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Heterocycl. Commun. 2018; 24(1): 1–10 Review Hao Jin, Hu-Guang Dan and Guo-Wu Rao* Research progress in quinazoline derivatives as multi-target tyrosine kinase inhibitors https://doi.org/10.1515/hc-2017-0066 applied synthetic methods. Microwave-assisted synthetic Received April 11, 2017; accepted December 30, 2017; previously methods, acid-catalyzed synthetic methods and metal- published online January 20, 2018 catalyzed synthetic methods are also applied in their syn- thesis. Quinazoline derivatives are important antitumor Abstract: Receptor tyrosine kinases (RTKs), such as epi- drugs as small-molecule inhibitors especially in the area dermal growth factor receptor (EGFR), are involved in mul- of receptor tyrosine kinase (RTK) inhibitors. The down- tiple human tumors. Therefore, RTKs are attractive targets stream signaling pathways of RTKs are closely related to for various antitumor strategies. Two classes of tyrosine the occurrence of the tumor, which can induce several kinase antagonists were applied in the clinic for monoclo- oncogenic effects including enhancing cell proliferation, nal antibodies and small-molecule tyrosine kinase inhibi- aberrant differentiation, malignant transformation and tors. A well-studied class of small-molecule inhibitors is migration in solid tumor cells. Inhibiting the activity of represented by 4-anilinoquinazolines, exemplified by the receptors could block the downstream signaling path- gefitinib and erlotinib as mono-targeted EGFR inhibitors, ways of growth factors and effectively inhibit the growth which were approved for the treatment of non-small-cell of tumors [7]. Cancer is a disease usually accompanied by lung cancer. Mono-target drugs may result in drug resist- a disorder of multiple signaling pathways. Mono-target ance and the innovation of multi-target drugs has grown drugs may result in drug resistance [8], and the innova- up to be an active field. Recent advances in research on tion of multi-target drugs has grown up to be an important antitumor bioactivity of 4-anilino(or phenoxy)quinazo- field. Developing multi-target RTK inhibitors acting on line derivatives with multiple targets are reviewed in this multiple signal pathways could regulate multiple signal- paper. At the same time, synthetic methods of quinazo- ing pathways at different levels resulting in better anti- lines were introduced from the point of building the ring neoplastic activity. skeleton and based on the types of reaction. The structure-activity relationship of quinazolines Keywords: antitumor; multiple targets; quinazoline; (Figure 1) can be summarized as follows: receptor tyrosine kinases; synthesis. 1. Modifications in the A and C rings affect the ability of the compounds to inhibit epidermal growth factor receptor (EGFR)-tyrosine kinases. Both of the nitrogen atoms of quinazoline are essential for inhibitory activ- Introduction ity. The phenyl ring with a small lipophilic substitu- ent such as a chloro, bromo or trifluoromethyl group Quinazolines (Figure 1) show extensive biological activi- is important as it occupies the lipophilic pocket. The ties [1–6]. Their synthetic methods are important topics character of the linking group between the quinazo- for pharmaceutical research. The 4(3H)-quinazolinone line ring and phenyl side chain makes a big difference core plays a significant role in the most commonly in the inhibitory activity. Replacing the nitrogen linker by an oxygen or sulfur atom may result in the reduc- *Corresponding author: Guo-Wu Rao, College of Pharmaceutical tion of EGFR inhibitory activity. On the other hand, Science, Zhejiang University of Technology, Hangzhou 310014, it may increase vascular endothelial growth factor P.R. China; and Institute of Drug Development and Chemical Biology, receptor (VEGFR) inhibitory activity. Derivatives of the Zhejiang University of Technology, Hangzhou 310014, P.R. China, urea or thiourea group linked to the phenyl side chain e-mail: [email protected] are more potent. Hao Jin and Hu-Guang Dan: College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, P.R. China; 2. Modifications in the B ring affect the inhibitory activ- and Institute of Drug Development and Chemical Biology, Zhejiang ity. The presence of a polar group at the 6- or 7-posi- University of Technology, Hangzhou 310014, P.R. China tion of the quinazoline ring is beneficial. The absence 2 H. Jin et al.: Quinazolines as multi-target tyrosine kinase inhibitors N atom may increase EGFR inhibitory activity, replacement of nitrogen linker by oxygen or sulfur may reduce the activity of EGFR and increase VEGFR or PDGFR inhibitory activity Neutral group at 5-position is favorable for ErbB2 inhibitory activity 3 Hydroxamic acid moiety at 6-position provides C R Small groups at 3′- and 4′-positions EGFR/ErbB2 multiple inhibitio n X are favorable 5 4 6 3 O N Alkyl substitution at N3-position R2 B A decreases the inhibitory