Design and Synthesis of New Quinoxaline Derivatives as Anticancer Agents and Apoptotic Inducers

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Abstract

The quinoxaline scaffold is a promising platform for the discovery of active chemotherapeutic agents. Three series of quinoxaline derivatives were synthesized and biologically evaluated against three tumor cell lines (HCT116 human colon carcinoma, HepG2, liver hepatocellular carcinoma and MCF-7, human breast adenocarcinoma cell line), in addition to VEGFR-2 enzyme inhibition activity. Compounds VIId, VIIIa, VIIIc, VIIIe and XVa exhibited promising activity against the tested cell lines and weak activity against VEGFR-2. Compound VIIIc induced a significant disruption in the cell cycle profile and cell cycle arrest at the G2/M phase boundary. In further assays, the cytotoxic effect of the highly active compounds was determined using a normal Caucasian fibroblast-like fetal lung cell line (WI-38). Compound VIIIc could be considered as a lead compound that merits further optimization and development as an anti-cancer and an apoptotic inducing candidate against the HCT116 cell line.

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Synthesis and in vitro antitumor activity of substituted quinazoline and quinoxaline derivatives: search for anticancer agent.

Malleshappa N. Noolvi, Harun Patel, Varun Bhardwaj … (2011)

The synthesis of some 2-furano-4(3H)-quinazolinones, diamides (open ring quinazolines), quinoxalines and their biological evaluation as antitumor agents using National Cancer Institute (NCI) disease oriented antitumor screen protocol are investigated. Among the synthesize compounds, seventeen compounds were granted NSC code and screened at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10(-5) M) in full NCI 60 cell panel. Among the selected compounds, 3-(2-chloro benzylideneamine)-2-(furan-2-yl) quinazoline-4(3h)-one 21 was found to be the most active candidate of the series at five dose level screening against Ovarian OVCAR-4 and Non-small cell lung cancer NCI-H522 with GI50 1.82 & 2.14 μM respectively. Rational approach and QSAR techniques enabled the understanding of the pharmacophoric requirement for quinazoline, diamides and quinoxaline derivatives.

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Cancer is the second leading cause of death in the western world. Despite advances in diagnosis and treatment, overall survival of patients remains poor. Scientific advances in recent years have enhanced our understanding of the biology of cancer. Human protein tyrosine kinases (PTKs) play a central role in human carcinogenesis and have emerged as the promising new targets. Several approaches to inhibit tyrosine kinase have been developed. These agents have shown impressive anticancer effects in preclinical studies and are emerging as promising agents in the clinic. The remarkable success of BCR-ABL tyrosine kinase inhibitor imatinib (STI571) in the treatment of chronic myeloid leukaemia has particularly stimulated intense research in this field. At least 30 inhibitors are in various stages of clinical development in cancer, and about 120 clinical trials are ongoing worldwide. In this review, we focus on the role of tyrosine kinases in cancer and the development of specific small molecule inhibitors for therapy. We also provide a critical analysis of the current data on tyrosine kinase inhibitors and highlight areas for future research. Issues with regards to the design of clinical trials with such agents are also discussed. Innovative approaches are needed to fully evaluate the potential of these agents, and a concerted international effort will hopefully help to integrate these inhibitors in cancer therapy in the near future.

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Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor.

Yujia Dai, Kresna Hartandi, Zhiqin Ji … (2007)

In our continued efforts to search for potent and novel receptor tyrosine kinase (RTK) inhibitors as potential anticancer agents, we discovered, through a structure-based design, that 3-aminoindazole could serve as an efficient hinge-binding template for kinase inhibitors. By incorporating an N,N'-diaryl urea moiety at the C4-position of 3-aminodazole, a series of RTK inhibitors were generated, which potently inhibited the tyrosine kinase activity of the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor families. A number of compounds with potent oral activity were identified by utilizing an estradiol-induced mouse uterine edema model and an HT1080 human fibrosarcoma xenograft tumor model. In particular, compound 17p (ABT-869) was found to possess favorable pharmacokinetic profiles across different species and display significant tumor growth inhibition in multiple preclinical animal models.

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Journal

Journal ID (nlm-ta): Molecules

Journal ID (iso-abbrev): Molecules

Journal ID (publisher-id): molecules

Title: Molecules

Publisher: MDPI

ISSN (Electronic): 1420-3049

Publication date (Electronic): 25 March 2019

Publication date Collection: March 2019

Volume: 24

Issue: 6

Electronic Location Identifier: 1175

Affiliations

[1 ]Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, October University for Modern Science and Arts (MSA), Cairo 12611, Egypt; anewahie@ 123456msa.eun.eg

[2 ]Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; yassin.nissan@ 123456hotmail.com

[3 ]Pharmaceutical Chemistry Department, Faculty of Pharmacy, October University for Modern Science and Arts (MSA), Cairo 12611, Egypt

[4 ]Pharmaceutical Chemistry Department, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo 12311, Egypt; saadnasser2003@ 123456yahoo.com

[5 ]Pharmaceutical Chemistry Department, Faculty of Pharmacy Ain Shams University, Abbassia, Cairo 11566, Egypt; dalal999@ 123456hotmail.com

[6 ]Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Nahda University, Beni Suef 62513, Egypt

[7 ]Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia; smkhojah@ 123456yahoo.com

[8 ]Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt

Author notes

[* ]Correspondence: Khaled.abouzid@ 123456pharma.asu.edu.eg ; Tel.: +20-122-2165-624; Fax: +20-225-0807-28

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Khaled A.M. Abouzid https://orcid.org/0000-0001-9851-5624

Article

Publisher ID: molecules-24-01175

DOI: 10.3390/molecules24061175

PMC ID: 6470675

PubMed ID: 30934622

SO-VID: db96684d-37a8-4f6b-b8d5-5660f02cdda7

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Design and Synthesis of New Quinoxaline Derivatives as Anticancer Agents and Apoptotic Inducers

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Most cited references 31

Synthesis and in vitro antitumor activity of substituted quinazoline and quinoxaline derivatives: search for anticancer agent.

Tyrosine kinase inhibitors in cancer therapy.

Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor.

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