C-terminal amide moiety

Like the C-terminal amide moiety, the presence of a sulfate group is required for sulfakinin myotropic activity. Nevertheless, as the active CCK analogs attest, the position of the sulfate is less critical (15). With the apparent flexibility of sulfakinin activity in relation to movement of sulfate position in the sequence, it was of interest to determine the limits of sulfate mobility without precipitating complete loss of activity. A series... 

Neoefrapeptins, neoefrapeptin A Ac-Pip-Aib- Pip- Iva-Aib- Leu-/3 -Ala-Gly-Acc-Aib-Pip-Gly-Leu-Iva-aX, a group of peptides with insecticidal activity isolated from the fungus Geotrichum candidum. AU 12 neoefrapeptins (A-I, L-N) contain the very rare amino acid 1-amino-cyclopropane-carboxylic acid (Acc), and some of them (F, I, L, M) also contain (2S,3S)-3-methyl-proline instead of pipecolic acid (Pip) in position 11. Further unusual building blocks are isovaline (Iva) and the C-terminal amide moiety X = 2,3,4,6,7,8-hexahydro-l-pyrrolo [ 1,2-a]pyrimidine. Neoefrapeptins show a close sequence similarity to the efrapeptins [A. Fredenhagen et al., J. Antibiot. 2006, 59, 2006]. 

Extensive research has been conducted to explore the C-28 side chain modifications of BA.30,37,38 A series of C-28 oo-aminoalkanoic acid derivatives of BA, which were first synthesised by Soler et al.,39 functions by blocking the viral entry into the host cells. Incremental chain lengthening significantly influenced the anti-HIV potency of the derivatives.4 Compounds with amide side chains between aminooctanoic acid and aminododecanoic acid (7 11 carbons between the C-28 amide moiety and the terminal carboxylic acid... 

All presently known allatostatins have strong structural homology in their amidated C-terminal hexapeptide moiety, aside from a neutral Val for Leu substitution in ASB2 and the various neutral hydrophilic variants of the type A allatostatins at position 10... 

Replacement of the C-terminal amide with an acid moiety reduces the myotropic potency of the pyrokinins and eliminates activity of the leucokinins and sulfakinins. During the course of these structure-activity studies, several fragments and/or analogs were found to exhibit greater activity than the parent natural products. The fragments [2-8]LPK (Table VI), [5-9]A-I (APFfTyr ] Table IV), and [4-11,Nle ]LSK demonstrated 1.5-, 2- and 7-fold increases in myotropic activity over their parent peptides. In addition, the amino acid substitution of His with 3-MeHis in position 8 of LSK (Table II) led to a 2-fold improvement in activity over the parent neuropeptide. 

Finally, the protecting group for the W -amino function of Tyr, the Bz-Arg moiety, was easily removed with trypsin. The disadvantage of this synthesis strategy seems to be the complicated route of selectively removing the C-terminal amide grouping by means of CDP-Y. This step followed by chemical esterification of the peptide had to be resorted to before it was possible to use the intermediate in the next coupling reaction as the carboxyl component. 

These amides can be categorized into two types based on the connection of the pyridyl moiety to the amide functionality (1) C-terminal (amides), when pyridine is connected to the C-atom of the amide and (2) N-terminal (reverse amides), when pyridine is connected to the N-atom of the amide. These two types are found to have different characteristics and therefore are discussed separately. 

A second strategy is to attach a linker (also referred to as a handle or anchor) to the resin followed by assembly of the molecule. A linker is bifunctional spacer that serves to link the initial synthetic unit to the support in two discrete steps (Fig. 3). To attach a linker to a chloromethyl-PS resin, a phenol functionality such as handle 4 is used to form an ether bond (Fig. 4). To attach the same handle to an amino-functionalized support, acetoxy function 5 or a longer methylene spacer of the corresponding phenol is applied to form an amide bond. Both of these resins perform similarly and only differ in their initial starting resin [4], An alternative approach is to prepare a preformed handle in which the first building block is prederivatized to the linker and this moiety is attached to the resin. For peptide synthesis, this practice is common for the preparation of C-terminal peptide acids in order to reduce the amount of racemization of the a-carbon at the anchoring position [5],... 

Arylhydrazides can serve as safety-catch linkers for C-terminal carboxylic acids, amides, or esters. Cleavage proceeds via oxidation with copper(II) salts and subsequent cleavage of the diazenyl moiety by means of a nucleophile [39] (Scheme 6.1.8). 

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