- Efficient N-arylation of 4-chloroquinazolines en route to novel 4-anilinoquinazolines as potential anticancer agents
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Microwave-mediated N-arylation of 4-chloroquinazolines in THF/H2O rapidly and efficiently afforded a library of novel 6-halo-2- phenyl-substituted 4-anilinoquinazolines. The methodology was compatible with numerous ortho-, meta-, and para-substituted N-methylanilines as well as substituted anilines and furnished the corresponding 4-anilinoquinazolines in good yields. Preliminary screening of the synthesized compounds against tumor cells (HCT-116 and T98G) showed promising antiproliferative properties.
- Clososki, Giuliano C.,Costa-Lotufo, Leticia V.,Dos Santos, Thiago,Furtado, Luciana C.,Murie, Valter E.,Nishimura, Rodolfo H. V.
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supporting information
p. 2968 - 2975
(2022/01/12)
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- Potential of substituted quinazolines to interact with multiple targets in the treatment of cancer
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The efficacy of quinazoline-based antiglioma agents has been attributed to their effects on microtubule dynamics.1,2 The design, synthesis and biological evaluation of quinazolines as potent inhibitors of multiple intracellular targets, including microtubules and multiple RTKs, is described. In addition to the known ability of quinazolines 1 and 2 to cause microtubule depolymerization, they were found to be low nanomolar inhibitors of EGFR, VEGFR-2 and PDGFR-β. Low nanomolar inhibition of EGFR was observed for 1–3 and 9–10. Compounds 1 and 4 inhibited VEGFR-2 kinase with activity better than or equal to that of sunitinib. In addition, compounds 1 and 2 had similar potency to sunitinib in the CAM angiogenesis assay. Multitarget activities of compounds in the present study demonstrates that the quinazolines can affect multiple pathways and could lead to these agents having antitumor potential caused by their activity against multiple targets.
- Choudhary, Shruti,Doshi, Arpit,Luckett-Chastain, Lerin,Ihnat, Michael,Hamel, Ernest,Mooberry, Susan L.,Gangjee, Aleem
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- Design, synthesis, and anticancer activities of sodium quinazolin-4-diselenide compounds
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Substituted 4-chloroquinazoline reacted with sodium diselenide to give novel sodium quinazoline-4-diselenide compounds. The reaction provides an efficient and facile approach to the synthesis of sodium quinazoline-4-diselenide compounds. Structures of title compounds were confirmed by IR, 1H NMR, 13C NMR, and elemental analysis. MTT assay was adopted to show anticancer activities of the compounds. Compounds 5a and 5h showed good activities against cancer-cell lines MDA-MB-435, MDA-MB-231, A549, SiHa, and HeLa. In addition, 5a exhibited quite good anticancer effects on relative above cell lines with 10μM concentration compared with oxaliplatin and gefitinib of the commercial anticancer drugs.
- Zhang, Yuchun,Niu, Pengpeng,Wen, Quanwu,Sun, Lin,Wang, Weili,Xu, Shengguang,Liu, Gang
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p. 497 - 502
(2019/11/03)
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- Design, synthesis and molecular modeling studies of 2-styrylquinazoline derivatives as EGFR inhibitors and apoptosis inducers
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Herein, we report the synthesis of novel 2-substituted styrylquinazolines conjugated with aniline or sulfonamide moieties, anticipated to act as potent anticancer therapeutic agents through preferential EGFR inhibition. In doing so, all the synthesized compounds were screened for their in vitro anticancer activities (nine subpanels) at the National Cancer Institute (NCI), USA. The resulting two most active anticancer compounds (7b and 8c) were then chemically manipulated to investigate feasible derivatives (12a-e and 15a-d). MTT cytotoxicity, in vitro cell free EGFR and anti-proliferative activity against EGFR/ A549 cell line evaluation for the most active broadly spectrum candidates (7a/b, 8c/e, 12b and 15d) was conducted. Promising results were obtained for the styrylquinazoline-benzenesulfonamide derivative 8c (IC50 = 8.62 μM, 0.190 μM and = 79.25%), if compared to lapatanib (IC50 = 11.98 μM, 0.190 μM, and 79.25%), respectively. Moreover, its apoptotic induction potential was studied through cell cycle analysis, Annexin-V and caspase-3 activation assays. Results showed a clear cell arrest at G2/M phase, a late apoptotic increase (76 folds) and a fruitful caspase-3 expression change (8 folds), compared to the control. Finally, molecular docking studies of compounds 7a/b, 8c/e, 12b and 15d revealed proper fitting into the active site of EGFR with a low binding energy score for compound 8c (?13.19 Kcal/mole), compared to lapatanib (?14.54 Kcal/mole).
