Isosterism modifications

Substances that are isosteric equivalents of substances that are toxic or pharmacologically active may also possess these biological properties. It is also possible that biological properties may be bestowed, exacerbated, or attenuated when isosteric modifications are made. This point is illustrated by the following examples. 7-Methyl-benz[a]anthracene (36) is a known carcinogen, whereas 7-methyl-l-fluorobenz[o]... 

Isosteric replacement of the thiourea moiety with the cyanoguanidine moiety gave cimetidine (39), a potent H2-receptor antagonist that lacks the toxicity of 38. Cimet-idine is a widely used anti-ulcer medication because of its effectiveness in treating ulcers and relative safety. It is noteworthy that in this example, this isosteric modification selectively reduced toxicity without affecting pharmacological activity. 

Thiocarbapyranoses are a quite rare compound class in the scenario of pyranoid carbasugars, although replacement of a hydroxyl group with a sulfurized moiety is a classical isosteric modification in medicinal chemistry. 

On the other hand, pseudopeptide analogs of the C-terminal tetrapeptide of gastrin U7b), such as (tert.butyloxycarbonyl)-L-tryptophyl-4 (CH2—NH)-L-leucyl-L-aspartyl-L-phenylalaninamide 51b, in which the amide linkage is replaced by the isosteric modification CH2—NH, are potent agonists of acid secretion. 

Indomethacin and Analogs - Among several isosteric modifications of indomethacin studied at Merck, an indene isoster, cis -1-p-chloro-benzylidenyl-5-methoxy-2-methyl-3-indenylacetic acid (VII), was found to be half as active as indomethacin. The corresponding "trans isomer was only one-tenth as active. The structure-activity relationship of Nj-aroyl and N.-aralkyl indole acetic acids is generally parallel to that of indene isosters, indicative of a similar mode of action. Based on X-ray diffraction data, the nonplanar configuraticn of the cis-isomer was suggested as the preferred conformation of... 

In the first case, isosteric modifications of the amide bond to produce peptide bond surrogates, insertion of unnatural amino acids, and introduction of conformational constraint, represent crucial steps along the path toward drug candidates [40,41]. 

The next chemical modification was an attempt to bury the isosteric modification more deeply within the molecule in order to lessen its effect on overall molecular shape, viz. (3a) and (3b) with -heptyl groups in place of methyl. Comparison of the powder patterns in Figures 7(a)-7(d) clearly indicates four different crystal structures for enantiomers and racemates of (3a)... 

Aldol addition of DHAP to aldehydes is catalyzed by DHAP-dependent aldolases. Two stereogenic centers are formed and therefore four possible stereoisomers can be obtained. Although nature has evolved a set of four distinct stereocomplementary types (Scheme 10.3), so far, only three of the known DHAP-dependent aldolases, namely the D-fructose-l,6-bisphosphate aldolase (FruA), L-rhamnulose-1-phosphate aldolase (RhuA), and L-fuculose-1-phosphate aldolase (FucA), have found broad synthetic applicability due to their high stereoselectivity and broad acceptor tolerance [5,77]. DHAP-dependent aldolases are highly selective for the nucleophilic substrate DHAP, tolerating only few isosteric modifications [84-88]. 

Tricyclic antidepressants (TCAs) are represented by a central, seven-membered, non-aromatic ring that is fianked by two benzene rings where the dihedral angle (a) between the two benzene rings can impact on the extend of antidepressant activity. Several isosteric modifications retain antidepressant activity. Secondary amines appear to show higher selectivity for the norachenaline reuptake hansporter (NAT). Then tertiary cormterparts tend to display a somewhat higher selectivity for the sero-torrin reuptake hansport protein (SERT) while others are less selective (mixed SERT/NAT). 

C W 1979. Isosterism and Molecular Modification in Drug Design. Chemical Society Reviews 53-580. 

Fig. 14 a, b. Two different and isosteric orientations of triplets of s-PS chains dark circles indicate the maih-chain carbon atoms. The presence of a statistical disorder of these orientations, in the positions indicated by large dashed circles in Fig. 7 a, characterize the disordered a modification [27, 9, 28]... 

