Basic Chain Functions

For the purposes of this book, chains have four basic functions  

These se n vray simple, and they are, but the details must be handled in a much different way for each class of chain. 

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DERIVATIVES OF DIBENZOLACTAMS A recurring theme in the present chapter has been the association of CNS activity with dibenzoheterocycles that bear a basic chain pendant from the central ring. As we have seen, considerable latitude exists as to the constitution of the central ring. The earlier volume in this series described the preparation of the antidepressant dibenzepin (90), in which the basic function is attached to a lactam nitrogen. 

The amino acids in question are the basic amino acids lysine, arginine, and histidine, and the acidic amino acids aspartic acid and glutamic acid. The side-chain functions of these amino acids, ionized at pH 7 (see Box 4.7), act as acids or bases. In a reverse sequence, protons may be acquired or donated to regenerate the conjugate acids and conjugate bases. 

We have seen that a key requirement in the ligation of unprotected protein fragments is chemoselectivity, so that only the intended sites react with each other in the presence of numerous side-chain functional groups. This requirement can be met by a general approach using carbonyl chemistry in which a weak base is ligated with an aldehyde under acidic conditions (Scheme 1). Under acidic conditions, the nucleophiles in basic side chains are... 

The pKa values for the side-chain functions of acidic and basic amino acids are given in Table 25-1. 

This raises another question. Why is the serine hydroxyl an effective nucleophile when water and other hydroxylic compounds clearly are not similarly effective Apparently, the nucleophilicity of the serine —CH2OH is enhanced by acid-base catalysis involving proton transfers between acidic and basic side-chain functions in the vicinity of the active site. The serine is believed to transfer its OH proton to an amphoteric10 site B—A—H on the enzyme at the same instant that the proton of B—A—H is transferred to another base B e (Equation 25-8). These proton transfers are, of course, reversible ... 

Benzimidazole (BIm) crystallizes in hydrogen-bonded chains with nearly linear N-H---N donor-acceptor contacts.185 Viewed down the chain axis, the benzene rings form a sawtooth alternation. This motif can accommodate substitution in the 2-position and on the benzene ring, while still retaining the basic chain structure, as seen in the large majority of structures from the CSD. Lahti recently summarized186 magnetostructural studies carried out on radicals linked to neutral aza-arenes. This chapter will focus only on BIm-functionalized radicals. 

Basic-stable protecting groups for sugar hydroxyl and amino acids side chain functional groups... 

Two side chains containing basic (amine) functions. 

Equation (2.2.12) may be directly obtained from minimizing the elastic free energy under the constraint that the mean-square radius of gyration has a fixed value [see Eqs. (2.1.63) and (2.1.39), C q) -+ ot q)C q) [10]. The physical meaning of this result is that under chain compression the free energy due to the interatomic contacts is basically a function of only, no matter what are the individual values of the a (q). As a consequence, all the mean-square distances (r (k)) may be expressed under a general form [53]. Defining... 

Spectral data over a wide range of frequencies are desirable, since internal vibrations of basic chain-repeat units occur above 1000 cm-, while skeletal and interchain frequencies are usually between 0 and 1000 cm. In general, skeletal and intermolecular vibrations are not characterized by single sharp frequencies, but by frequency distributions that are a function of the phase difference between adjacent oscillating units of a chain or between chains. Theoretical predictions of phase-... 

To overcome the problems associated with these reaction conditions, Backes et al. developed an alkanesulfonamide safety-catch linker for solid-phase s)rnthesis [34]. In this method, acylation of a sulfonamide support affords a support-bound iV-acylsulfonamide that is able to withstand the basic and strongly nucleophilic reaction conditions required for Fmoc-based SPPS. On completion of the solid-phase synthesis sequence, iodoacetonitrile treatment yields iV-cyanomethyl derivatives that can be cleaved under mild nucleophilic reaction conditions to afford the target compounds. Coupling conditions of alkanesulfonamide resin with Boc- and Fmoc-amino acids were developed to minimize the racemization. Using this method, a short synthesis sequence, followed by iodoacetonitrile activation and nucleophilic displacement is able to form dipeptide products from a number of support-bound amino acids incorporating diverse side-chain functionalities. 

Most of the enzyme modification reactions, and hence of the coupling reactions, are nucleophilic reactions, in particular bimolecular nucleophilic substitution reactions following an 5 2-type mechanism. Therefore, the chemical reactivity is basically a function of nucleophilicity of the amino acid side chain. Following the overall nucleophilic order of Edwards and Pearson [22], the sulfhydryl group of cysteine is the most potent nucleophile in the protein, especially in its thiolate form. 

Usually chiral centers are eliminated in creating symmetry. Thus, in a series of muscarinic agonists derived from 3-aminopyridazines, one of the most favorable side-chains, was the racemic 2-Ai-ethylpyrroMmyl-methyl chain, that is, the side-chain of sulpiride (Figure 26.8). The 5-methyl-6-phenylpyridazine bearing this basic chain at its 3-amino function presented a 0.26 micromolar affinity for Ml muscarinic receptor preparations. ... 

Some amino acids, including those listed in the last two sections of Table 27.1, have side chains that bear acidic or basic groups. As Table 27.3 indicates, these amino acids are characterized by three pTfa values. The extra pK value (it can be either pK or pK s) reflects the nature of the function present in the side chain. The isoelectric points of the amino acids in Table 27.3 are midway between the pK values of the monocation and monoanion and are well removed from neutrality when the side chain bears a carboxyl group (aspartic acid, for example) or a basic amine function (lysine, for example). 

Swath width is basically a function of the spray angle, provided that the user maintains the nozzle at a constant distance from the target area being treated. Some users have added a weighted chain or string to part of the lance as a guide... 

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