Discovery of novel quinazolines as potential anti-tubulin agents occupying three zones of colchicine domain

Abstract

A series of novel quinazolines as tubulin inhibitors occupying three zones of colchicine domain have been designed and synthesized inspired by the recently disclosed crystal structure of verubulin analogue 6 with tubulin. Among the newly synthesized compounds, 19c showed noteworthy potency against K562, HepG2, KB, HCT-8 and MDB-MB-231 cancer cells. In vitro microtubule polymerization assays identified 19c as a potent tubulin assembly inhibitor, the binding mode of which with tubulin was confirmed by molecular modelling studies to occupy three zones of tubulin domain. Furthermore, 19c disrupted the intracellular microtubule network, caused G2/M phase arrest, induced cell apoptosis and depolarized mitochondria of K562 cells. 19c also reduced the cell migration and disrupted the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs). Importantly, 19c significantly and dose dependently inhibited tumor growth in H22 liver cancer xenograft mouse model. All these results suggested that 19c deserves further research as a novel and potential anti-tubulin agent for the treatment of cancers.

MSCs as Tumor-Specific Vectors for the Delivery of Anticancer Agents—A Potential Therapeutic Strategy in Cancer Diseases: Perspectives for Quinazoline Derivatives

“…Verubulin (derivative 14 ) had reached phase II of a trial for the treatment of glioblastoma, but it was halted due to cardiovascular toxicity. Recently, Li et al described a new potent tubulin inhibitor with a pyridine ring ( 16 ) showing nanomolar activity against some cancer cell lines ( Figure 3 ) [ 126 ].…”

“…Another effect of compounds that inhibit tubulin is the ability to inhibit cell migration and invasiveness. Thus, these agents prevent metastases in neoplastic diseases [ 125 , 126 ]. Some compounds act as multifunctional ligands.…”

Quinazoline Derivatives as Potential Therapeutic Agents in Urinary Bladder Cancer Therapy

“…Quinazolines can also exhibit apoptotic properties in cancerous cell lines ( Li et al, 2019 ) by means of acting as tubulin inhibitors. Tubulin is the structural protein of microtubules and plays a crucial role in cell division.…”

“…Vinblastine is used in the treatment of Hodgkin’s disease, a form of lymphoid cancer, and vincristine is used clinically in combating children’s leukemia ( Lönnerholm et al, 2008 ). A series of new effective inhibitors from the group of 2,4-diamino-N,N-disubstituted quinazolines has been described as being effective anti-cancer compounds ( Figure 2 : 14) ( Li et al, 2019 ).…”

Microwave-Assisted Synthesis of Potential Bioactive Benzo-, Pyrido- or Pyrazino-thieno[3,2-d]pyrimidin-4-amine Analogs of MPC-6827

“…Based on these data, this benzo[ e ]pyrimidine emerged as a good candidate for phase I and phase II clinical trials in patients with metastatic melanoma and glioblastoma multiforme [ 12 , 13 , 14 ]. Despite these investigations revealing some cardiotoxicity and leading to the suspension of clinical development in phase II [ 15 ], MPC-6827 remains an excellent model for the design of potential cytotoxic agents [ 16 ].…”