- Amin, Noha H.,Elsaadi, Mohammed T.,Zaki, Shimaa S.,Abdel-Rahman, Hamdy M.
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- Synthesis, docking and biological evaluation of 2,4-disubstituted quinazolines with multi-target activities as anti-cancer and antimicrobial agents
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A series of 2,4-disubstituted quinazoline derivatives was designed and synthesized as multi-target therapeutic agents that may act as anti-cancer and antimicrobial agents. The target compounds were evaluated for primary anti-cancer activity followed by EGFR inhibition assay for most potent compounds. Compounds 6 and 8c exhibited good EGFR inhibition activity with IC50 values of 0.201 and 0.405 μM, respectively, in comparison to lapatinib as a reference with IC50 value of 0.115 μM. Docking study of the synthesized compounds into the binding site of EGFR tyrosine kinase was performed to compare the binding mode of these compounds to the known EGFR inhibitor, lapatinib. Moreover, antimicrobial activity, cytotoxity and hemolytic analysis were estimated according to CO-ADD (The Community for Antimicrobial Drug Discovery) procedures. Compounds 4 and 5c possessed potent antifungal activity with minimum inhibitory concentration (MIC) values of 8 and 4 μg/mL against C. albicans and C. neoformance, respectively, compared to fluconazole as a reference drug with MIC values of 0.125 and 8 μg/mL against same fungi.
- Elsaadi, Mohammed T.,Amin, Noha H.,Zaki, Shimaa S.,Abdel-Rahman, Hamdy M.
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p. 3721 - 3734
(2020/11/18)
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- HISTONE DEACETYLASE INHIBITOR, AND PREPARATION METHOD AND USE THEREOF
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A compound represented by Formula I or pharmaceutically acceptable salt thereof. The present invention relates to a 4-arylamino quinazoline hydroxamic acid compound having a histone deacetylase inhibitory activity, preparation method of the compound, pharmaceutical composition comprising the compound, and use of the compound and the pharmaceutical composition in the preparation of a histone deacetylase inhibitor medicine. The present invention aims at acquiring, via a medicine design and a synthetic technology, a series of selective histone deacetylase inhibitors having good hypotype selectivity and favorable pharmacokinetic characteristics based on optimization of an enzyme surface recognition region and connection region of 4-arylamino quinazoline, thus reducing an effect on normal tissues or cells while improving an antineoplastic activity of the normal tissues or cells.
- -
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Paragraph 0236-0237
(2018/04/20)
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- A histone deacetylase inhibitor and its preparation and use (by machine translation)
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The invention provides a compound of formula I illustrated compound or its pharmaceutically acceptable salt, relates to has the histone deacetylase inhibitory activity of the 4 - aryl amino [...] novel class of compound, the preparation of the compounds, comprising the pharmaceutical composition and the compounds and pharmaceutical compositions in the preparation of histone deacetylase enzyme inhibitor drug in its class of use; aimed at through the drug design and synthesis means based on obtaining a series of 4 - aryl amino [...] surface of the cleat and linkage area optimization, with subtype selective and good medicine generation of dynamics characteristic of selective histone deacetylase inhibitors, in order to improve the anti-tumor activity at the same time to reduce the impact of the normal tissue or cells. (by machine translation)
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Paragraph 0344; 0345; 0346; 0347
(2017/02/17)
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- Looking for new antiplasmodial quinazolines: DMAP-catalyzed synthesis of 4-benzyloxy- and 4-aryloxy-2-trichloromethylquinazolines and their in vitro evaluation toward Plasmodium falciparum
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A DMAP catalyzed synthesis of new 4-benzyloxy- and 4-aryloxy-2-trichloromethylquinazolines was studied, in a view to react 4-chloroquinazolines with poorly nucleophilic alcohols such as benzylic alcohols, via a simple and cheap SNAr reaction ap
