4-anilinoquinazoline Derivatives Research Articles

Application of a Deep Eutectic Solvent for the Synthesis of Novel Imidazole-Containing Quinazoline Derivatives as Potent Cytotoxic Agents

Background: Drugs containing the 4-anilinoquinazolines scaffold play a critical role in cancer treatment by inhibiting protein kinases, especially tyrosine kinases. In this study, a novel series of 4-anilinoquinazoline derivatives were synthesized and evaluated as cytotoxic agents. Methods: All final compounds were synthesized using two methods, including a conventional approach using potassium iodide and dimethylformamide as well as a green method using a deep eutectic solvent (DES) comprising choline chloride: urea. The cytotoxicity was tested on the A431, HUVEC, and HU02 cell lines. To evaluate the binding pattern of the compounds with EGFR and VEGFR-2, a molecular docking investigation was performed. Finally, the wound healing assay was carried out to assess the potency of compounds in inhibiting cell migration. Results: The final reaction time was approximately 15-20 min with yields of 60-72% using DES, while the conventional method took 3 to 4 h to complete, with yields between 30% and 42%. Compounds 8k and 8l showed better cytotoxicity against both cell lines compared to vandetanib (IC50=0.11 µM and 0.26 µM on A431 and IC50=5.01 µM and 5.24 µM on HUVEC, respectively). Molecular docking studies revealed that compound 8k, which contained 3-methylaniline at the 4-position of the quinazoline core, showed efficient binding affinity to both EGFR and VEGFR-2. An essential hydrogen bond was formed between quinazoline N1 of 8k and the Met796 residue of EGFR with a docking score of -8.76 kcal/mol. The imidazole N3 of 8k interacted with the Cyc919 residue of VEGFR-2, forming a hydrogen bond with a docking score of -9.03 kcal/mol. Moreover, compound 8k exhibited the best inhibitory activity on cell migration and wound healing. Conclusion: DES significantly improved the time and yield of the final reactions. Compound 8k, which showed the best cytotoxicity and inhibitory activity on cell migration, could be a suitable candidate for further structural optimization.

Comparative Effectiveness and Safety of Biologic Treatments in Giant Cell Arteritis: A Network Meta-analysis of Randomized Controlled Trials

Background: Drugs containing the 4-anilinoquinazolines scaffold play a critical role in cancer treatment by inhibiting protein kinases, especially tyrosine kinases. In this study, a novel series of 4-anilinoquinazoline derivatives were synthesized and evaluated as cytotoxic agents. Methods: All final compounds were synthesized using two methods, including a conventional approach using potassium iodide and dimethylformamide as well as a green method using a deep eutectic solvent (DES) comprising choline chloride:urea. The cytotoxicity was tested on the A431, HUVEC, and HU02 cell lines. To evaluate the binding pattern of the compounds with EGFR and VEGFR-2, a molecular docking investigation was performed. Finally, the wound healing assay was carried out to assess the potency of compounds in inhibiting cell migration. Results: The final reaction time was approximately 15-20 min with yields of 60-72% using DES, while the conventional method took 3 to 4 h to complete, with yields between 30% and 42%. Compounds 8k and 8l showed better cytotoxicity against both cell lines compared to vandetanib (IC50=0.11 µM and 0.26 µM on A431 and IC50=5.01 µM and 5.24 µM on HUVEC, respectively). Molecular docking studies revealed that compound 8k, which contained 3-methylaniline at the 4-position of the quinazoline core, showed efficient binding affinity to both EGFR and VEGFR-2. An essential hydrogen bond was formed between quinazoline N1 of 8k and the Met796 residue of EGFR with a docking score of -8.76 kcal/mol. The imidazole N3 of 8k interacted with the Cyc919 residue of VEGFR-2, forming a hydrogen bond with a docking score of -9.03 kcal/mol. Moreover, compound 8k exhibited the best inhibitory activity on cell migration and wound healing. Conclusion: Tocilizumab may be the most efficient remission-inducing and relapse-lowering biological agent for patients with GCA, and TNF inhibitors pose the highest risk of infection among the biologics studied.

