TOWARD A BIOISOSTERIC ALKAEST – APPLICATION TO THE BIOISOSTERIC MODULATION OF IMD-0354

Bio(iso)steric replacement is a powerful tool for the Medicinal chemist.1 Two functional groups should be called isoster if they share similar physico-chemical properties and bioisosters if they have the same biological profile. It could be said that while chemistry rules the isosteric similarity between groups, only the biological target will be able to answer positively to the following bioisosteric hypothesis. The word “alkahest’’ came directly from the alchemist’s word. It reflects the importance at those times of searching the universality in properties. As for alchemists, the term “alkahest” when applied to bioisosterims represents a dream for any Medicinal Chemist: the finding of such bioisosteric universal tool that, avoiding any biological target judgment, when applied to a structure is always able to afford compounds optimized in terms of biological properties. Beside the fact that unfortunately, as for the alchemists, this theory is going to remain a dream, in recent years our group at DSTF is directing its efforts towards the investigation of a general tool able mimic the acidic group in an universal “alkahest” way. Instead of deeply investigating a single moiety, we focused our attention on a pool of over ten acidic hydroxylated pentatomic heterocyclic systems. The result of this effort is the development of flexible tools capable of adapting to the requirments of different targets both in terms of acidity as well as general chemio-physical profile. We called this pool the “bioisosterc alkahest” (BA). In this study, the application of the BA toward the structure to IMD-0354, a novel NF-kB inhibitor agent claimed to selectively inhibit IKKbeta,2 is presented with the aim to obtain new and potent anticancer drugs. Starting from IMD-0354 structure, the bioisosteric substitution of the acidic phenolic substructure with a substituted hydroxylated heterocyclic should mimick the phenol role and also generate additional binding opportunities. The synthesis and the pharmacological characterization of powerful IMD-0354 analogues are presented and discussed, together with the characterization of the mechanism of action of IMD-0354.