- Gellis, Armand,Primas, Nicolas,Hutter, Sébastien,Lanzada, Gilles,Remusat, Vincent,Verhaeghe, Pierre,Vanelle, Patrice,Azas, Nadine
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- A new DMAP-catalyzed and microwave-assisted approach for introducing heteroarylamino substituents at position-4 of the quinazoline ring
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We report herein a new methodology for synthesizing quinazoline derivatives bearing a heteroarylamino moiety at position-4 of the quinazoline ring. As an alternative to the Buchwald-Hartwig cross-coupling reaction, which appears, until now, as the only efficient way to react 4-chloroquinazolines with numerous amino nitrogen-containing heterocycles displaying poor nucleophilicity, we developed a DMAP-catalyzed reaction involving microwave irradiation. Optimization of the reaction conditions led to the use of 30 mol % of DMAP in toluene, using a monomode microwave reactor and sealed vials. Moreover, the SNAr reaction intermediate salt was isolated and fully characterized. Finally, the procedure was extended to two different 2-substituted-quinazoline series and also to various anilines, demonstrating that this approach was a general efficient way to access to such 4-substituted quinazoline scaffolds of high pharmaceutical interest.
- Gellis, Armand,Kieffer, Charline,Primas, Nicolas,Lanzada, Gilles,Giorgi, Michel,Verhaeghe, Pierre,Vanelle, Patrice
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p. 8257 - 8266
(2015/03/03)
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- Selective inhibitors of fibroblast activation protein (FAP) with a xanthine scaffold
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Fibroblast activation protein (FAP) is a serine protease that is selectively expressed in many diseases involving activated stroma, including cancer, arthritis and hepatic and pulmonary fibrosis. FAP is closely related to dipeptidyl peptidase IV (DPPIV), of which many inhibitors are known and several are marketed as drugs. One of these is the xanthine derivative linagliptin. In a broad literature screen amongst reported DPPIV inhibitors, linagliptin was the only druglike compound identified that possessed significant FAP potency. Hence, this compound served as a starting point for a SAR study that aimed to identify structural determinants that selectively increase FAP-potency of linagliptin analogues. By investigating the influence of the substitution pattern on N1, N7 and C8 of the xanthine scaffold, we managed to decouple DPPIV and FAP potency and identified the first selective xanthine-based FAP inhibitors with low micromolar potency. Furthermore, these compounds are the only known FAP-inhibitors that do not rely on a warhead functionality to obtain potencies in this range.
- Jansen, Koen,De Winter, Hans,Heirbaut, Leen,Cheng, Jonathan D.,Joossens, Jurgen,Lambeir, Anne-Marie,De Meester, Ingrid,Augustyns, Koen,Van Der Veken, Pieter
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supporting information
p. 1700 - 1707
(2014/12/12)
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- Synthesis of substituted quinazolines: Application to the synthesis of verubulin
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Through newly adapted methodology, 2-methyl-3H-quinazolin-4-one was activated using a number of methods followed by displacement to afford 4-aminoquinazolines. The most useful of these processes utilize the p-toluenesulfonate ester or I2/PPh3 activation. Using this methodology, the anticancer vascular targeting clinical candidate verubulin (1) was synthesized in a highly efficient manner. Copyright Taylor & Francis Group, LLC.
- Lockman, Jeffrey W.,Klimova, Yevgeniya,Anderson, Mark B.,Willardsen, J. Adam
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experimental part
p. 1715 - 1723
(2012/04/10)
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- One-pot synthesis of 4-aminoquinazolines by hexamethyldisilazane-mediated reaction of quinazolin-4(3h)-ones with amines
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Hexamethyldisilazane-mediated reaction of quinazolin-4(3H)-ones with primary amines led to facile formation of 4-aminoquinazolines through tandem silylation and substitution in a single pot. Excellent yields of the products (83-97%) and environmental friendliness (avoiding the use of chlorination reagents) are the advantages of this method. Copyright Taylor & Francis Group, LLC.