Synthesis, Antitumor Activities, and Molecular Modeling of 4-Anilinoquinazoline Derivatives as EGFR-TK Inhibitors

Synthesis, Antitumor Activities, and Molecular Modeling of 4-Anilinoquinazoline Derivatives as EGFR-TK Inhibitors

Design and synthesis of gefitinib derivatives as potential drugs for cancer treatment: antiproliferative activity, molecular docking, and ADMET prediction

Background: Non-small cell lung cancer is one of the most common cancers worldwide, and targeted chemotherapy has become a kind of the main treatment. Gefitinib, the most widely studied targeted agent in non-small cell lung cancer, is an orally active tyrosine kinase inhibitor. However, gefitinib inevitably generates acquired drug resistance, leading to treatment failure. Objective: A new class of compounds containing 4-anilinoquinazoline lead structure was designed and synthesized by modifying the structure of gefitinib. These compounds are expected to exert better anticancer activity and better binding to the EGFR-TK domain, enrich the structure of 4-anilinoquinazoline derivatives and inspire further structural modifications. Method: The antiproliferative activity of nine derivatives was determined in three cancer cell lines (A549, PC9, and HepG2) using the MTT method. The ADMET profile of all compounds was predicted, and the binding affinity of the compounds (5 and 6) to EGFR was predicted by Schrödinger. In addition, the effect of these compounds (3-6) in inducing apoptosis in HepG2 cells was also studied. Results: Four (3, 5, 6 and 9) of the newly synthesized derivatives exhibited superior antiproliferative activity against A549 to gefitinib (IC50 = 12.64 ± 3.59 μM), with compound 5 having the best activity (IC50 = 7.39 ± 1.24 μM). Moreover, the ability of compounds (3-6) to induce HepG2 cell apoptosis was significantly better than that of gefitinib. Conclusion: Nine structures (compounds 2-10) were synthesized and characterized, and compound 5 had the best antiproliferative activity. Compound 3 possessed the best ability to induce HepG2 apoptosis. Also, ADMET calculations were performed in silico, and the results revealed that compound 3 has more suitable characteristics as a potential drug candidate.

Design, Synthesis and Cytotoxic sSudies of Novel 4-anilinoquinazoline Derivatives of Potential Agents for Non-small-cell Lung Cancer

Background: The pre-existing EGFR (Epidermal Growth Factor Receptors) inhibitors (Gefitinib, Afatinib and osimertinib) show significant resistance after one year of EGFR therapy in NSCLC (Non-small cell lung cancer) patients. With the aim of overcoming the resistance problem associated with a current therapeutic regimen, there is an imperative need for the development of novel 4-anilinoquinazoline derivatives that are specifically designed for resistance cases of NSCLC patients. Objective: We designed and synthesized eighteen 4-anilinoquinazolines derivatives as a novel scaffold and evaluated their anti-cancer potential against different NSCLC cell lines. Methods: Molecular docking study of designed compounds were performed on Glide v5.8 (Schrodinger, LLC, New York, NY). Synthesis of 4-anilinoquinazoline derivatives was performed, based on the docking score and was characterized by various spectroscopic methods. Further, in-vitro anti-cancer activity was performed using MTT assay on different cancer cell lines. Results: Molecular docking analysis [EGFRT790M mutant (4I22)] indicated that most of these analogs (6g, 6j, 6l, 6m and 6o) were found to be higher docking scores than gefitinib. Furthermore, spectral analysis revealed that the designed compounds were synthesized successfully. The compounds 6a, 6d, 6g, 6i, 6j and 6m were identified as the potent inhibitors against (A431, H1975, A549) cell lines as compared to reference standard gefitinib. Excitingly, compound 6j (with IC50 values of 4.88±0.13, 4.38±0.08 & 11.97±0.14 µM) was identified as the most potent inhibitor for (A431, H1975, A549) cell lines. Conclusion: The study suggested that the six derivatives showed significant therapeutic potential against different NSCLC cell lines as compared to reference standard gefitinib.

Antitumor activity and mechanisms of dual EGFR/DNA-targeting strategy for the treatment of lung cancer with EGFRL858R/T790M mutation

Dual- or multi-targeted EGFR inhibitors as single drugs can overcome EGFR inhibitor resistance and circumvent many disadvantages of combination therapy. In this work, fifteen 4-anilinoquinazoline derivatives bearing nitrogen mustard or hemi mustard moieties were designed and synthesized as dual EGFR-DNA targeting anticancer agents. Structures of target molecules were confirmed by 1H NMR, 13C NMR and HR-MS, and evaluated for their in vitro anti-proliferative activities using MTT assay. Compound 6g emerged as the most potent derivative against mutant-type H1975 cells with IC50 value of 1.45 μM, which exhibited 4-fold stronger potency than Chl/Gef (equimolar combination of chlorambucil and gefitinib). Kinase inhibition studies indicated that 6g showed excellent inhibitory effect on EGFRL858R/T790M enzyme, which was 8.6 times more effective than gefitinib. Mechanistic studies indicated that 6g induced apoptosis of H1975 cells in a dose-dependent manner and caused DNA damage. Importantly, 6g could significantly inhibit the expression of p-EGFR and its downstream p-AKT and p-ERK in H1975 cells. Molecular docking was also performed to gain insights into the ligand-binding interactions of 6g inside EGFRWT and EGFRL858R/T790M binding sites. Moreover, 6g efficiently inhibited tumor growth in the H1975 xenograft model without side effects.