activity N 7 2 H N Substituent at 6-position 8 No substituent at 2-position is favorable provides irreversible inhibition 1 6- or 7-position polar group N atom at 1-positon is essential for favors inhibitory activity inhibitory activity Figure 1 Structure-activity relationship of quinazolines. of a substituent at the 2- or 3-position of quinazoline a series of EGFR/ErbB2 irreversible inhibitors 1b–e with favors the inhibitory activity. Otherwise, the presence the IC50 at the nanomolar level for EGFR kinase and HER2 of a propylene amide or acetylene group at the 6-posi- kinase. Structure-activity and molecular modeling studies tion of quinazoline can result in EGFR/ErbB2 irre- suggested that positioning of the acrylamide moiety at the versible inhibition. Introducing the hydroxamic acid 6-position can effectively reduce the resistance to the first moiety at the 6-position of quinazoline can result in generation of EGFR inhibitors [12–15]. A neutral hydroxy- EGFR/ErbB2 multiple kinase inhibition. The presence acylamino moiety was introduced into the anilinoquina- of a large neutral substituent at the 5-position can zoline to furnish a RTK inhibitor 1f. Its IC50 values for the enhance ErbB2 inhibitory activity. EGFR and ErbB2 kinases are around 2 nm [16]. Compound AZD8931 (1g) is a reversible inhibitor of phosphoryla- tion of EGFR, HER2 and HER3 and demonstrates potent Quinazoline derivatives as multi- in vitro inhibition against isolated HER2 and EGFR tyros- ine kinases with the respective IC50 values of 14 nm and target EGFR family kinase inhibitors 12 nm against HER2 and EGFR [17]. Compound 1h with an oxazine ring shows significant cytotoxic activities with the EGFR is overexpressed in the majority of non-small-cell IC values of 3 nm and 250 nm against HER2 and EGFR, lung cancers and its expression is inversely related to 50 respectively. It shows better inhibitory activities against survival outcome. EGFR and ErbB2 are two important several cell lines compared to gefitinib and erlotinib, with validated target molecules in cancer treatment. Several extensive antiproliferative activities [18]. single-target EGFR 4-aminoquinazoline compounds are applied in the clinic. Drug resistance is inevitable among the first generation [9]. Research on 4-anilinoquinazoline mono-target drugs shows that introducing a bulky lipo- Quinazoline derivatives as philic group at the 4-position of quinazoline can improve multiple inhibitory activities of the EGFR family, hence multi-target EGFR and VEGFR family the occurrence of drug resistance can be reduced. Based kinase inhibitors on this finding, lapatinib (1a) in Table 1 was developed as a new kind of selective EGFR/ErbB2 dual inhibitor with VEGFR-2 plays a major role in tumor angiogenesis, which an inhibitory concentration (IC50) value of 10.2 nm and is regarded as the most important molecular target for 9.8 nm, respectively. The downstream cell proliferation inhibiting angiogenesis [19]. The drug targeting the EGFR signal is blocked by the reversible combination of EGFR/ and VEGFR-2 pathways can inhibit both tumor cells and ErbB2 and adenosine triphosphate (ATP) active sites [10]. tumor angiogenesis, hence a better therapeutic effect can Our research group [11] also designed and synthesized be achieved. Vandetanib (ZD6474, 1i) is a potent tyrosine several highly effective compounds, some of which are kinase inhibitor targeting the VEGFR tyrosine kinase active in the micromolar range of IC50 values against MCF-7 (IC50 = 40 nm) and the EGFR tyrosine kinase (IC50 = 500 nm) and A-549 cells. Propylene amide or acetylene groups [20]. Compound 1j has two individual reactive centers and were introduced at the 6-position of quinazoline to afford was designed to target a cysteine residue located in the H. Jin et al.: Quinazolines as multi-target tyrosine kinase inhibitors 3 Table 1 Quinazoline derivatives as multi-target tyrosine kinase inhibitors. R2 R3 X 5 4 R4 6 N3 5 1 R 7 N 2 R 8 1 Compd. Target X R1 R2 R3 R4 R5 NH 1a EGFR/ErbB2 NH H – O – O S O F O Cl F H 1b EGFR/ErbB2 NH H – N O N O Cl O F H CH3O 1c EGFR/ErbB2 NH H – N N Cl O F O 1d EGFR/ErbB2 NH H – N N Cl HN H3C CH3 H 1e EGFR/ErbB2 NH H – N – Br O 1f EGFR/ErbB2 NH H – – O O N O N Cl OH O CH O 1g EGFR/ErbB2/ NH H – O 3 ErbB3 N Cl N F H O 1h EGFR/ErbB2 NH H – N N 6 7 O Br CH O 1i EGFR/VEGFR NH H – 3 O N F H CH3O 1j EGFR/VEGFR NH H – N O O N F O O O CH O CH O 1k EGFR/VEGFR NH Cl – 3 3 NH2 F HO 1l EGFR/VEGFR NH H O – – N O N N Cl H H 4 H. Jin et al.: Quinazolines as multi-target tyrosine kinase inhibitors Table 1 (continued) Compd. Target X R1 R2 R3 R4 R5 O 1m EGFR/VEGFR NH H – 6 O 7 F Cl CH O HO 1n EGFR/VEGFR NH H – 3 O Br HO H CH3O 1o VEGFR/ O H N – N O PDGFR F H H CH3O CH3O 1p VEGFR/ O H N N – PDGFR O O S CH O 1q VEGFR/ O H – 3 N O PDGFR N N H CH3O CH3O 1r VEGFR/ O H N – N PDGFR O N H H CH3O 1s VEGFR/ O H N N Br – N O PDGFR O CH3 ATP binding pocket of both EGFR and VEGFR-2.

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