The association between anti-tumor potency and structure-activity of protein-kinases inhibitors based on quinazoline molecular skeleton

Quinazoline was originally utilized as an anti-tumor treatment, and its various derivatives can be directly extracted from plants. In recent years, protein kinases (PK) have been well recognized in the development of tumor drugs. Functionally, PK serves a vital role in the apoptosis, proliferation, differentiation, migration and cell cycle of tumor cells. Due to its good physicochemical properties, quinazoline skeleton, a superior type of PK inhibitor, has been extensively used in anti-tumor drug design. An increasing number of studies on quinazoline synthesis have been reported and used by different groups to effectively develop novel derivatives. Thus, several studies have been approved for the use of quinazoline derivatives as inhibitors of other kinases, including Src and histone deacetylase. The aim of the present review was to summarize the mechanism of quinazoline compounds as PK inhibitors, their biological structure-activity relationship such as the substituted quinazoline compounds with different functional groups in the apoptotic process, and their effect on the proliferation of tumor cells. The development of novel agents based on the antitumor functions of quinazoline molecular compounds may improve the clinical outcomes of the affected population, particularly in patients with cancer.     

Biological evaluation of novel 6-Arylbenzimidazo[1,2-c]quinazoline derivatives as inhibitors of LPS-induced TNF-alpha secretion

This study describes the effect of novel 6-Arylbenzimidazo [1,2-c] quinazoline derivatives as tumor necrosis factor alpha (TNF-á) production inhibitors. The newly synthesized compounds were tested for their in vitro ability to inhibit the lipolysaccharide (LPS) induced TNF-á secretion in the human promyelocytic cell line HL-60. The compound 6-Phenyl-benzimidazo [1,2-c] quinazoline, coded as Gl, resulted as the most potent inhibitor and with no significant cytotoxic activity. Thus, 6-Arylbenzimidazo [1,2-c] quinazoline derivatives may have a potential as anti-inflammatory agents.     

~(18)F标记表皮生长因子受体酪氨酸激酶抑制剂4-苯氨基-喹唑啉类方法进展

分子成像可在活体状态下直观判断分子靶向药物靶位点存在状态,分子靶向药物与靶位点结合率及精确监测分子靶向药物的治疗疗效,为临床治疗方案的选择和调整提供依据。EGFR是多种恶性肿瘤的关键靶点。研究表明放射性核素标记的表皮生长因子酪氨酸激酶抑制剂是很有潜力的成像探针,其中尤以4-苯氨基-喹唑啉类研究最为广泛。本文简要介绍4-苯氨基-喹唑啉不同衍生物的结构及性质。阐述了18F标记4-苯氨基-喹唑啉类的主要方法:先用18F标记苯氨基,然后将18F标记化合物与喹唑啉或衍生物进行连接,和18F标记喹唑啉或其衍生物,然后与苯胺或其衍生物进行连接。并且进一步比较不同示踪剂在体外、动物和人体内生物分布、肿瘤摄取和代谢的异同。特别是对18F标记示踪剂与11C标记示踪剂在动物和人体分布进行比较。尤其是[18F]ML04肝脏摄取低,肿瘤-本底高,多数学者认为[18F]ML04是最有潜力成为18F标记表皮生长因子受体酪氨酸激酶抑制剂4-苯氨基-喹唑啉类示踪剂。     

Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: Exploration of P2 quinazoline substituents

Novel NS3/4A protease inhibitors comprising quinazoline derivatives as P2 substituent were synthesized. High potency inhibitors displaying advantageous PK properties have been obtained through the optimization of quinazoline P2 substituents in three series exhibiting macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution in the P2 cyclopentane dicarboxylic acid series improved on the metabolic stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. Pharmacokinetic properties in vivo were assessed in rat on selected compounds, where excellent exposure and liver-to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series.     