Ruthenium(II) polypyridyl complexes with visible light-enhanced anticancer activity and multimodal cell imaging.

Ruthenium(II) polypyridyl complexes have drawn growing attention due to their photophysical properties and anticancer activity. Herein we report four ruthenium(II) polypyridyl complexes [(N^N)2RuII(L)]2+ (1-4, L = 4-anilinoquinazoline derivatives, N^N = bidentate ligands with bis-nitrogen donors) as multi-functional anticancer agents. The epidermal growth factor receptor (EGFR) is overexpressed in a broad range of cancer cells and related to many kinds of malignance. EGFR inhibitors, such as gefitinib and erlotinib, have been approved as clinical anticancer drugs. The EGFR-inhibiting 4-anilinoquinazoline ligands greatly enhanced the in vitro anticancer activity of these ruthenium(II) polypyridyl complexes against a series of human cancer cell lines compared to [Ru(bpy)2(phen)], but interestingly, these complexes were actually not potent EGFR inhibitors. Further mechanism studies revealed that upon irradiation with visible light, complexes 3 and 4 generated a high level of singlet oxygen (1O2), and their in vitro anticancer activities against human non-small-cell lung (A549), cervical (HeLa) and squamous (A431) cancer cells were significantly improved. Specifically, complex 3 displayed potent phototoxicity upon irradiation with blue light, of which the photo-toxicity indexes (PIs) against HeLa and A431 cells were 11 and 8.3, respectively. These complexes exhibited strong fluorescence emission at ca. 600 nm upon excitation at about 450 nm. A subcellular distribution study by fluorescence microscopy imaging and secondary ion mass spectrometry imaging (ToF-SIMS) demonstrated that complex 3 mainly localized at the cytoplasm and complex 4 mainly localized in the nuclei of cells. Competitive binding with ctDNA showed that complex 4 was more favorable to bind to the DNA minor groove than complex 3. These differences support that complex 3 possibly exerts its anticancer activities majorly by photo-induced 1O2 generation and complex 4 by binding to DNA.

P-09 - Synthesis, characterization and biodistribution of a new ‘2+1’ 99mTc/Re tricarbonyl complex bearing bis(2-hydroxyethyl) carbamodithioate and 4-anilinoquinazoline derivative

P-09 - Synthesis, characterization and biodistribution of a new ‘2+1’ 99mTc/Re tricarbonyl complex bearing bis(2-hydroxyethyl) carbamodithioate and 4-anilinoquinazoline derivative

Discovery and optimization of 4-anilinoquinazoline derivatives spanning ATP binding site and allosteric site as effective EGFR-C797S inhibitors

Epidermal growth factor receptor (EGFR) is an effective drug target for the treatment of non-small cell lung cancer (NSCLC). However, a tertiary point mutation (C797S) at the ATP binding pocket of the EGFR induces resistance to the third-generation EGFR inhibitors, due to the loss of covalent interaction with Cys797. Here, we designed a series of 4-anilinoquinazoline derivatives that simultaneously occupied the ATP binding pocket and the allosteric site. The newly-synthesized compounds displayed high potency against EGFR-C797S resistance mutation. Among them, compound 14d presented high anti-proliferative effect against BaF3-EGFRL858R/T790M/C797S (IC50 = 0.75 μM) and BaF3-EGFR19del/T790M/C797S (IC50 = 0.09 μM) cells. Moreover, 14d resulted in obvious inhibition activities against EGFR and its downstream signaling pathways in a dose-dependent manner in BaF3-EGFR19del/T790M/C797S cells. Finally, 14d significantly inhibited tumor growth in BaF3-EGFR19del/T790M/C797S xenograft model (30 mg/kg, TGI = 67.95%). These results demonstrated that 14d is a novel and effective EGFR-C797S inhibitor which spanning the ATP binding pocket and the allosteric site and effective both in vitro and in vivo.

Computer-Aided Design and Synthesis of (Functionalized quinazoline)-(α-substituted coumarin)-arylsulfonate Conjugates against Chikungunya Virus.

