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Cl HO O Fmoc N R O O Fmoc 25 N R Pyperidine, 20% in DMF HATU or PyBOP repeat Scheme 1.1. monomer synthesis of peptoids Peptoids can be constructed by coupling N-substituted glycines using standard α-peptide synthesis methods, but this requires the synthesis of individual monomers 4 , this is based by a two-step monomer addition cycle. First, a protected monomer unit is coupled to a terminus of the resin-bound growing chain, and then the protecting group is removed to regenerate the active terminus. Each side chain requires a separate N α -protected monomer. Peptoid oligomers can be thought of as condensation homopolymers of N-substituted glycine. There are several advantages to this method, but the extensive synthetic effort required to prepare a suitable set of chemically diverse monomers is a significant disadvantage of this approach. Additionally, the secondary N-terminal amine in peptoid oligomers is more sterically hindered than primary amine of an amino acid, for this reason coupling reactions are slower. Sub-monomeric method, instead, was developed by Zuckermann et al. (Scheme 1.2) 56 . Cl HO O Br O O Br DIC R-NH 2 repeat Scheme 1.2. Sub-monomeric synthesis of peptoids Sub-monomeric method consists in the construction of peptoid monomer from C- to N-terminus using N,N-diisopropylcarbodiimide (DIC)-mediated acylation with bromoacetic acid, followed by amination with a primary amine. This two-step sequence is repeated iteratively to obtain the desired oligomer. Thereafter, the oligomer is cleaved using trifluoroacetic acid (TFA) or by hexafluorisopropanol, scheme 1.2. Interestingly no protecting groups are necessary for this procedure. The availability of a wide variety of primary amines facilitates the preparation of chemically and structurally divergent peptoids. 1.6 Synthesis of PNA monomers and oligomers The first step for the synthesis of PNA, is the building of PNA‘s monomer. The monomeric unit is constituted by an N-(2-aminoethyl)glycine protected at the terminal amino group, which is essentially a pseudopeptide with a reduced amide bond. The monomeric unit can be synthesized following several methods and synthetic routes, but the key steps is the coupling of a modified nucleobase with the secondary amino group of the backbone by using standard peptide coupling reagents (N,N'dicyclohexylcarbodiimide, DCC, in the presence of 1-hydroxybenzotriazole, HOBt). Temporary masking the carboxylic group as alkyl or allyl ester is also necessary during the coupling reactions. The 56 R. N. Zuckermann, J. M. Kerr, B. H. Kent, and W. H. Moos, J. Am. Chem. Soc., 1992, 114, 10646. O O O O H N R H N R
protected monomer is then selectively deprotected at the carboxyl group to produce the monomer ready for oligomerization. The choice of the protecting groups on the amino group and on the nucleobases depends on the strategy used for the oligomers synthesis. The similarity of the PNA monomers with the amino acids allows the synthesis of the PNA oligomer with the same synthetic procedures commonly used for peptides, mainly based on solid phase methodologies. The most common strategies used in peptide synthesis involve the Boc and the Fmoc protecting groups. Some ―tactics‖, on the other hand, are necessary in order to circumvent particularly difficult steps during the synthesis (i.e. difficult sequences, side reactions, epimerization, etc.). In scheme 1.3, a general scheme for the synthesis of PNA oligomers on solid-phase is described. PGt N H B-PGs N O O NH PGt 2 N PGt N OH H First monomer loading O Repeat deprotection and coupling O N H B-PGs B-PGs B-PGs N First cleavage O O N H H NH 26 PGt N H B B-PGs N N H O O Coupling N PNA O O OH NH2 n H 2N PGs: Semi-permanent protecting group PGt: Temporary protecting group O O N N H Deprotection B-PGs Scheme 1.3. Typical scheme for solid phase PNA synthesis. The elongation takes place by