Synthesis of a 5,8-quinolinedione derivative and its potential antineoplastic use

Abstract

Introduction: Antineoplastic chemotherapy is a fundamental therapeutic strategy for the treatment of cancer, but its lack of selectivity and the development of drug resistance limit its clinical efficacy. Quinoline-5,8-diones are emerging as promising pharmacophores, given that natural structures derived from this core exhibit proven cytotoxic activity. The incorporation of additional heterocyclic rings via aza-fusion enhances this activity in related quinone systems. Objective: The objective was to synthesize and characterize the aza-fused derivatives 5-chloro-3,4-dihydropyrido[3,2-f]quinoxalin-6(2H)-one and 5-chloro-3,4-dihydropyrido[2,3-f]quinoxalin-6(2H)-one. Methodology: A four-step synthetic route was employed starting from 8-hydroxyquinoline, involving nitrosation, selective reduction, oxidative chlorination, and iminocyclization with ethylenediamine in acetonitrile. Characterization was performed by one-dimensional (¹H and ¹³C) and two-dimensional (HMBC) NMR. Results: The iminocyclization reaction did not yield the target compounds but instead generated the unexpected product 5-chloropyrido[2,3-f]quinoxalin-6-ol, with a 36% yield. Discussion: Spectroscopic analyses showed that the product underwent in situ dehydrogenation and aromatization, resulting in a fully aromatized aza-annulated structure, in which the hydroxyl group (-OH) is attached to a carbon atom of the aromatic system, corresponding to compound 5-chloropyrido[2,3-f]quinoxalin-6-ol. Conclusion: The synthetic route used does not allow for the preparation of the target compounds under the conditions evaluated. However, the synthesis of compound 7, which has not been reported in the literature, establishes it as a new chemical entity of interest for the evaluation of antineoplastic activity and the design of molecules with enhanced biological activity.