Among the strategies used for the development of GST Pl-1 inhibitors is the modification of the GSH backbone to leverage its inherent affinity for GST Pl-1. One approach centered on the incorporation of a carbamate group as an isosteric replacement of the y-carboxylic Glu linkage in GSH. Synthesis and in vitro testing of 42 and 43 showed that this carbamate-replacement approach was not well tolerated [67]. 

T.E. Christos, A. Arvanitis, G.A. Cain, A.L. Johnson, R.S. Potorf, S.W. Tam, W.K. Schmidt, Stable isosteres of neurotensin C-terminal pentapeptides derived by modification of the amide function, Bioorg. Med. Chem. Lett. 3 (1993) 1035-1040. 

Cyclic peptides have been synthesized not only for the purpose of improving biological activities and selectivity, but also to explore basic features of secondary structures in peptides and to investigate with such mimetic compounds the conformational behavior of proteins. For this purpose artificial building blocks have been frequently used or amide bonds have been modified isosterically. Nature also offers a variety of modifications in cyclic peptides that are critically involved in their bioactivity. Some of the most common natural and synthetic modifications including unusual structural elements such as thiazoles (and dihy-drothiazoles) and oxazoles (and dihydrooxazoles) with broad synthetic applications will be presented in the following section. 

The oldest example of the use of nonclassical isosteres involves the replacement of the carboxamide in foUc acid by sulfonamide, to give the sulfanilamides. Diaminopyrimidines, as antimalarial agents, are also based on folate isosterism, in addition to the exploitation of auxiliary binding sites on dihydrofolate reductase. This concept of nonclassical isosteres or bioisosteres — that is, moieties that do not have the same nnmber of atoms or identical electron structure — is really the classical structure modification approach. 

The discovery of yet other nonhydrolyzable amide bond isosteres has particularly impacted the design of protease inhibitors, and these include hydroxymethylene or FfCF OH)], 12 hydroxyethylene or T fCF OFQCFy and T fCFkCHiOH)], 13 and 14, respectively dihydroxyethylene or ( [ )], 15, hydroxyethylamine or 4 [CH(0H)CH2N], 16, dihydroxyethylene 17 and C2-symmetric hydroxymethylene 18. In the specific case of aspartyl protease inhibitor design (see below) such backbone modifications have been extremely effective, as they may represent transition state mimics or bioisosteres of the hypothetical tetrahedral intermediate (e.g., xF[C(OH)2NH] for this class of proteolytic enzymes. 

Peptidomimetics are peptide molecules characterized by modifications to the side chain (Section 9), to the a-carbon (Sections 10.3 and 10.4), or, to the components of a peptide bond itself either singularly (e.g., Sections 10.1 and 10.2), or, in combination. Peptidomimetics containing a modification to the nature of the peptide bond are often referred to as pseudopeptides or peptide bond surrogates. 1 These compounds are sometimes termed as peptide bond isosteres, although the isosteric nature of the replacement is often not obvious or may even be dubious. 

To connect the C2 and C3 atoms of the 1-hydroxyethylene moiety, Wuts et al.[341 and Poss and Reid 35 used the Wadsworth-Emmons reaction between a (3-amino-a-hydroxy-aldehyde and a phosphonate (two-carbon fragment) to give the desired isostere after reduction of the alkene. In the synthesis reported by Poss and Reid (Scheme 17) the stereochemistry of the hydroxyl group at C4 is established by a highly diastereoselective aldol addition to furan. A slight modification was employed by Chakravarty et all36 and Plata et al.[37 where 4-amino-3-oxo phosphonates were reacted with an aldehyde or ketone form of the two-carbon fragment. 

Prostacyclin (11.53) is a signal molecule in the body that inhibits clotting and acts as a vasodilator. Prostacyclin is unstable and has an extremely short half-life (Figure 11.10). The instability of prostacyclin in the body is primarily attributed to its enol ether functionality, which readily undergoes hydrolysis. Isosteric replacement of the ring oxygen with a CH2 group and small modifications of the side chain afforded iloprost (Ilomedine, 11.54), an FDA-approved treatment for certain... 

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