Turn mimetics

According to Venkatachalam, p-tums are classified into conformational types depending on the values of four backbone torsional angles (0, 4 4 2,4 2) (Table 2.2.1).  

Turn nomenclature according to Venkatalacham t ) Turn nomenclature according to Wilmot and Thornton  

To date, eight different types of P-tums have been classified and the torsional angles (OpYpt j.yj) of the most important naturally occurring P-tums are depicted in Table 2.2.1. 

Mimicking a p-tum consists in constraining correctly four torsional angles (4 ,4 2, P, P2) and four bonds (bonds a-d, cf. Fig. 2.3.3). Bonds a and d direct the entry and the exit of the peptide chain through the turn, respectively, whereas bonds b and c are responsible for the spatial dispositon of the amino acid side chains at position i+1 and i+2 of a turn. The torsional angles determine the backbone geometry of the turn and consequently the shape of the turn hydrogen 

Peptidic p-tum mimetics are generally based on cyclic backbone mimetics (e.g. replacing the turn hydrogen bond by a covalent bond) or by introducing one or several unusual amino acids, which constrain the backbone in P-tum conformations. Synthetic approaches to non-peptidic turn mimetics can be grouped into two classes 1) external P-turn mimetics, and 2) internal P-turn mimetics.  

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Bioactive Peptides Based on Open-Chain y -Turn Mimetics... 

In light of the importance of the / -turn motif in peptide and protein recognition, and the design and synthesis of bioactive small molecules, / -turn mimetics has attracted considerable attention. Seebach and coworkers have shown recently that low molecular weight open-chain / - and y-peptides designed to promote turn formation can be used as templates for mimicking the a-peptide hormone somatostatin. 

Finally, the chiral auxiliary was removed by a Birch reduction or a catalytic hydrogenation. After ring opening several optically active 6-aminohexanoic acids served as linkers in cyclic peptides as /1-turn mimetics (Table 12, Scheme 49) [51c],... 

Libraries of /3-turn mimetics have been prepared by solid-phase syntheses. The synthesis of the chiral saturated pyrazino[l,2- ]pyrazine 243 starts from Merrifield resin-bound a-iV-BOC-/3-./V-Fmoc-L-diaminopropionic acid as the central framework. The variable substituents are introduced during the synthesis (Scheme 43) <20000L2615>. The scope and limitations of the method are described <2002JC0584>. 

Chemical libraries of /3-turn mimetics, among them highly saturated pyrazino[l,2-tf]pyrazines, were synthesized and patented as biologically useful compounds <2001W02001/000210>. Solid-phase syntheses starting from substituted a,/3-unsaturated ester templates provided differently substituted saturated heterocyclic systems, among them saturated 2,4,8-trisubstituted-pyrazino[l,2- ]pyrazine-l,6-diones <2003W02003/013740>. 

Acylation of monoprotected azaproline 425 with protected asparagic acid 426 using 0-(7-azabenzotriazol-l-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATLJ), followed by deprotection and thermal cyclization of 427 yields 428, a compound used in construction of a class of /3-turn mimetics (Scheme 68) <1997TL4935>. 

Based on the CAAX motif, peptide analogues were designed in which peptide amide bonds are replaced by amine and ether groups [18]. In particular /I-turn mimetic 1 (Fig. 1) inhibits the FTase in vitro with an IC50 value of 1.8 nmol/1 and shows highly specific activity in comparison to inhibition of GGTase I. 

The less polar methyl ester 2 as prodrug showed better results in vivo and inhibits both farnesylation of the Ras protein and growth of Ras-transformed cells, whilst proliferation of Raf- or Mos-transformed cells was not influenced. Growth of human pancreatic adenocarcinoma cells with mutated K-Ras, c-Myc and p53 genes was inhibited by application of 2. If the compound is administered over a period of 5 days to mice with implanted Ras-dependent tumors, tumor growth can be reduced by up to 66% compared to untreated mice, whereas application of the antitumor antibiotic doxorubicin only resulted in 33% reduction under the same conditions. It is particularly noteworthy that treatment with the /1-turn mimetic - in contrast to treatment with doxorubicin - was without any visible side effects, such as weight loss. 

Ojima and coworkers have developed a similar approach to the synthesis of piperidine and related ring systems, which they describe as cyclohydrocarbonylation. In this approach, carbamate-protected allylglydnes (for example, 32) are subjected to rho-dium(I)-catalyzed hydroformylation in an alcohol solvent (Scheme 5.13) [17]. 6-Alkoxy-pipecolates 33 are isolated in good yield and were shown to be amenable to further stereoselective transformations. This methodology has recently been expanded to include fully intramolecular variants that can form two rings in a single reaction. Thus, alkenes 34 are subjected to the cyclohydrocarbonylation conditions to provide azabicy-clo[4.4.0]aUcane amino acids 35 which can serve as conformationaUy restricted dipeptide surrogates and /9-turn mimetics [18]. 