Chikungunya virus (CHIKV) has repeatedly spread via the bite of an infected mosquito and affected more than 100 countries. The disease poses threats to public health and the economy in the infected locations. Many efforts have been devoted to identifying compounds that could inhibit CHIKV. Unfortunately, successful clinical candidates have not been found yet. Computations through the simulating recognition process were performed on complexation of the nsP3 protein of CHIKV with the structures of triply conjugated drug lead candidates. The outcomes provided the aid on rational design of functionalized quinazoline-(α-substituted coumarin)-arylsulfonate compounds to inhibit CHIKV in Vero cells. The molecular docking studies showed a void space around the β carbon atom of coumarin when a substituent was attached at the α position. The formed vacancy offered a good chance for a Michael addition to take place owing to steric and electronic effects. The best conjugate containing a quinazolinone moiety exhibited potency with EC50 = 6.46 μM, low toxicity with CC50 = 59.7 μM, and the selective index (SI) = 9.24. Furthermore, the corresponding 4-anilinoquinazoline derivative improved the anti-CHIKV potency to EC50 = 3.84 μM, CC50 = 72.3 μM, and SI = 18.8. The conjugate with 4-anilinoquinazoline exhibited stronger binding affinity towards the macro domain than that with quinazolinone via hydrophobic and hydrogen bond interactions.

P-293 - Synthesis of a new 6-substituted 4-anilinoquinazoline derivative as irreversible inhibitor for EGFR imaging

P-293 - Synthesis of a new 6-substituted 4-anilinoquinazoline derivative as irreversible inhibitor for EGFR imaging

Novel 4-Anilinoquinazoline Derivatives as Potent Anticancer Agents: Design, Synthesis, Cytotoxic Activity, and Docking Study

The simultaneous inhibition of EGFR and VEGFR-2 is a promising method in cancer treatment. In the present work, several 4-anilinoquinazoline derivatives encompassing different substitutions at the C-4 and C-7 positions of a quinazoline core were designed, synthesised, and evaluated for their cytotoxicity on A431, HUVEC, and HU02 cell lines. Docking studies were carried out to test the interactions of all synthesised compounds with EGFR and VEGFR-2. Furthermore, a wound healing assay was done for the investigation of cell migration. The most potent compound was 8l followed by the compounds 8i and 8j which showed better cytotoxic activities on A431 and HUVEC cell lines than the standard (Vandetanib). The compounds 8f and 8a represented the best docking energies of 8.99 and 9.35 kcal mol−1 for EGFR and VEGFR, respectively. Moreover, molecular docking studies exhibited that compound 8l showed efficient binding affinity against both EGFR and VEGFR-2. It can bind to these receptors through the formation of essential hydrogen bonds between the quinazoline N1 atom and the Met796 backbone of EGFR and two hydrogen bonds with Cys919 and Thr916 of VEGFR-2 with energies of –7.99 and –7.85 kcal mol−1, respectively. In addition, this compound displayed the highest activity on cell migration and wound healing. Compound 8l with the highest cytotoxic activity can be considered a candidate for further investigation and structural optimisation as an antiproliferative agent.

In Silico studies of 4-Anilino Quinazoline derivatives as Anti-tubercular Agents

Inh A, the Enoyl Acyl Carrier protein Reductase from Mycobacterium tuberculosis is one of the pivotal enzyme involved in the mycobacterial fatty acid elongation cycle and has been considered as an important target for anti-tubercular screening. Inhibition of Inh A affects the biosynthesis of the mycolic acids, which are the central constituents of the mycobacterial cell wall. In the present research work, 4-anilino quinazoline derivatives were designed based on the quinazoline based drugs by means of lipophilic insertion and Fragment replacement. The designed compounds were synthesized, and molecular docking studies were performed on the human pathogenic bacterial enzyme InhA from its parent domain Mycobacterium Tuberculosis. Molecular docking study revealed that compounds SMOQ2, SNAQ3, 4AAQ7, 2AP9, PABAQ10 were found to possess good binding affinity towards the target InhA. With reference to the binding energy obtained from molecular docking study, five compounds were subjected to in vitro anti-tubercular activity against M. tuberculosis H37Rv and I2487 (Resistant strain) using BACTEC MGIT method. Compound SMOQ2 and 4AAQ7 showed sensitivity in both H37Rv (Sensitive strain) and I2487 (Resistant strain) at the concentration of 250, 500, 1000 and 1500 mcg/mL. In silico Pharmacokinetic predictions of the synthesized compounds were determined using SwissADME online web tool. All the synthesized compounds obeyed the Lipinski's rule of five properties.

