Design of 2-cyclopentenone derivatives with enhanced NF-κB:: DNA binding inhibitory properties

In this work we derived a series of new inhibitors for the association between nuclear factor kappa B (NF-kappaB) and the corresponding kappaB site in DNA. They were derived through optimization of the lead compound 2-cyclopentenone (Cl?), which corresponds to the reactive unit of natural product 15-DeoXY-Delta(12,14)-prostaglandin J(2) (PGJ2). Both CP and PGJ2 possess demonstrated inhibitory efficiency for this and other biological important systems. We began by studying the docking of CP to NF-kappaB. Subsequently, a set of rational strategies were derived to insert substituents into CP which increase its association to NF-kappaB, in terms of both the affinity and the specificity. Molecular mechanics calculations have been performed to decide on the suitability of the substitutions, and to evaluate the energies of association with NF-kappaB. One of the important chemical properties of CP is that it is a weak electrophile, hence it selects attacking nucleophilic sites in proteins, rather than the nucleic acids. To assure that the designed compounds were not substantially more reactive than CP we performed high level density functional theory calculations. Important conclusions have been obtained concerning the optimization of this inhibitor; namely, a set of methodologies for rational drug design have been derived to enhance the affinity of the CP derivatives to NF-kappaB. The efficacy of these methodologies has been demonstrated by generating a set of substituted CPs, exhibiting increased affinity for NF-kappaB, and opening new ways to broaden the therapeutic applications of this class of drugs. (C) 2004 Elsevier B.V. All rights reserved.