Basic side chains

Ammo acids with basic side chains... 

Some ammo acids have side chains that bear acidic or basic groups As Table 27 3 indicates these ammo acids are characterized by three values The third pK reflects the nature of the side chain Acidic ammo acids (aspartic and glutamic acid) have acidic side chains basic ammo acids (lysine arginine and histidine) have basic side chains The isoelectric points of the ammo acids m Table 27 3 are midway between the pK values of the zwitterion and its conjugate acid Take two examples aspartic acid and lysine Aspartic acid has an acidic side chain and a pi of 2 77 Lysine has a basic side chain and a pi of 9 74... 

It is interesting to note that the amino acid side chains may be either neutral as in valine, acidic as in glutamic acid or basic as in lysine. The presence of both acidic and basic side chains leads to proteins such as casein acting as amphoteric electrolytes and their physical behaviour will depend on the pH of the environment in which the molecules exist. This is indicated by Figure 30.2, showing a simplified protein molecule with just one acidic and one basic side group. 

The miotic effect induced by physostigmine lends itself to investigation of the interrelation of chemical constitution and pharmacological action, and Stedman has devoted much attention to this subject. Eseroline is devoid of miotic activity, so that the latter action in physostigmine must be mainly due to the fact that it is a methylurethane, and, since activity only becomes evident in the urethanes of phenolic bases or phenols with a basic side-chain, a basic nucleus for the urethanes appears also to be essential. 

Amino acids with basic side chains Basic amino acids are the opposite of acidic... 

The isoelectric points of the amino acids in Table 27.3 are midway between the pK values of the zwitterion and its conjugate acid. Take two exanples aspartic acid and lysine. Aspartic acid has an acidic side chain and a pi of 2.77. Lysine has a basic side chain and a pi of 9.74. 

A new solid phase method to synthesize libraries of compounds based on 1,2,5-thiadiazolidine heterocycle was developed (00TL(41)3161). Starting from the coupling of the protected aminoacid to the resine functionalized with p-alkoxybenzylalcohol as the linker, a series of sulfahydantoins 251 could be obtained. The method is applicable to aminoacids with a basic side chain, aliphatic aldehydes or aldehydes with basic functionalities. 

Inclusion of the basic side chain nitrogen atom in a hetero-... 

Esters of diphenylacetic acids with derivatives of ethanol-amine show mainly the antispasmodic component of the atropine complex of biologic activities. As such they find use in treatment of the resolution of various spastic conditions such as, for example, gastrointestinal spasms. The prototype in this series, adiphenine (47), is obtained by treatment of diphenyl acetyl chloride with diethylaminoethanol. A somewhat more complex basic side chain is accessible by an interesting rearrangement. Reductive amination of furfural (42) results in reduction of the heterocyclic ring as well and formation of the aminomethyltetrahydro-furan (43). Treatment of this ether with hydrogen bromide in acetic acid leads to the hydroxypiperidine (45), possibly by the intermediacy of a carbonium ion such as 44. Acylation of the alcohol with diphenylacetyl chloride gives piperidolate (46). ... 

The low order of structural specificity required for classical antihistaminic activity was noted earlier. It has been found possible to substitute an indene nucleus for one of the two aromatic rings that most of these agents possess. The basic side chain may be present as either dimethylaminoethyl or itself cyc-lized to provide an additional fused ring. 

Inclusion of fluorine on the pendant aromatic ring and the basic side chain seems to emphasize the anticonvulsant and hypnotic effects of this class of drugs. Thus alkylation of the benzodiazepinone, 24 (prepared from the corresponding substituted aminobenzophenone), with 2-chlorotriethylamine via its sodium salt affords fluazepam. ... 

Attachment of the basic side chain to the phenothiazine nucleus by means of a carbonyl function apparently abolishes the usual CNS or antihistamine effects shown by most compounds in this class. The product azaclorzine instead is... 

More specifically, the pi of any amino acid is the average of the two acid-dissociation constants that involve the neutral zwitterion. For the 13 amino acids with a neutral side chain, pi is the average of pKal and p/amino acids with either a strongly or weakly acidic side chain, pi is the average of the two lowest pKa values. For the three amino acids with a basic side chain, pi is the average of the two highest pKz values. 

It is of interest to note that attachment of a basic side chain on carbon of an isomeric dibenzazepine affords a compound in which anticholinergic activity predominates, elantrine (50). Reaction of anthra-quinone (45) with the Grignard reagent from 3-chloro-N,N-dimethylaminopropane in THF in the cold results in addition to but one of the carbonyl groups to yield hydroxyketone 46. This is then converted to oxime 47 in a straightforward manner. Treatment of that intermediate with a mixture of phosphoric and polyphosphoric acids results in net dehydration of... 