- Shen, Zhen-Lu,He, Xiao-Fei,Hong, Yi-Ming,Hu, Xin-Quan,Mo, Wei-Min,Hu, Bao-Xiang,Sun, Nan
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experimental part
p. 3644 - 3653
(2011/10/09)
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- Discovery of N-(4-methoxyphenyl)-N,2-dimethylquinazolin-4-amine, a potent apoptosis inducer and efficacious anticancer agent with high blood brain barrier penetration
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As a continuation of our structure-activity relationship (SAR) studies on 4-anilinoquinazolines as potent apoptosis inducers and to identify anticancer development candidates, we explored the replacement of the 2-Cl group in our lead compound 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine (6b, EP128265, MPI-0441138) by other functional groups. This SAR study and lead optimization resulted in the identification of N-(4-methoxyphenyl)-N,2- dimethylquinazolin-4-amine (6h, EP128495, MPC-6827) as an anticancer clinical candidate. Compound 6h was found to be a potent apoptosis inducer with EC 50 of 2 nM in our cell-based apoptosis induction assay. It also has excellent blood brain barrier penetration, and is highly efficacious in human MX-1 breast and other mouse xenograft cancer models.
- Sirisoma, Nilantha,Pervin, Azra,Zhang, Hong,Jiang, Songchun,Willardsen, J. Adam,Anderson, Mark B.,Mather, Gary,Pleiman, Christopher M.,Kasibhatla, Shailaja,Tseng, Ben,Drewe, John,Cai, Sui Xiong
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experimental part
p. 2341 - 2351
(2010/03/31)
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- Synthesis leading to novel 2,4,6-trisubstituted quinazoline derivatives, their antibacterial and cytotoxic activity against thp-1, hl-60 and a375 cell lines
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A series of novel 2,4,6-trisubstituted quinazoline derivatives 6 have been synthesized from anthranilic acids 1 in five steps via benzoxazinones 2, N-benzoyl benzamides 3, quinazol-4-ones 4, 4-chloroquinazolines 5. Products 6 have been screened for antibacterial and cytotoxic activity, promising compounds have been identified.
- Chandrika, P Mani,Yakaiah,Narsaiah,Sridhar,Venugopal,Rao, J Venkateshwara,Kumar, K Pranay,Murthy,Rao, A Raghu Ram
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experimental part
p. 840 - 847
(2009/12/24)
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- COMPOSITIONS AND METHODS FOR MODULATING GATED ION CHANNELS
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Disclosed are compounds that modulate the activity of the gated ion channels. Compounds that modulate these gated ion channels are useful in the treatment of diseases and disorders related to pain, inflammation, the neurological system, the gastrointestinal system and genitourinary system. Preferred compounds include compounds of the Formulae 1, 2, 3, 4, and 5.
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Page/Page column 65
(2009/02/11)
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- METHOD OF TREATING NON-SMALL CELL LUNG CANCER
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A method of treating non-small cell lung cancer (NSCLC), and especially NSCLC that has metastasized to brain is disclosed.
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Page/Page column 9
(2009/04/25)
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- METHODS FOR TREATING CANCER
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Disclosed is (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride effective as a vascular disrupting agent. (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride is useful in the treatment of a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs, and in particular to its use in treating cancer.
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Page/Page column 12
(2008/12/04)
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- METHOD OF TREATING BRAIN CANCER
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Disclosed is (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride effective as a cytotoxic agent. (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride is useful in the treatment of a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs, and in particular to its use in treating brain cancer.
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Page/Page column 12-13
(2008/12/04)
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- METHOD OF TREATING MELANOMA
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Disclosed is (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride effective as a cytotoxic agent. (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride is useful in the treatment of a variety of clinical conditions i
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Page/Page column 10-11
(2008/12/04)
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- DOSAGES AND METHODS FOR THE TREATMENT OF CANCER
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In general, the invention relates to a pharmaceutical dose having (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride as the active ingredient that upon administration to a subject provides a Cmax of about 1 ng/mL to about 250 ng/mL. The dose may be used in methods of treating cancer through the administration of (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride. The composition of the invention is formulated with one or more pharmaceutically acceptable excipients, salts or carriers.
