Analog design

Unlike desferrioxamine analogs designed for specific therapeutic purposes described above, chiral DFO analogs that form conformationally unique complexes with iron(lll) were designed to serve as chemical probes of microbial iron(lll) uptake processes. As mentioned above, ferrioxamine B can form a total of five isomers when binding trivalent metal ions, each as a racemic mixture. Muller and Raymond studied three separate, kinetically inert chromium complexes of desferrioxamine B (N-cis,cis, C-cis,cis and trans isomers), which showed the same inhibition of Fe-ferrioxamine B uptake by Streptomyces pilosus. This result may indicate either that (i) ferrioxamine B receptor in this microorganism does not discriminate between geometrical isomers, or that (ii) ferrioxamine B complexes are conformationally poorly defined and are not optimal to serve as probes. 

Kinder et al. (123,124) utilized a similar approach to the illudins, more specifically to illudin analogs such as 241 that retain efficacy against various cell lines, but are less toxic. The analog design involves a spirocyclopropyl cyclohexane that contains two electrophilic moieties (Scheme 4.63). Some of the analogs formed are as active as adriamycin against several human tumor cell lines. 

Schramm, V.L. (1998) Enzymatic transition states and transition state analog design. Annu. Rev. Biochem. 67, 693-720. 

Fig. 3. Structure of a cyclic enkephalin analog designed by Schiller and co-workers (DiMaio el al., 1982).

Bioisosteres are defined as groups or molecules that have chemical and physical properties producing broadly similar biological properties. " Bioisosteres likely affect the same receptor site or pharmacological mechanism. This analog design principle was apphed to our DCK modification, and thio-DCK and DCK lactam derivatives were developed. 

Homologation of an alkyl chain and alteration of ring size are also useful approaches in analog design. Therefore, 3 / ,4 l -di-0-( )-camphanoyl-2, 2 -dimethylnaphtho[5,6-fl]pyran (125), 3 /f,4 /f-di-0-(—)-camphanoyl-2, 2 -dimethyl-dihydropyrano[2,3-e]-l-indanone (DCl, 126), and three compounds with opened A ring (127-129) were designed and synthesized. These compounds vary... 

Low water solubility, less potency against dmg-resistant HIV strains, and fast metabolism are three main obstacles that limit the development of DCK analogs. Additional analog design is likely to use DCP as a new lead to increase the potency against drug-resistant viral strains and improve water solubility and pharmacological properties. 

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