Design, Synthesis, and Biological Evaluation of 4-Methyl Quinazoline Derivatives as Anticancer Agents Simultaneously Targeting Phosphoinositide 3-Kinases and Histone Deacetylases

Abstract

Polypharmacology is a promising paradigm in modern drug discovery. Herein, we have discovered a series of novel PI3K and HDAC dual inhibitors in which the hydroxamic acid moiety as the zinc binding functional group was introduced to a quinazoline-based PI3K pharmacophore through an appropriate linker. Systematic structure–activity relationship studies resulted in lead compounds 23 and 36 that simultaneously inhibited PI3K and HDAC with nanomolar potencies and demonstrated favorable antiproliferative activities. Compounds 23 and 36 efficiently modulated the expression of p-AKT and Ac-H3, arrested the cell cycle, and induced apoptosis in HCT116 cancer cells. Following pharmacokinetic studies, 23 was further evaluated in HCT116 and HGC-27 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 45.8% (po, 150 mg/kg) and 62.6% (ip, 30 mg/kg), respectively. Overall, this work shows promise in discovering new anticancer therapeutics by the approach of simultaneously targeting PI3K and HDAC pathways with a single molecule.

Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach

“…It is designed by introducing hydroxamic acid moiety as the zinc binding functional group to a morpholinothienopyrimidine-based PI3K pharmacophore through an appropriate linker [135]. Recently, another dual HDAC-PI3K hybrid drug is reported, which is designed by introducing hydroxamic acid moiety as the zinc binding functional group to a quinazoline-based PI3K pharmacophore through an applicable linker [143]. Different therapeutic approaches involving HDAC-specific epi-drugs and PI3KIs directed against neoplastic diseases are narrated in the following section.…”

“…Taken together, this study further supports the dual HDAC-PI3K hybrid drugs that have potential anticancer activity. Using the polypharmacology-based paradigm, two other dual HDAC-PI3K inhibitors were recently reported [143]. These inhibitors were designed by introducing hydroxamic acid moiety as the zinc binding functional group to a quinazoline-based PI3K pharmacophore through an appropriate linker.…”

“…This concept has resulted in the design and development of multitarget epigenetic hybrid drugs. Among the several epigenetic hybrid drugs produced, CUDC-907 is a promising single dual HDAC-PI3K inhibitor molecule with an ability to simultaneously inhibit HDACs and PI3K [15,16,[134][135][136][137][138][139][140][141][142][143][144]. CUDC-907 is an orally bioavailable small -molecule dual HDAC and PI3K inhibitor targeting class I and II HDACs and PI3Kα, β, and δ isoforms [135].…”

“…CUDC-907 is an orally bioavailable small -molecule dual HDAC and PI3K inhibitor targeting class I and II HDACs and PI3Kα, β, and δ isoforms [135]. Its extensive antitumor activities in hematologic and solid tumors show promise as an HDAC-PI3K inhibitor [134][135][136][137][138][139][140][141][142][143][144]. Considering the pleiotropic effects of HDAC inhibition and the multiple downstream effectors of PI3K, it is not surprising CUDC-907 has a better opportunity to reverse the altered molecular pathways linked to oncogenesis.…”

The SYNTHESIS, SCREENING OF NOVEL 1-SUBSTITUTED-3-(4-OXO-2-PHENYLQUINAZOLIN-3(4H)-YL) UREA AND THIOUREA ANALOGUES AS POTENT ANTIBACTERIALS

“…In the present research work we have mainly focused on antibacterial activity; because nowadays, worldwide bacterial resistance to available drugs is a growing problem. Antimicrobial agents can benefit in cancer treatment by killing oncogenic-related microorganisms by protecting from recurring immune-suppressioninduced infection and by their direct antiproliferative/cytotoxic effects [4]. Quinazoline possess antibacterial activity against the gram positive strains and fungi through their interaction with cell wall and DNA structure.…”