4-Anilino Quinazoline Derivatives: Molecular Docking and Evaluation of In vitro Cytotoxic Activity

A novel scaffold of 4-anilino quinazoline derivatives was designed on the basis of known inhibitor of quinazoline based drugs. The designed derivatives were synthesized using optimized reaction condition. Their structures were confirmed by FT-IR, 1H-NMR, 13C-NMR and Mass spectral data. The structures of synthesized compounds were subjected to in silico molecular docking using AutoDock software against the target Poly (ADP-ribose) polymerase-1 (PARP-1) enzyme. The compounds were evaluated for their in vitro cytotoxic activity against Daltons Lymphocyte Ascites (DLA) Cell lines. Molecular docking study of the newly synthesized compounds showed good binding mode in the active site of PARP-1. The docking results were compared with the standard drug Doxorubicin. Doxorubicin showed binding energy of -8.94 kcal/mol and formed one hydrogen bond with Asn767 with a distance of 1.98 Å. Compound SMOQ2 showed the least binding energy, i.e., 11.87kcal/mol and formed one hydrogen bond with Arg 878 with a distance of 1.895.A° Compound DMUQ5 showed binding energy of -11.42 kcal/mol and produced two hydrogen bonds with Arg 878 and Asn 767. Among the synthesized compounds, compounds SMOQ2 and DMUQ5 showed significant binding affinity compared to the standard drug Doxorubicin. The in vitro cytotoxic evaluation indicated that compounds SMOQ2 and DMUQ5 showed significant cytotoxic activity against Daltons Lymphoma Ascites cell line.

In-silico Studies of the Antiproliferative Activity of New Anilinoquinazoline Derivatives Against NSCLC Cells

The current reversible epidermal growth factor (EGFR) tyrosine kinase inhibitors of non-small cell lung cancer (NSCLC) have been resisted by T790M mutation, while the irreversible inhibitors introduced to overcome the mutation have faced resistance from C979S mutation. In the effort to discover potentially improved reversible EGFR inhibitors, a series of new anilinoquinazoline derivatives with modification on the 2nd carbon on the aniline ring was synthesized. The derivatives were tested for their antiproliferative activity against NSCLC cell lines with wild-type (A549), exon 19 deletion mutated (H1650) and L858R+T790M (H1975) mutated EGFR kinases. Three derivatives (4-6) performed better than the standard drug, gefitinib, in all cell lines. Derivative 5 recorded the lowest IC50 values in all cell lines (A549: 24.60 ± 0.75 µM, H1650: 14.83 ± 0.54 µM, H1975: 21.72 ± 1.21 µM). A molecular docking study followed by molecular dynamics simulations was performed on derivative 5 and gefitinib using wild-type EGFR kinase (WT-EGFR) and L858R+T790M mutated kinase (LRTM-EGFR) to provide an understanding of their binding mechanisms. In WT-EGFR kinase, derivative 5 recorded better hydrogen bonding occupancy with MET793 (94.16%) and binding energy profile (-35.287 kcal/mol) as compared to gefitinib (91.80%, -26.071 kcal/mol). In LRTM-EGFR kinase, derivative 5 recorded better hydrogen bonding occupancy with MET793 (93.68%) as compared to gefitinib (91.48%). Derivative 5 also recorded additional hydrogen bonding interactions with ASP855, with a total of 60.61% occupancy as well as a better energy profile (-42.867 kcal/mol) as compared to gefitinib (-41.778 kcal/mol).

Synthesis, In Vitro Antiproliferative Activity, and In Silico Studies of New Anilinoquinazoline Derivatives as Potential AntitumorAgents

A series of anilinoquinazoline derivatives with modification on the 2nd carbon of the aniline ring has been synthesized and characterized. The compounds have been tested for their in vitro antiproliferative activity against three NSCLC cell lines, including A549, H1650 and H1975. One of the products has demonstrated the highest IC50 value against A549 (17.60 ± 1.70 µM), surpassing the standard drug, gefitinib (34.32 ± 1.30 µM), another one has exhibited IC50 value against H1975 (9.75 ± 1.06 µM), surpassing gefitinib (31.12 ± 0.38 µM). The best performing derivatives in the antiproliferative assay have been selected for further in silico study for investigating their plausible binding mode in different EGFR kinases through molecular docking and molecular dynamics simulations.

