I. Structure-Activity Relationship Studies of 6,7-Annulated-5-Substituted Libraries. II. Current Efforts Towards The Synthesis of 4-Azaindole Aryne Precursors

Abstract

A contemporary and highly valued method for drug discovery involves the synthesis of libraries or collections of novel compounds from interesting molecular scaffolds, often inspired by biologically active, naturally occuring products. Such scaffolds that are unlike those found in the National Institutes of Health PubChem and Molecular Libraries Small Molecule Repository (MLSMR) are especially sought as they are considered more likely to exhibit interesting or unknown modes of action, for example, as anticancer drugs . The Buszek laboratories recently created a library of structurally unique polycyclic, benzannulated indole compounds (i.e., those that have a ring fused on the benzene side of the indole nucleus) that were inspired by the rare class of cytotoxic benzannulated indole alkaloids, the trikentrins and the herbindoles. This effort represented the first library of its kind based on this type of scaffold. Subsequent biological screening of these compounds revealed high activity against L1210 leukemia and HL-60 promyelocytic leukemia cell lines, at concentrations of 0.5 μM and 10 μM, respectively. The 5,6,7-tribromoindole was synthesized via Leimgruber-Batcho indole synthesis and was N-alkylated. This indole underwent selective metal-halogen exchange at C-7 and subsequent elimination to give the 6,7-indole aryne which underwent Diels-Alder cycloadditions with cyclopentadiene, furan give respective cycloadducts which were subjected to give olefin reduction. The reduced cycloadducts which have bromine at C-5 intact were then employed in the Pd(0)-catalysed cross-coupling reactions such as the Suzuki-Miyuara and Buchwald-Hartwig cross-coupling reactions to afford a novel suite of 5-substituted libraries. Related efforts to generate a new class of hetaryne, namely, the azaindole aryne, are in progress. Azaindoles comprise important therapeutic agents such as vemurafenib (melanoma). Novel libraries of azaindoles are unknown. Our initial attempts involved the synthesis of the 4-aza-6,7-dibromoindole aryne precursor via the Bartoli route. So, we are now looking into the different routes to synthesize these precursors.