable than the ts conformation. These calculations also showed that conformation te had three properly oriented hydrogen bonding sites and should be capable of efficient nucleation of helices in conjugate consisting of this template and a peptide sequence. Indeed, NMR showed that peptide conjugates of the helical template can assume helical conformations in CDCI,, CD3CN, DMF-d, and, for short helices, in DMSO-d, " (Figure 19). Using this template it was also possible to study the helical s constant of alanine, which together with helix initiation parameter n is a measure of the degree to which amino acids favor the helical state 86.

Recently two new templates were introduced (Figure 201, which could serve as template for N-terminal helix induction. The cage compound, when conjugated to an Ala- and Aib-containing nonapeptide, increased the helic- ity significantly, as monitored by CD, as compared to the

CN

cbz 0 0 A0 I

Bn

Scheme 27

Recueil ilcs Truouiuc Cliirniques des Pays-Bus, 113/0l, Junuuty 1994 15

peptide peptide peptide 0 &NQNAo L N 2 N k ry

’., s ’.. s 2/ 5/ ‘S

ts te Fig. 19. cs

peptide 0 7 II 0

peptide ‘r 0 ~a Fig. 20.

same peptide containing the Boc group instead of the cage compound. The second template was based o n Kemp’s triacid. In this template, two carbonyl oxygens as are present in the cage template, were replaced by one carboxylic acid moiety, which served as the hydrogen bond acceptor for two N-H groups. However, as was shown from X-ray, CD and NMR data the first amino acid attached to Kemp’s triacid had to be a D-Ala before attaching the remainder of the peptide chain. The crystal structure showed that the peptide conjugate is more related to a 3,,, helix, which is narrower than an a-helix having three amino acids per turn instead of 3.6. Never- theless, the basic concept is valid and may be applied to the design of other helix-inducing templates.

p-sheet mimetics

As outlined above, turns are very important e.g. in the conformation of hormones at their receptor- and antigen- antibody interactions. However sheets and helices domi- nate the architecture of proteins. In parallel and antiparallel p-sheets the polypeptide backbones assume a nearly extended conformation with alternating orientations of the amide functions. The adjacent peptide strands are linked by hydrogen bonds, that lie parallel to and near the plane bisecting the sheet structure The C,-C, bonds are nearly perpendicular to - alternating above and below -

Fig. 21.

the bisecting plane (uide supra, Figure 1). By restraining the 4, and w , torsion angles Smith and Hirschmann et al. “Sbtained molecules which could adopt an antiparallel P-pleated sheet (Scheme 13). In a more nonpeptide approach an epindolinone structure (Figure 21) was synthesized as a P-sheet template 8sc.88. This molecule contained a sequence-reversing element so that an antiparallel structure could be formed. The dipeptide sequence L-Pro-D-Ala, which was expected to form a p-turn, was first symmetrically attached to the epindolidione nucleus, followed by attachement of two additional amino acids (Figure 21). About a third of the two dozen of synthesized conjugates has been shown to assume antiparallel p-sheet conformations in solution 85c.

By using a turn inducer (uide infra) i.e. a dibenzofuran amino acid 89, an antiparallel p-sheet could be nucleated (Scheme 29). The water-soluble p-sheet was partially characterized by CD and NMR

TsQ NdNH, -78” H9, 1. MeOH, HCI

%OH 3. TsCI, pyr DCC Ac 0

S O M e 1, MeOH, NaOH ~

2.NaSBn 2. A c ~ O , NaHC03

Ac 0 Ac 0 H O

1. H,JPd/C, 40” 3 bar 1 .LiBH4

0 Boc

2. ( B O C ) ~ ~

Eto’f‘’&oEt 3. MeOH, NaOH 0 Bn 0 0 Boc 0

Scheme 28

16 R.M.J. Liskunzp / Conformutionully restricted unlino ucids and dipeptide.c

0

NBoc H

--

R = (CHz),NHz (side chain Lys) Schenie 29.

Turn inducers

In the nonpeptide mimetics discussed above it was still possible to identify some structural similarities with the original p- turn, sometimes these similarities could only be distinguished with difficulty, but in general o n e tried to mimic the p- turn as much as possible in terms of a diminished flexibility, the presence of functional side- chains, etc. In this section, systems are discussed which a re indicated as "turn inducers". T h e sole aim of these often very rigid systems is the enforcement or introduc-

a

\

gH / 0

b

tion of a turn in a peptide chain, which can b e favorable for e.g. P-sheet formation and helix bundle aggregation. Other similarities with p-turns a re virtually absent and it would be inappropriate to classify these systems as nonpeptide mimetics of the p-turn. F'eigel ')I proposed the use of a spacer derived from phe- noxathiin S-dioxide (Figure 22a) to force hydrogen bridging between antiparallel and parallel peptidc strands. Related fuscd-ring systems (Figure 22b, c) have been derived from xanthene, phenoxazine and phenothiazine and have been utilized by Muller et al. t o prepare R G D -

\

P O H

R-N.

