Metal-free internal nucleophile-triggered domino route for synthesis of fused quinoxaline [1,4]-diazepine hybrids and the evaluation of their DNA binding properties.

An unprecedented metal-free synthesis of fused quinoxaline 1,5-disubstituted-[1,4]-diazepine hybrids have been reported under mild conditions through a domino intermolecular SAr followed by an internal nucleophile-triggered intramolecular SAr pathway. Our strategy offers the flexibility for the introduction of a broad variety of functionalities at the N-1 position of fused diazepine moiety by using suitable diamine tails to design structurally diverse scaffolds. The DNA binding properties of representative quinoxaline diazepine hybrids were studied using UV-vis absorbance and EtBr displacement assay and were found to be governed by the functionalities at the N-1 position. Interestingly, compound 11f containing the N-1 benzyl substitution demonstrated significant DNA binding (K ∼ 2.15 ± 0.25 × 10 M and Ksv ∼ 12.6 ± 1.41 × 10 M) accompanied by a bathochromic shift (Δλ ∼ 5 nm). In silico studies indicated possible binding of diazepine hybrid 11f at the GC-rich major groove in the ct-DNA hexamer duplex and showed comparable binding energies to that of ethidium bromide. The antiproliferative activity of compounds was observed in the given order in different cell lines: (HeLa > HT29 > SKOV 3 > HCT116 > HEK293). Lead compound 11f demonstrated maximum cytotoxicity (IC value of 13.30 μM) in HeLa cell lines and also caused early apoptosis-mediated cell death in cancer cell lines. We envision that our work will offer newer methodologies for the construction of fused quinoxaline 1,5-disubstituted-[1,4]-diazepine class of molecules.