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Page/Page column 12-13
(2008/12/04)
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- METHODS FOR TREATING VASCULAR DISRUPTION DISORDERS
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Disclosed is (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride effective as a vascular disrupting agent. (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride is useful in the treatment of a variety of clinical co
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Page/Page column 11
(2008/12/04)
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- ANTIPROLIFERATIVE PYRIMIDYL, FUSED PYRIMIDYL AND PYRIMIDYL HYDRAZONES
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The present invention is related to a novel series of pyrimidyl or fused pyrimidyl hydrazones. Compounds of Formula (I) wherein A is selected from the group consisting of Formulas (A1), (A2), (A3), (A4), (A5) are useful for the treatment and/or prevention of a proliferative disease.
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Page/Page column 37
(2010/11/27)
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- METHOD OF TREATING BRAIN CANCER
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Disclosed are 4-arylamino-quinazolines and analogs thereof effective as activators of caspases and inducers of apoptosis. The compounds of this invention are useful in the treatment of a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs, and in particular to the use of these compounds in treating brain cancer.
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Page/Page column 54
(2008/06/13)
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- COMPOUNDS AND THERAPEUTICAL USE THEREOF
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Disclosed are 4-arylamino-quinazolines and analogs thereof effective as activators of caspases and inducers of apoptosis. The compounds of this invention are useful in the treatment of a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.
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- Preparation and resolution of a modular class of axially chiral quinazoline-containing ligands and their application in asymmetric rhodium-catalyzed olefin hydroboration
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The preparation and resolution of a series of axially chiral quinazoline-containing ligands is described in which the key steps are the metal-catalyzed naphthyl-phosphorus bond formation, the naphthalene-quinazoline Suzuki coupling, and the preparation of the Suzuki electrophilic components from the corresponding imidate and anthranilic acid. Diastereomeric palladacycles derived from the racemic phosphinamines and (+)-di-μ-chlorobis[(R)- dimethyl(1-(1-naphthyl)ethyl)-aminato-C2,N]dipalladium(II) were separated by fractional crystallization. The configuration of the resulting diastereomers was determined by X-ray crystallographic analysis. Displacement of the resolving agent by reaction with 1,2-bis(diphenylphosphino)ethane afforded enantiopure ligand in each case. Their rhodium complexes were prepared and applied in the enantioselective hydroboration of a range of vinylarenes. The quinazolinap catalysts were found to be extremely active, giving excellent conversions, good to complete regioselectivities, and the highest enantioselectivities obtained to date for several members of the vinylarene class, including cis-β-methylstyrene (97%), cis-stilbene (99%), and indene (99.5%).
- Connolly, David J.,Lacey, Patrick M.,McCarthy, Mary,Saunders, Cormac P.,Carroll, Anne-Marie,Goddard, Richard,Guiry, Patrick J.
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p. 6572 - 6589
(2007/10/03)
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- Structure-activity relationships of quinazoline derivatives: Dual-acting compounds with inhibitory activities toward both TNF-α production and T cell proliferation
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We synthesized 4-chlorophenethylaminoquinazoline derivatives and evaluated their inhibitory activities toward both TNF-α production and T cell proliferation responses. Compound 2f, containing a piperazine ring at the C(7)-position of the quinazoline ring, exhibited more potent inhibitory activities toward both than the lead compound 1a. A smaller N-substituent in the piperazine ring was required for inhibition of TNF-α production.
- Tobe, Masanori,Isobe, Yoshiaki,Tomizawa, Hideyuki,Matsumoto, Mitsuhiro,Obara, Fumihiro,Nagasaki, Takahiro,Hayashi, Hideya
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p. 545 - 548
(2007/10/03)
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- A facile and versatile route to 2-substituted-4(3H)-quinazolinones and quinazolines
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A range of 2-aryl and 2-alkyl quinazolinones have been prepared in moderate to good yields from the reaction of anthranilic acid and the appropriately substituted imidate in a facile, mild, onepot procedure. Subsequent reaction with phosphorus oxychloride afforded the corresponding 4-chloro-2-substituted quinazolines, which are useful synthetic intermediates, in good to high yields. Product isolation was facilitated by the development of work up procedures for both reactions that did not include purification by column chromatography.
- Connolly,Guiry
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p. 1707 - 1710
(2007/10/03)
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