^18F标记表皮生长因子受体酪氨酸激酶抑制剂4-苯氨基-喹唑啉类方法进展

分子成像可在活体状态下直观判断分子靶向药物靶位点存在状态,分子靶向药物与靶位点结合率及精确监测分子靶向药物的治疗疗效,为临床治疗方案的选择和调整提供依据。EGFR是多种恶性肿瘤的关键靶点。研究表明放射性核素标记的表皮生长因子酪氨酸激酶抑制剂是很有潜力的成像探针,其中尤以4-苯氨基．喹唑啉类研究最为广泛。本文简要介绍4-苯氨基-喹唑啉不同衍生物的结构及性质。阐述了^18F标记4-苯氨基．喹唑啉类的主要方法：先用^18F标记苯氨基,然后将^18F标记化合物与喹唑啉或衍生物进行连接,和^18F标记喹唑啉或其衍生物,然后与苯胺或其衍生物进行连接。并且进一步比较不同示踪剂在体外、动物和人体内生物分布、肿瘤摄取和代谢的异同。特别是对^18F标记示踪剂与11c标记示踪剂在动物和人体分布进行比较。尤其是[^18F]ML04肝脏摄取低,肿瘤．本底高,多数学者认为[^18F]ML04是最有潜力成为^18F标记表皮生长因子受体酪氨酸激酶抑制剂4-苯氨基-喹唑啉类示踪剂。     

Kinase inhibitions in pyrido[4,3-h] and [3,4-g]quinazolines: Synthesis,SAR and molecular modeling studies

New pyrido[3,4-g]quinazoline derivatives were prepared and evaluated for their inhibitory potency toward 5 protein kinases (CLK1, DYRK1A, GSK3, CDK5, CK1). A related pyrido[4,3-h]quinazoline scaffold with an angular structure was also synthesized and its potency against the same protein kinase panel was compared to the analogous pyrido[3,4-g]quinazoline. Best results were obtained for 10-nitropyrido[3,4-g]quinazoline 4 toward CLK1 with nanomolar activities.     

Development of erlotinib derivatives as CIP2A-ablating agents independent of EGFR activity

Cancerous inhibitor of PP2A (CIP2A) is a novel human oncoprotein that inhibits PP2A, contributing to tumor aggressiveness in various cancers. Several studies have shown that downregulation of CIP2A by small molecules reduces PP2A-dependent phosphorylation of Akt and induces cell death. Here, a series of mono- and di-substituted quinazoline and pyrimidine derivatives based on the skeleton of erlotinib (an EGFR inhibitor) were synthesized and their bioactivities against hepatocellular carcinoma were evaluated. The di-substituted quinazoline and pyrimidine derivatives were more potent inhibitors of cancer-cell proliferation than the mono-substituted derivatives. In particular, compound 1 with chloride at position 2 of quinazoline was as potent as erlotinib in inducing cell death but no inhibition for EGFR activity. Further assays confirmed a correlation between cell death, and CIP2A and Akt inhibition by these derivatives. Among all the derivatives, compounds 19 and 22 showed the most potent antiproliferative activities and the strongest inhibition of CIP2A and p-Akt expression.     

Quinazolines and quinazolinones as ubiquitous structural fragments in medicinal chemistry: An update on the development of synthetic methods and pharmacological diversification

Nitrogen-rich heterocycles, particularly quinazolines and quinazolinones, represent a unique class of diversified frameworks displaying a broad spectrum of biological functions. Over the past several years, intensive medicinal chemistry efforts have generated numerous structurally functionalized quinazoline and quinazolinone derivatives. Interest in expanding the biological effects, demonstrated by these motifs, is growing exponentially, as indicated by the large number of publications reporting the easy accessibility of these skeletons in addition to the diverse nature of synthetic as well as biological applications. Therefore, the main focus of the present review is to provide an ample but condensed overview on various synthetic approaches providing access to quinazoline and quinazolinone compounds with multifaceted biological activities. Furthermore, mechanistic insights, synthetic utilization, structure–activity relationships and molecular modeling inputs for the potent derivatives have also been discussed.     

Discovery of 6-substituted 4-anilinoquinazolines with dioxygenated rings as novel EGFR tyrosine kinase inhibitors

It had been reported that some dioxygenated rings fusing with the quinazoline scaffold could lead to new EGFR inhibitors. Based on this, several kinds of oxygenated alkane quinazoline derivatives were synthetized and evaluated as EGFR inhibitors. Their antiproliferative activities were tested against four cancer cell lines: A431, MCF-7, A549, and B16-F10. Most derivatives could counteract EGF-induced EGFR phosphorylation, and their potency was comparable to the reference compound Erlotinib. The size of the fused dioxygenated ring was crucial for the biological activity and the heptatomic ring derivative 19 showed potent in vitro inhibitory activity in the enzymatic assay as well as in the cellular assay.     

