Discovery of Novel Quinazoline Derivatives as Potent Antitumor Agents

Abstract

In this work, we designed and synthesized a novel series of quinazoline derivatives 6-19 and then evaluated their broad-spectrum antitumor activity against MGC-803, MCF-7, PC-9, A549, and H1975, respectively. Most of them demonstrated low micromolar cytotoxicity towards five tested cell lines. In particular, compound 18 exhibited nanomolar level inhibitory activity against MGC-803 cells with an IC50 value of 0.85 μM, indicating approximately a 32-fold selectivity against GES-1 (IC50 = 26.75 μM). Further preclinical evaluation showed that compound 18 remarkably inhibited the migration of MGC-803 cells, induced cell cycle arrest at G2/M, and induced MGC-803 apoptosis, resulting in decreasing the expression of both Bcl-2 and Mcl-1, and up-regulating the expression of both Bax and cleaved PARP. No death or obvious pathological damage was observed in mice by acute toxicity assay. The in vivo antitumor evaluation suggested that compound 18 significantly decreased the average tumor volume and tumor weight without any effect on body weight, which is better than 5-Fu. Therefore, compound 18 can be used as a lead compound for the further development of antitumor drugs in the future.

An Updated Overview on the Synthesis and Anticancer Evaluation of Quinazoline Derivatives

“…Zhang et al successfully synthesized a series of quinazoline derivatives and assessed their efficacy as broad-spectrum antitumor agents against MGC-803, MCF-7, PC-9, A549, and H1975 cell lines. [62] Most of the derivatives displayed promising cytotoxicity at low micromolar concentrations across all five cell lines. Notably, compound 36 exhibited exceptionally potent inhibitory activity against MGC-803 cells, with an IC 50 value of 0.85 μM, demonstrating a remarkable 32-fold selectivity over GES-1 cells (IC 50 = 26.75 μM) (Scheme 23).…”

“…Zhang et al . successfully synthesized a series of quinazoline derivatives and assessed their efficacy as broad‐spectrum antitumor agents against MGC‐803, MCF‐7, PC‐9, A549, and H1975 cell lines [62] . Most of the derivatives displayed promising cytotoxicity at low micromolar concentrations across all five cell lines.…”

"Versatile Mechanisms of Substituted Quinazolines in Targeted Cancer Therapy"

“…Cancer is a group of cells that initiated from a single cell with no control on its growth and rapid proliferation properties. The main three options for cancer treatment are chemotherapy, radiotherapy, and surgery [1]. A wide range of cytotoxic drugs are used alone or in combination with other drugs to treat cancer.…”

“…Therefore, continuous efforts are being made to develop effective anti-cancer drugs with minimal side effects and targeting only cancerous cells [2] to save the lives of millions of people worldwide. Heterocyclic compounds are widely found in natural products as well as synthetic compounds, and most of them have been reported to have numerous biological activities such as anticancer, antiviral, antimalarial, antimicrobial, anti-inflammatory, anticonvulsant, antioxidant, and antihypertensive [3]. As a promising nitrogen-containing heterocycle nucleus, quinazoline is formed by the fusion of pyrimidine and benzene [3].…”

“…Heterocyclic compounds are widely found in natural products as well as synthetic compounds, and most of them have been reported to have numerous biological activities such as anticancer, antiviral, antimalarial, antimicrobial, anti-inflammatory, anticonvulsant, antioxidant, and antihypertensive [3]. As a promising nitrogen-containing heterocycle nucleus, quinazoline is formed by the fusion of pyrimidine and benzene [3]. The properties of quinazoline derivatives depend on three factors which are [4]:…”