6,7-Disubstituted-4-anilinoquinazoline: Design, Synthesis and Anticancer Activity as a Novel Series of Potent Anticancer Agents

Background: Epidermal Growth Factor Receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are responsible for several pathological conditions such as the development of different kinds of tumors. The combined inhibition of both signal transduction pathways seems to be a promising novel approach for cancer treatment. Methods: In this study, novel 4-anilinoquinazoline derivatives with various substituents on-7 position of quinazoline moiety were designed, synthesized, and evaluated for their antiproliferative activity against A431 and HU02 cell lines. Results: Compounds 8a, 8d, and 8f displayed the most potent anticancer activities against A431(IC50 = 1.78 μM, 8.25 μM, and 7.18 μM, respectively) in comparison with reference standards(erlotinib IC50=8.31 μM and vandetanib IC50=10.62 μM). Molecular docking studies proved that8a as the most potent compound could be efficiently accommodated in the ATP binding site ofEGFR and VEGFR-2 through the formation of essential hydrogen bonds between quinazolineN1 atom and the Met796 backbone of EGFR as well as the Cys919 backbone of VEGFR-2 with a distance of 1.94 Å and 1.398 Å, respectively. Conclusion: Compound 8a as the most potent compound with morpholine and 3-bromoaniline at the 7 and 4 positions of quinazoline scaffold, respectively, deserves more study and structural optimization as an anticancer agent.

Synthesis and Biological Evaluation of Novel Substituted 4-Anilinoquinazolines as Antitumor Agents.

Eleven novel 4-anilinoquinazoline derivatives were synthesized and evaluated for their invitro antiproliferative activity. Among them, compound 9a exhibited the best potency, with IC50 values of 25-682nm against various types of cancer cell lines. In addition, 9a was confirmed that it could arrest the cell cycle at G2 /M phase and trigger apoptosis. Indirect immunofluorescence staining revealed its antitubulin property. Importantly, 9a significantly inhibited tumor growths in SM-7721 xenograft models (57.0% tumor mass change) without causing significant loss of body weight, suggesting that 9a is a promising new anticancer agent to be developed.

Platinum(II) Terpyridine Anticancer Complexes Possessing Multiple Mode of DNA Interaction and EGFR Inhibiting Activity.

Platinum(II) terpyridine complexes has attracted increasing attention as they have displayed great potential as antitumor agents due to their high intercalation affinity with nucleic acids. Epidermal growth factor receptor (EGFR) is often overexpressed in various tumor cells, leading to uncontrolled growth of tumor, and is regarded as an important target for developing novel antitumor drugs. Herein, we report four platinum(II) terpyridine complexes bearing EGFR inhibiting 4-anilinoquinazoline derivatives as potent multi-targeting antiproliferation agents against a series of cancer cells. EGFR inhibition assay revealed that these complexes are highly potent EGFR inhibitors. But competitive DNA binding assay and docking simulations also suggested that these complexes exhibited multiple modes of DNA interaction, especially great affinity toward DNA minor groove. Finally, cellular uptake and distribution measurements by inductively coupled plasma mass spectrometry (ICP-MS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) demonstrated that both nucleus DNA and membrane proteins are important targets for their anticancer mechanisms. The complexes herein can therefore be regarded as promising multi-targeting anticancer agents.

AQ-4, a deuterium-containing molecule, acts as a microtubule-targeting agent for cancer treatment

The important physiological function of microtubules makes them an indispensable and clinically effective target of anti-tumor agents. Herein, we sought to design, synthesize, and evaluate a novel 4-anilinoquinazoline derivative and identify its anti-tumor activity in vitro and in vivo. The novel compound, N-(4-methoxyphenyl)-N-methyl-2-(methyl-d3)quinazolin-4-amine (AQ-4), was identified as a representative scaffold and potent microtubule-targeting agent. As a promising antimitotic agent, AQ-4 displayed remarkable anti-tumor activity with an average IC50 value of 19 nM across a panel of 14 human cancer cell lines. AQ-4 also exhibited nearly identical potent activities against drug-resistant cells, with no evidence of toxicity towards normal cells. A further target verification study revealed that AQ-4 targets the tubulin-microtubule system by significantly inhibiting tubulin polymerization and disrupting the intracellular microtubule spindle dynamics. According to the results of mechanism study, AQ-4 induced cell cycle arrest in the G2/M phase, promoting evident apoptosis and a collapses of mitochondrial membrane potential. The superior anti-tumor effect of AQ-4 in vivo suggests that it should be further investigated to validate its use for cancer therapy.