Cryptic solvation dynamics of potential antineoplastic Azapodophyllotoxin: Short and long range charge transfer and distinct H-bonding motifs demystify its swinging emissive behaviour

Azapodophyllotoxin, the nitrogen analogue of antitumor podophyllotoxin, are new series of fascinating aspirants of anticancer drugs. The potential bioactive azapodophyllotoxin 5-(2-Hydroxyethyl)-9-(3,4,5-trimethoxyphenyl)6,9-dihydro-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (HTDQ) has been found to be highly effective against various cancer cell lines as compared to its minimal toxicity against normal cell lines. With an ulterior motive of exploring fluorescence properties of this promising antineoplastic candidate in biological environment, the intricate details of its ground and excited state solvation and solvation dynamics are investigated using steady state and Time resolved spectroscopic techniques. The experimental observations are substantiated by DFT and TD-DFT based quantum chemical calculations along with in silico molecular dynamics simulation. The solvatochromic behaviour of HTDQ reveals its sensitivity towards solvent polarity and proticity. The charge delocalization within HTDQ framework in ground state (G.S) entirely differs from that of in excited state (E.S). The change in polarity of the medium induces a peculiar short range intramolecular charge delocalization in G.S itself, forming a zwitterionic structure and endorses the unusual absorption characteristics. Whereas, in the E.S, it undergoes a long range intramolecular charge transfer (ICT). In non-polar solvents, the long range ICT induces stacking interaction between two dipolar HTDQ molecules leading to the formation of a new short-lived less emissive excimer species. However, in aprotic and protic polar solvents, the scenario is individually different due to the presence of H-bond donor (hydroxyl hydrogen atom) as well as acceptor sites (oxygen atoms) in the molecular framework of HTDQ. In aprotic solvents, the formation of H-bonds occurs due to presence of hydrogen acceptor site in the solvent that boost up the emission intensity to its maxima. In polar protic solvents, HDTQ subsumes both of its H-bond donor and acceptor sites and further strengthens the H-bonding interactions, which essentially stabilizes the probe molecule within the solvent shell and open up the non-radiative decay channels thereby reducing the emission intensity. HTDQ exhibits bathochromic shift in the emission spectra with increasing solvent polarity, with some exceptional shifts in 1,4 dioxane and THF, which may stem from another interesting conformational polarization of non-polar chair form to polar boat form of the solvent itself. Thus, the different spectroscopic aspects dealt herein demystify the impact of solvent milieu on the solute-solvent interactions and the interesting emissive nature of this potential therapeutic HTDQ that may provide impetus to develop new class of theragnostic agent with promising imaging capability and improved anti-neoplastic activities.

Automated summary

This study investigated the fluorescence properties of the potential anticancer drug candidate HTDQ in biological environment, revealing its sensitivity to solvent polarity and proticity, as well as the differences in solvation behavior and spectral characteristics in various solvents.