Synthesis and characterization of novel quinazoline type inhibitors for mutant and wild-type EGFR and RICK kinases

The development of selective protein kinase inhibitors has become an important area of drug discovery for the treatment of different diseases. We report the synthesis and characterization of a series of novel quinazoline derivatives against three therapeutically important and pharmacologically related kinases: 1) epidermal growth factor receptor (EGFR; wild type and mutant) in the field of cancer, 2) receptor-interacting caspase-like apoptosis-regulatory kinase (RICK) in the field of inflammation, and 3) pUL97 of human cytomegalovirus (HCMV). For reference purpose we have synthesized the four clinically relevant quinazolines, including the lead compounds, which we previously identified for RICK and pUL97. A total of 52 quinazoline derivatives were synthesized and tested on the basis of these leads to specifically target the hydrophobic pocket of the ATP-binding site. Selected compounds were tested on wild-type and mutant forms of EGFR, RICK, and pUL97 kinases; their logP and logS values for assessing suitability as drugs were calculated and hit or lead compounds identified.     

Synthesis and Characterization of Novel Quinazoline Type Inhibitors for Mutant and Wild-Type EGFR and RICK Kinases

The development of selective protein kinase inhibitors has become an important area of drug discovery for the treatment of different diseases. We report the synthesis and characterization of a series of novel quinazoline derivatives against three therapeutically important and pharmacologically related kinases: 1) epidermal growth factor receptor (EGFR; wild type and mutant) in the field of cancer, 2) receptor-interacting caspase-like apoptosis-regulatory kinase (RICK) in the field of inflammation, and 3) pUL97 of human cytomegalovirus (HCMV). For reference purpose we have synthesized the four clinically relevant quinazolines, including the lead compounds, which we previously identified for RICK and pUL97. A total of 52 quinazoline derivatives were synthesized and tested on the basis of these leads to specifically target the hydrophobic pocket of the ATP-binding site. Selected compounds were tested on wild-type and mutant forms of EGFR, RICK, and pUL97 kinases; their logP and logS values for assessing suitability as drugs were calculated and hit or lead compounds identified.     

Prediction of inhibitory activity of epidermal growth factor receptor inhibitors using grid search-projection pursuit regression method

The epidermal growth factor receptor (EGFR) protein tyrosine kinase (PTK) is an important protein target for anti-tumor drug discovery. To identify potential EGFR inhibitors, we conducted a quantitative structure-activity relationship (QSAR) study on the inhibitory activity of a series of quinazoline derivatives against EGFR tyrosine kinase. Two 2D-QSAR models were developed based on the best multi-linear regression (BMLR) and grid-search assisted projection pursuit regression (GS-PPR) methods. The results demonstrate that the inhibitory activity of quinazoline derivatives is strongly correlated with their polarizability, activation energy, mass distribution, connectivity, and branching information. Although the present investigation focused on EGFR, the approach provides a general avenue in the structure-based drug development of different protein receptor inhibitors.     

Expeditious synthesis and cytotoxic activity of new cyanoindolo[3,2-c]quinolines and benzimidazo[1,2-c]quinazolines

Novel 6-cyanoindolo[3,2-c]quinoline and 6-cyanobenzimidazo[1,2-c]quinazoline derivatives have been synthesised by treatment of the appropriate aromatic amines with 4.5-dichloro-1,2,3-dithiazolium chloride 1 (Appel salt). The cytotoxicity and the effect of these compounds on cellular growth were measured.     

Radioiodination of new EGFR inhibitors as potential SPECT agents for molecular imaging of breast cancer

In our search for the development of novel SPECT radioligands for EGFR positive tumours, new potentially irreversible tyrosine kinase (TK) inhibitors are being explored. The radioiodination of N-{4-[(3-chloro-4-fluorophenyl) amino]quinazoline-6-yl}-3-bromopropionamide, a novel EGFR-TK inhibitor synthesised in our laboratory, was accomplished via halogen exchange. Purification by RP-HPLC gave [125I]-N-{4-[(3-chloro-4-fluorophenyl)amino]quinazoline-6-yl}-3-iodopropionamide with a radiochemical purity higher than 95% and a high specific activity. In vitro studies indicate that both iodinated quinazoline and its bromo precursor inhibit A431 cell growth and also possess higher potency than the parent quinazoline to inhibit the EGFR autophosphorylation. In vivo stability studies suggest metabolization of the radioiodinated quinazoline indicating a short biological half-life. The in vitro results point out that these quinazoline derivatives could be promising candidates for SPECT imaging of EGFR positive tumours provided that they are selectively modified in order to achieve better in vivo radiochemical stability.     