An increase in sensitivity is realized by silver-staining, where residues containing sulfur (cysteine, methionine) or basic side chains (arginine, lysine, histidine) reduce Ag+, leading to brown or black colored bands. Here, down to 0.1 ng of protein can be detected. 

Modification of the basic side-chain and aromatic substitution 302... 

MODIFICATION OF THE BASIC SIDE-CHAIN AND AROMATIC SUBSTITUTION... 

Modification of the basic side-chain of metoclopramide has been the subject of numerous investigations. Earlier work led to the synthesis of YM 09151-2 (15a) [8], clebopride (15b) [9], dazopride (15c) [10] and cisapride (15d) [11]. Modification of the basic side-chain and aromatic ring substitution led to the synthesis of alizapride (4a) [5], sulpiride (16a) [ 12] and cinitapride (16b) [13]. Although a number of analogues have found clinical use for various indications,... 

E. Jacobson in 1882 fused phthalic anhydride with quinoline bases obtained from coal tar, which also contained quinaldine (136). He thus received quinophthalone (137). Quinophthalone derivatives bearing sulfonic or carboxylic acid functions represent suitable anionic dyes. Derivatives carrying basic side chains containing quarternary nitrogen, on the other hand, provide cationic dyes. The compounds are used especially as disperse dyes [1]. 

Fig. 5.20. Modes of coordination of transition metal ions with /3-lactam antibiotics. Complex A In penicillins, the metal ion coordinates with the carboxylate group and the /3-lactam N-atom. This complex stabilizes the tetrahedral intermediate and facilitates the attack of HO-ions from the bulk solution. Complex B In benzylpenicillin Cu11 binds to the deprotonated N-atom of the amide side chain. The hydrolysis involves an intramolecular attack by a Cu-coordinated HO- species on the carbonyl group. Complex C In cephalosporins, coordination of the metal ion is by the carbonyl O-atom and the carboxylate group. Because the transition state is less stabilized than in A, the acceleration factor of metal ions for the hydrolysis of cephalosporins is lower than for penicillins. Complex D /3-Lactams with a basic side chain bind the metal ion to the carbonyl and the amino group in their side chain. This binding mode does not stabilize the tetrahedral transition complex and, therefore, does not affect the rate of... 

Another chelate structure exists for fi-lactams bearing a basic side chain. In ampicillin and cephalexin, e.g., the metal ion is bound by the carbonyl and amino groups (D, Fig. 5.20) [137]. When so attached, the metal ion does not appear to stabilize the tetrahedral transition-state complex, and, indeed, Cu11 ions did not significantly affect the hydrolysis of cefaclor [125]. 

The examples found in the literature concern mostly oligopeptides, with the reactive N-terminal amino acid being Gly, His, or Arg. Interestingly, the former is particularly flexible, whereas His and Arg contain a basic side chain. Whether these are fortuitous observations or have general value remains to be seen. 

Aromatic acids with a basic side chain are also of considerable interest. Since the determining feature is the basic group, prodrugs derived from such acids are discussed in Sect. 8.5.5.2. 

Benzoic acids substituted with a basic side chain also are also of interest as pro-moieties whose physicochemical properties and rates of enzymatic hydrolysis can readily be modulated. A number of drugs have been converted to prodrugs with this type of pro-moiety, e.g., hydrocortisone, prednisolone, acyclovir, chloramphenicol, and paracetamol [148] [149], These prodrugs appear well suited as parenteral formulations, being water-soluble, stable in slightly acidic solution, and readily hydrolyzed enzymatically. As examples, we consider here the hydrolysis in human plasma of a number of (aminomethyl)ben-zoates of metronidazole (8.109-8.115, Sect. 8.5.5.1, Table 8.9) [138], These prodrugs are very rapidly activated, which may be beneficial for parenteral administration. However, this type of pro-moiety may be cleaved too rapidly after oral administration to be of interest for poorly absorbed drugs. 

There are at least three possibile ways in which the inhibitor can bind to the active site (1) formation of a sulfide bond to a cysteine residue, with elimination of hydrogen bromide [Eq. (10)], (2) formation of a thiol ester bond with a cysteine residue at the active site [Eq. (11)], and (3) formation of a salt between the carboxyl group of the inhibitor and some basic side chain of the enzyme [Eq. (12)]. To distinguish between these three possibilities, the mass numbers of the enzyme and enzyme-inhibitor complex were measured with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI). The mass number of the native AMDase was observed as 24766, which is in good agreement with the calculated value, 24734. An aqueous solution of a-bromo-phenylacetic acid was added to the enzyme solution, and the mass spectrum of the complex was measured after 10 minutes. The peak is observed at mass number 24967. If the inhibitor and the enzyme bind to form a sulfide with elimination of HBr, the mass number should be 24868, which is smaller by about one... 

---