&NHZ 0

/

x = 0,s C

f 9 h

Fig. 22.

HzN d O H

d

"OZC%

i

0

e

0 0

--- 0

0

&OH

0 0

R = (Leu-Ser-Leu-Aib-Leu-Ser-Leu)&(O)NH2

Fig. 23

Reciiccl de., Truuacu Chrmiques des Pays-Bas, 113 /01, Junuary 1994

containing loop peptides. A dibenzofuran amino-acid- based turn inducer was recently used (vide supra) to nucleate and form antiparallel P-sheets. Even such simple systems as 3-aminobenzoic acid and 2-aminocyclopen- tanecarboxylic acid (Figure 22d, e) have been used to obtain conformationally constricted peptide analogs e.g. of cholecystokinin (CCK) y2. Three novel bicyclic turn inducers (Figure 22f-h) were designed and introduced by Mutter et al. y3. The naphthalene-based inducer was used successfully for the construction of a cyclic peptide template to obtain a four-helix bundle protein like TASP (template-assembled synthetic protein) y4. Recently ”, a tetraphenylporphyrin framework was also used for the building of a four-helix bundle, which was a model for a proton channel (Figure 23). Thcse examples also serve to illustrate that there are probably many molecules to be found in the literature, which have been synthesized for various other reasons, but which might be potentially interesting as (part of) nonpeptide mimetics. An example of such a compound, which could be a @-turn inducer was recently described by Beeson and Dir Yh (Figure 22i).

Conclusions

The last couple of years have seen a tremendous increase in the possibilities of limiting the conformational flexibility of a peptidc by introducing conformationally restricted amino acids or by introducing (non)peptidomimetics ”. Although some conformationally restricted amino acids and dipeptides or (non)peptido-mimetics are emerging as suitable mimetics, e.g. the spirolactams as a mimetic of the p-turn, i t seems that there is n o general strategy as to which conformationally restricted molecule should be introduced in a particular case. The starting point will always be the structure of the peptide to be mimicked. However, there are already a considerable number of mimetics available which be can be evaluated first, using for example, computer-assisted molecular modeling, before moving to a tailor-made mimetic. Since in many cases the bio-active conformation of a peptide is unknown because of its inherent flexibility, the availability of a number of secondary structure mimetics of e.g. y,p-turn (type I, 1’, I1 and 11’) and incorporation into a peptide, will allow the “probing” of the bio-active conformation; e.g. a highly biologically active compound containing a @-turn type 11’ mimetic is certainly indicative of the presence of a p-turn in the parent peptide. In the near future, the availability of secondary structure mimetics will undoubtedly allow the study of the role of individual secondary structure elements such as are present in proteins. This will present new challenges in de nouo protein design in the construction of artificial miniproteins, (partly) composed of secondary structure mimetics. As was shown above, a-helix mimetics can already be used to nucleate an a-helix and turn inducers can be employed to nucleate a p-sheet or to align a-helix bundles. Many mimetics have become accessible through clever amino acid chemistry in which advantage was taken of the inherent properties of an amino acid uiz. chirality and the presence of functional groups. Other areas of organic chemistry have contributed heavily too. However, the starting position was always the structure and the properties of a peptide. Therefore it is understandable that essential roles are also played by computer-assisted molecular modeling, structural analysis [both in solution (NMR) and in the solid-state (X-ray)], and also, especially in the case of biologically active peptides, by pharmacol-

17

ogy and medicinal chemistry. I t is therefore justified to state that this field can and will only continue to flourish through a good and fair interplay of these disciplines.