Benzoquinazoline derivatives as new agents affecting DNA processing

A new series of benzo[h]quinazoline and benzo[f]quinazoline derivatives was prepared and studied for the biological activity. The compounds carrying a dimethylaminoethyl side chain (6c, 8c and 12) inhibit cell growth. The ability to form a molecular complex with DNA and to interfere with topoII and topoI relaxation activity was evidenced for the most active 6c and 8c, along with the capacity to induce apoptosis on HeLa cells.     

Synthesis and anti-TMV activity of novel β-amino acid ester derivatives containing quinazoline and benzothiazole moieties

Here, a series of β-amino acid ester derivatives containing quinazoline and benzothiazoles was synthesized and evaluated for anti-tobacco mosaic virus (TMV) activity. The compounds 3n, 3o, 3p and 3q showed good antiviral activity against TMV at a concentration of 500 μg/mL, with curative rates of 55.55%, 52.32%, 52.77% and 50.91%, respectively, and protection rates of 52.33%, 55.96%, 54.21% and 50.98%, respectively. These values were close to those of the commercially available antiviral agent ningnanmycin (which has curative and protection rates of 55.27% and 52.16%, respectively). To our knowledge, this is the first report of the anti-TMV activity of β-amino acid ester derivatives containing quinazoline and benzothiazoles moieties; the results indicate that these novel compounds can potentially be used as protective agents against TMV diseases.     

Molecular docking studies on quinazoline antifolate derivatives as human thymidylate synthase inhibitors

We have performed molecular docking on quinazoline antifolates complexed with human thymidylate synthase to gain insight into the structural preferences of these inhibitors. The study was conducted on a selected set of one hundred six compounds with variation in structure and activity. The structural analyses indicate that the coordinate bond interactions, the hydrogen bond interactions, the van der Waals interactions as well as the hydrophobic interactions between ligand and receptor are responsible simultaneously for the preference of inhibition and potency. In this study, fast flexible docking simulations were performed on quinazoline antifolates derivatives as human thymidylate synthase inhibitors. The results indicated that the quinazoline ring of the inhibitors forms hydrophobic contacts with Leu192, Leu221 and Tyr258 and stacking interaction is conserved in complex with the inhibitor and cofactor.     

Click chemistry for improvement in selectivity of quinazoline-based kinase inhibitors for mutant epidermal growth factor receptors

Discovery of mutant-selective kinase inhibitors is one of the challenges in medicinal chemistry and is a main issue for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. We tried to improve the selectivity of pan-HER inhibitors for mutant EGFRs. Utilizing click chemistry, triazole-tethered quinazoline derivatives were synthesized, based on a quinazoline scaffold showing pan-HER inhibition. The representative compound 5j exhibited 17- and 52-fold improved selectivity for EGFR L858R/T790M over wild-type EGFR and HER2, respectively, and demonstrated 6.7-fold more potent antiproliferative activity against PC9 cells harboring EGFR-activating mutation than gefitinib. Although the described quinazolines did not surpass pyrimidines as 3rd generation EGFR inhibitors in terms of selectivity for mutant EGFRs, our approach might provide information that would help in the identification of mutant-selective compounds among pan-HER inhibitors using the quinazoline scaffold.     

De novo design of quinazoline derivatives as CDK2 inhibitors: 3D-QSAR,molecular fragment replacement and Volsurf predictions

Cyclin-dependent kinase 2 (CDK2) has appeared as an important drug target over the years with a multitude of therapeutic potentials. To design compounds with enhanced inhibitory potencies against CDK2, 3D-QSAR and molecular fragment replacement studies were performed on the pyrazolo[4,3-h]quinazoline derivatives, a class of potent CDK2 inhibitors. The contours of 3D-QSAR model revealed important structural features of the inhibitors related to the active site of CDK2. Based on the pyrazolo[4,3-h]quinazoline core, the different substituents at three important points were replaced with diverse molecular fragments. The compounds resulting from fragments assembly with pyrazolo[4,3-h]quinazoline core were then scored with the robust 3D-QSAR model. Furthermore, the absorption, distribution, metabolism and excretion properties of these compounds were predicted by Volsurf to eliminate inappropriate compounds. Thirty-one new potential compounds were finally obtained. These results initiated us to further optimise and design new potential inhibitors.