Mass Spectrometry-Based Discovery of New Chemical Scaffold Rearrangement Ions: Aza-biphenylene as a Novel Potent Biradical Agent in Cancer Chemotherapy

Abstract

Discovery of a new drug is time-consuming, laborious, and expensive. Herein, a novel integrative strategy for discovering potential new lead compounds has been developed, which was based on the characteristics of mass spectrometry (MS). MS was used to predict the potential forced degradation products (DPs) and metabolites of drugs by electrospray ionization and collision-induced dissociation (CID). Special rearrangement ions representing unique predicted DPs and metabolites were identified. The consistency between the predicted and the measured results was proven by in vitro metabolism and forced degradation of a commercial drug, respectively. From this, new chemical scaffold rearrangement ions named (aza)-biphenylenes, as potent anticancer agents, were discovered. As a representative aza-biphenylene analogue, 2-azabiphenylene was proven in vitro to induce apoptosis and inhibit the growth of various human cancer cells in a dose-dependent manner. Surprisingly, 2-azabiphenylene exhibited the best comparable bioactivity with the positive control sorafenib, but showed significantly lower in vitro cytotoxicity than sorafenib (at least a 5-fold decrease in cytotoxicity) because it could be targeted to the tumor microenvironment at low pH. A biradical mechanism accompanied by a mitochondrion-dependent oxidative stress mechanism was proposed to explore its anticancer mechanism. The highly reactive intermediate aza-biphenylenediyl worked as an active pharmaceutical ingredient and induced apoptosis of cancer cells. This provided the basis for the potential applications of CID-induced special rearrangement ions in developing new lead compounds.

Chiral Analysis of Lactate during Direct Contact Coculture by Single-Cell On-Probe Enzymatic Dehydrogenation Derivatization: Unraveling Metabolic Changes Caused by d-Lactate

“…With our previous knowledge, 2-azabiphenylene is a biradical agent and can be targeted to the low pH of cancer cells. 57 In this study, 2-azabiphenylene could be targeted to both cocultured A549 and cocultured Beas-2B in the TME because cancer cells shared the low pH tumor microenvironment with direct contact cocultured normal cells. Then, protonated 2-azabiphenylenediyl reacted with excess D-lactate in Beas-2B cells.…”

Mass Spectrometry in China

“…investigated the fragmentation pathway of fentanyl analogues and opioids for forensic applications . Guo et al demonstrated the use of tandem MS fragments in predicting degradation products of metabolites in drug discovery . Wang et al utilized gas-phase reactions for limited charge reduction of heterogeneous intact glycoproteins that were otherwise not resolvable with direct MS analysis .…”

“…15 Guo et al demonstrated the use of tandem MS fragments in predicting degradation products of metabolites in drug discovery. 16 Wang et al utilized gas-phase reactions for limited charge reduction of heterogeneous intact glycoproteins that were otherwise not resolvable with direct MS analysis. 17 chemistry is important in medicine and neurological diseases such as Alzheimer's disease.…”

Mass Spectrometry Rearrangement Ions and Metabolic Pathway-Based Discovery of Indole Derivatives during the Aging Process in Citrus reticulata ‘Chachi’

“…We have previously established a method [ 17 ] to simulate and predict the degradation products and metabolites of special drugs based on electrospray ionization–collision-induced dissociation–mass spectrometry (ESI–CID–MS). The acidic microdroplets [ 18 ] formed in ESI can accelerate degradation [ 19 ] and the metabolism of pharmaceuticals.…”