References and notes

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n

Y

I 0

I I

12

13

14

IS

I6

17

I n

19

20

21

22

R.A. Lerner, Nature 318, 480 (f985);’ D. Piconi, P.A. TemLsi M.M. Marastoni, R. Tomatis, A. Motta, FEBS Lett. 231, 159 (1988). J.M. Rini, U. Schulze-Gahmen, I.A. Wilson, Science, 255, 959 (1 992). R.H. Meloen, R.M. Liskamp, J. Goudsmit, J. Gen. Virol. 70, 1505 (1 990). M. Mutter, Angew. Chem. 87, 639 (1985). The trans-amide bond is generally found in peptides. However cis bonds are found in a number of small peptides and in peptides containing amide bonds involving proline 12. The cis content of Xxx-Pro-containing peptides generally increases when Xxx is a bulky, hydrophobic amino acid e.g. Leu-Pro us. Ala-Pro 13.

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47 a. M.J. Genin, W.B. Cleason, R.L. Johnson, J. Org. Chem. 58, 860 (1993); b. M.J. Genin, W. H. Ojala, W.B. Gleason, R.L. Johnson, J. Org. Chem. 58, 2334 (1993).

48 P. Ward, G.B. Ewan, C.C. Jordan, S.J. Ireland, R.M. Hagan, J.R. Brown, J. Med. Chem. 33, 1848 (1990).

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52 N. Manesis, M. Hassan, R. Glaser, M. Goodman, Biopolymers 25, S97 (1986); R. Rone, N. Manesis, M. Hassan, M. Goodman, A.T. Hagler, D.H. Kitson, V.A. Roberts, Tetrahedron 44, 895 (1988).

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55 U. Nagai, K. Sato, Tetrahedron Lett. 26, 647 (1985); U. Nagai, K. Sato, R. Nakamura, R. Kato, Tetrahedron 49, 3577 (1993).

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" J.E. Baldwin, C. Hulme, C.J. Schofield, A.J. Edwards, J . Chem. SOC., Chem. Comm. 935 (1993). "' R. Gonzklez-Mu&, M.J. Dominguez, M. T. Garcia-Lbpez, Tetrahe- dron 48, 5191 (1992). G.A. Flynn, E.L. Giroux, R.C. Dage, J. Am. Chem. SOC. 109, 7914 ( 1987).

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" Modified peptides are being defined as peptides in which in essence the amino acid sequence is unchanged but the peptide contains e.g. some unnatural amino acids, a modification of N-terminus by a lipophilic side chain (see e.g.: T. Eichholfz, H.B.A. de Bont, J. de Widt, R.M.J. Liskamp, H.L. Ploegh, J . Biol. Chem. 268, 1982 (1993)), a phosphate (see e.g.: H.B.A. de Bont, W.J. Moree, J.H. uan Boom, R.M.J. Liskamp, J . Org. Chem. 58, 1309 (1993)) or carbohydrate moiety. Peptide isosteres are being defined as peptides in which notably the amide bond is replaced by another (isosteric) functionality e.g. a double bond, leading to alkene dipeptide isosteres (see e.g.: K.M. Bol, R.M.J. Liskamp, Tetrahedron 48, 6425 (1992)), or by a (sulfonamide) transition- state isostere (see e.g.: W.J. Moree, L.C. //an Gent, G.A. oari der Murel, R.M.J. Liskamp, Tetrahedron 49, 1133 (1993)). As such the peptide isosteres represent a subclass of peptide mimetics, which is most closely related to the original peptide.

" M. Kahn, B. Deuens, Tetrahedron Lett. 27, 4841 (1986). '' M. Kahn, B. Chen, P. Zieske, Heterocycles 25, 29 (1987). " M. Kahn, T. Su, Proceedings of the Tenth American Peptide

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l4 P.J. Gilbert, W.A. Thomas, J . Chem. SOC. Perkin 11, 1077 (19x5): W.A. Thomas, I.W.A. Whitcombe, ibid., 747 (1986).

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lY Applied to the synthesis of alkene dipeptide isosteres: see refer-

'" R.M.J. Liskamp, K.M. Sliedregt-Bol, unpublished results. 'I

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ence in footnote 65.

W.F. Huffman, J.F. Callahan, D.S. Eggleston, K. A . Newlander, D. T. Takata, E.E. Codd, R.F. Walker, P. W. Schiller, C. Lemieux, W.S. Wire, T.F. Burks, Proceedings of the Tenth American Pep- tide Symposium, St. Louis, MO, 105 (1988).

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** D.S. KenIp, B.R. I3uwen, Tetrahedron Lett. 29, 5077; D.S. Kemp, B.R. Bowen, ibid. 5081; D.S. Kemp, B.R. Bowen, C.C. Muendel, J. Org. Chem. 55, 4650 (1990).

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conformationally restricted amino acids and dipeptides, (non)peptidomimetics and secondary structure...

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