deprotecting the N-terminus of the anchored monomer and by coupling the following N-protected monomer. Coupling reactions are carried out with HBTU or, better, its 7-aza analogue HATU 57 which gives rise to yields above 99%. Exocyclic amino groups present on cytosine, adenine and guanine may interfere with the synthesis and therefore need to be protected with semi-permanent groups orthogonal to the main N-terminal protecting group. In the Boc strategy the amino groups on nucleobases are protected as benzyloxycarbonyl derivatives (Cbz) and actually this protecting group combination is often referred to as the Boc/Cbz strategy. The Boc group is deprotected with trifluoroacetic acid (TFA) and the final cleavage of PNA from the resin, with simultaneous deprotection of exocyclic amino groups in the nucleobases, is carried out with HF or with a mixture of trifluoroacetic and trifluoromethanesulphonic acids (TFA/TFMSA). In the Fmoc strategy, the Fmoc protecting group is cleaved under mild basic conditions with piperidine, and is 57 Nielsen P. E., Egholm M., Berg R. H., Buchardt O., Anti-Cancer Drug Des. 1993, 8, 53. N O O N H
Page 1 and 2: UNIVERSITA' DEGLI STUDI DI SALERNO
Page 3 and 4: Cbz Benzyl chloroformate DCC N,N’
Page 5 and 6: number of possible conformations wh
Page 7 and 8: Backbone peptides modifications are
Page 9 and 10: While computational studies initial
Page 11 and 12: circular peptoids 20 , showing redu
Page 13 and 14: assays for its high affinity to the
Page 15 and 16: Each peptoid molecule was capped wi
Page 17 and 18: constraints induced by macrolactami
Page 19 and 20: The ability of cyclic peptoids to e
Page 21 and 22: 1. RNA targeting 2. DNA targeting 3
Page 23 and 24: iii) Improving bioavailability, (ce
Page 25: However, annealing experiments demo
Page 29 and 30: charges on the oligoamide backbone,
Page 31 and 32: MeO HO HO O O O O N HO N N O O O N
Page 33 and 34: HO N O O O N N N O O O O TrS N N 78
Page 35 and 36: The N-(carboxymethyl) and the N-(ca
Page 37 and 38: NH2 t-BuO + O O OH a R t-BuO N OH O
Page 39 and 40: deoxyribonucleic strands (5 μM con
Page 41 and 42: esulting residues were purified by
Page 43 and 44: AcOEt/petroleum ether) 0.38; H (300
Page 45 and 46: OOCCH2CH2), 2.82 (2H, t, J 6.0 Hz,
Page 47 and 48: CH2CHFmoc and CH2-thymine), 7.02 (1
Page 49 and 50: Chapter 3 3. Structural analysis of
Page 51 and 52: Figure 3.4. Cyclic octamer 103. Top
Page 53 and 54: Cl HO O Br O O 52 O Br NH 2 NH 2 HO
Page 55 and 56: Table 3.1. Results of crystallizati
Page 57 and 58: Trough these crystallizations, we h
Page 59 and 60: μ (cm -1 ) 0.638 0.663 0.692 2.105
Page 61 and 62: Monoclinic (56A) and Triclinic (56B
Page 63 and 64: 1 H-NMR studies confirmed the prese
Page 65 and 66: 3.4 Conclusions In this chapter, th
Page 67 and 68: Linear 104 (37 mg, 0.0611 mmol) was
Page 69 and 70: It was based on squares of structur
Page 71 and 72: Chapter 4 4. Cationic cyclopeptoids
Page 73 and 74: especially at the vector concentrat
Page 75 and 76: H 3N H 3N O H 3N N O N O N 74 N O 6
Page 77 and 78:
HO O 113 HO N O O 114 N N O N 6 NHB
Page 79 and 80:
esin was then filtered away and the
Page 81 and 82:
8H, -CH2NH3 + ), 1.75 -1.30 (m, 32
Page 83 and 84:
(III) complexes causes a dramatic e
Page 85 and 86:
Figure 5.2. Model of Gd(III)-based
Page 87 and 88:
5.3 Results and discussion 5.3.1 Sy
Page 89 and 90:
MeO t-BuO O O t-BuO N N O N O O O N
Page 91 and 92:
Table 5.1. Parameters determined by
Page 93 and 94:
oom temperature. Subsequent specifi
Page 95 and 96:
5.4.4 Synthesis of 133 by click che
Page 97 and 98:
Chapter 6 6. Cyclopeptoids as mimet
Page 99 and 100:
HO N O O N O STr STr N O NHBoc 68 N
Page 101 and 102:
Disulfide bonds play an important r
Page 103 and 104:
developed for the deprotection of t
Page 105 and 106:
Compound 137 Aminoethanethiol hydro
Page 107 and 108:
Compound 139: δH (400 MHz, CD3OD,
Page 109:
108
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