The important difference between linear and cyclic peptides is the reduced conformational flexibility imposed by the cyclization. 14,151 Cyclic peptides have, therefore, been under intense investigation with respect to their conformational preferences 30,31 and their different turn motifs, e.g. reverse turns. 32 35 To differentiate between the structural influences of the numerous sequence elements the following special concepts have been described 161 (1) Global constraints are structural characteristics that restrict the whole molecule, e.g. the macrocyclic structure of the peptide framework and (2) local constraints comprise a large number of structure-inducing building blocks, such as proline, D-amino acids, and turn mimetics. 

In principle every compound with an amino and a carboxy group can be used for such purpose ranging from simple co-amino acids [e.g., 5-aminopentanoic acid (6-aminovaleric acid) (1, n = 3)]1541 or 6-aminohexanoic acid (e-aminocaproic acid) (1, n = 4)]135,57,4 791 and related derivatives of 3-aminobenzoic acid 14801 or more sophisticated structures. A few examples (1-6) are shown in Scheme 28. Numerous cyclic turn mimetics have been developed in the past years and for details on this subject the reader is directed to Vol. E 22c, Section 12. To explore the rigidification introduced by nonnatural amino acids or equivalent structures into cyclic peptides, a careful NMR conformational analysis is required, since frequently the so-called p-turn mimetics do not enable such turns to be established, conversely other secondary structure elements may be induced.14811... 

The incorporation of these artificial structural elements as well as the subsequent cycliza-tions are generally performed according to standard procedures e.g. in the case of 5-aminopentanoic acid (1, n = 3) and 6-aminohexanoic add (1, n=4) the cyclization proceeds in good yields without particular difficulties. 35 Conversely, real turn mimetics may increase cyclization yields as a result of the anticipated rearrangement of the linear precursors. t28-87-481-482 in most cases, the nonnatural amino adds or equivalent building blocks are used in the synthetic steps in complete analogy to natural amino acids. 

Kahn, M.S., Eguchi, M., Kim, H.-O. (Molecumetics Ltd ) Reverse-turn mimetics and methods relating thereto, W09849168 (1998). 

A similar strategy was used to examine the potential role of a reverse turn as a recognition element adjacent to the cleavage site of substrates of HIV protease.197 A series of inhibitors was prepared, the synthesis of which involved the solution coupling of the statine-like transition state mimic to the (3-turn mimetic to provide 46 (Scheme 22). Subsequent sodium in ammonia reduction provided analogue 47. One of the compounds was a reasonably potent inhibitor of protease activity (IC50=2.6 x 10-8 M) (Table 1). 

Similarly, a turn mimetic analogue of Leu-enkephalin (Scheme 27) was prepared.1"11 The compound exhibited significant in vivo analgesia despite relatively low affinity in a binding assay. 

Baca et al. 112 made use of Nagai and Sato s176 type-II thiazolidine lactam (1-turn mimetic 18 (Scheme 11) to replace the type-I (1-tum between Gly16 and Gly17 in HIV-1 protease. The 1-turn-mimetic-containing enzyme dimerized similarly to the native enzyme. It was fully active, possessed the same substrate specificity as the native enzyme, and showed enhanced thermal stability. 

Utilizing the Grubbs alkene metathesis reaction, Katzenellenbogen et al. 164 described the synthesis of the ten-membered-ring lactam p-turn mimetic 129 (Scheme 47, some experimental details given below) and prepared a mimetic 130 of the neuropeptide substance P, and in particular of the four C-terminal amino acid sequence -Phe8-Gly-Leu-Metn-. Compound 130 was unable to inhibit the binding of radiolabeled substance P. 

The immunodominant portion of the malaria circumsporozoite surface protein contains a tetrapeptide motif (-Asn-Pro-Asn-Ala-), tandemly repeated almost 40 times. Bisang et aft165 incorporated the (I-turn mimetic 131 into the cyclic template 132 (Scheme 48). BALB/c mice... 

Azetidinone mimetic precursor 107 (13 mg, 0.014 mmol) was dissolved in freshly distilled CH2Q2 (2.5 mL) and cooled to —10 °C. Anhyd TFA (500 pL) was added and the reaction was stirred at —10 °C for 3 h. The volatiles were removed under reduced pressure, and the residue was dried under high vacuum for 30 min, and subsequently dissolved in CH2C12 (2.5 mL). The reaction was cooled to 0°C and TEA (200 pL) was added. The soln was stirred at 0°C for lh. Volatiles were removed under reduced pressure and the residue was dissolved in freshly distilled THF (2 mL). The soln was cooled to 0°C and TBAF (50 mg) was added. The reaction was stirred to rt over the course of 2h. The volatiles were removed under reduced pressure and the residue was chromatographed (MeOH/CH2Cl2 6 94) to give the 10-membered-ring 4—1 (1-turn mimetic 100 yield 8mg (94%) FAB-MS mlz 596. 

In the design of any type of turn mimetic systems, there are a number of concerns and criteria that need to be addressed. The interaction of the amino acid side chains with their complementary receptor groups is the critical determinant of biological specificity. A successful inducer or mimic must limit the possible conformational arrays and thereby correctly... 

Bean et al. 38 have also designed, synthesized, and investigated the conformations of two diazocine y-turn mimetics 12 and 13 (Scheme 8). 

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