Follow-up libraries

Fig. 18.2 Elaboration-based strategies. Left In SHAPES screening [3], simple drug-like scaffolds are screened using ligand-detected experiments. In the follow-up step, information about binding scaffolds is used to design a follow-up library comprised of analogous compounds. Successive rounds of screening lead to increasingly complex...

As a result of the observed Library A SAR, a 29-member follow-up library (fredericamycin A Library B) was designed using fredericamycin A aldehyde building blocks 20a, 20c, 20d, 20e, and 0-alkyl hydroxylamines and acyl hydrazines. The diversity focused around substituents found in Library A exhibiting the highest activity. Not aU hydroxylamines and hydrazines were combined with each of the four aldehydes for Library B, because some of the combinations were already included in Library A. Furthermore, a third and final set of 107 fredericamycin derivatives (fredericamycin A Library C) related to the analogs described in Libraries A and B was synthesized. The synthesis of Library C was based mainly on the procedures described for Libraries A and B. 

FIGURE 5.13 Potency (inhibition of cell viability) of the 29-member follow-up Library B of fredericamycin derivatives (gray bars) in comparison to fredericamycin A (18, black bar). 

Follow up library using expanded co-hort of Het-X Figure 18.11 Concept of enabled monomers. 

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