"Synthesis and Biological Evaluation of Discorhabdin Alkaloids"
Hypoxia is a defining feature of solid tumors, driving new blood vessel growth and reducing the effectiveness of many cancer therapies. Central to this process is hypoxia-inducible factor 1 (HIF-1), a key regulator of tumor progression and an attractive, yet challenging, target for drug development due to its complex regulation and the toxicity of known inhibitors. Discorhabdins belong to the pyrroloiminoquinone alkaloids and are a family of structurally complex marine natural products that exhibit diverse biological activities, including inhibition of HIF-1. However, their complex structures have limited synthetic access and slowed their broader study.
This work describes the first total synthesis and complete stereochemical assignment of the natural product (+)-discorhabdin V, along with the first synthesis of the natural product 14-bromo-1-hydroxydiscorhabdin V, a C1-hydroxylated analogue. A convergent synthetic strategy was developed featuring a key N-alkylation/oxidative aminocyclization/bromination cascade to construct the pyrroloiminoquinone core from multigram-scale intermediates. Subsequent intramolecular Heck cyclization enables stereoselective formation of the spirocyclic framework, followed by a reductive N,O-acetal cyclization to furnish the piperidine ring system. Preliminary in vitro studies evaluating discorhabdins as HIF-1 inhibitors are also presented, highlighting their potential as leads for anticancer drug development.
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