Novel azulene-based derivatives as potent multi-receptor tyrosine kinase inhibitors

Chen, Chih‐Hung; Lee, On; Yao, Chung-Niang; Chuang, Meng-Yun; Chang, Yow-Lone; Chang, May-Hua; Wen, Yen-Fang; Yang, Wenting; Ko, Ching-Huai; Chou, Nien-Tzu; Lin, Mai-Wei; Lai, Chin-Pen; Sun, Chung-Yuan; Wang, Ling-Mei; Chen, Yen-Chun; Hseu, Tzong-Hsiung; Chang, Chih Ming; Hsu, Hui‐Chun; Lin, Hui-Chi; Chang, Yu-Li; Shih, Ying-Chu; Chou, Shuen-Hsiang; Hsu, Yi Ling; Tseng, Hsiang-Wen; Liu, Chih-Peng; Tu, Chia-Mu; Hu, Tsan-Lin; Tsai, Yi‐Ling; Chen, Ting-Shou; Lin, Chih‐Lung; Chiou, Shu-Jiau; Liu, Chung Cheng; Hwang, Chrong-Shiong

doi:10.1016/j.bmcl.2010.08.025

Cited by 23 publications

(9 citation statements)

References 11 publications

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“…After that, an evaluation of their in vitro activity against 60 human cancer cell lines, including melanoma, leukemia, lung, colon, renal, ovarian, central nervous system, breast, and prostate lines, was performed according to standard National Cancer Institute protocols. Results indicated that compound 49 could be considered a potent inhibitor of EKVX non-small cell lung cancer cell line growth with IC 50 A very interesting study on a series of azulene derivatives as potent multi-receptor tyrosine kinase inhibitors for the treatment of acute myeloid leukemia (AML) or gastrointestinal stomach tumors (GIST) was performed by Chen et al [59]. After synthesis and screening tests, compound 51 presented high cytotoxicity against human peripheral blood cell line MV4-11 with IC 50 values in the submicromolar range.…”

Section: Antineoplastic Activitymentioning

confidence: 99%

In vitro and in vivo biological activities of azulene derivatives with potential applications in medicine

Bakun

Czarczyńska-Goślińska

Gośliński

et al. 2021

Med Chem Res

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Azulene is an aromatic hydrocarbon that possesses a unique chemical structure and interesting biological properties. Azulene derivatives, including guaiazulene or chamazulene, occur in nature as components of many plants and mushrooms, such as Matricaria chamomilla, Artemisia absinthium, Achillea millefolium, and Lactarius indigo. Due to physicochemical properties, azulene and its derivatives have found many potential applications in technology, especially in optoelectronic devices. In medicine, the ingredients of these plants have been widely used for hundreds of years in antiallergic, antibacterial, and anti-inflammatory therapies. Herein, the applications of azulene, its derivatives and their conjugates with biologically active compounds are presented. The potential use of these compounds concerns various areas of medicine, including anti-inflammatory with peptic ulcers, antineoplastic with leukemia, antidiabetes, antiretroviral with HIV-1, antimicrobial, including antimicrobial photodynamic therapy, and antifungal.

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Section: Antineoplastic Activitymentioning

confidence: 99%

In vitro and in vivo biological activities of azulene derivatives with potential applications in medicine

Bakun

Czarczyńska-Goślińska

Gośliński

et al. 2021

Med Chem Res

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“…[14] Furthermore, the azulene scaffold has rarely been used in medicinal chemistry:o nly af ew examples of azulenes are found in the scientific literature, which is reflected in the fact that, at the time of this study, no 1-benzoylazulenesc ould be identified in the ChEMBL database.T he published compounds have preclinical applications as antiulcer,a ntidiabetic, anticancer and pro-erectile agents. [15][16][17][18] Notably,t he azulene framework has been previously used to target the orthosteric site in Gprotein-coupled dopamine D 4 receptors. [13] In this study,w ee xpanded the chemical space aroundt he azulene-scaffolded compounds that we previously reported, with the objective to challenge the two aspects of the azulene ring that had initially attractedu s: the scaffold itself and the presence of ad ipole moment.…”

Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationships of 1‐Benzoylazulenes at the OX₁ and OX₂ Orexin Receptors

et al. 2019

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and carboxyl or ester groups at the 6-position,w hile af ew compounds with only one of these features were inactive (as an example compound 3 in Figure2). We therefore synthe-sized and tested 21 new 1,6-disubstituted azulenes. At the 1position, we aimed to modify the benzoyl group either by polar substitutionso rb yr eplacing it with other aromatic Figure 2. A) Screeningo fC a 2 + responses of all 21 azulene-based and six indole-basedc ompounds at 10 mm.Azulene derivativesa re presenteda sh ollow diamondsa nd indole derivatives as filled circles. B) Structureso fc ompounds 15, 26,and 28 that displayed the highest Ca 2 + responses in the screening, and previouslydisclosedc ompounds 1, 3, 37,and 40.[12] C)-F) To tal and orexin-receptor-specific Ca 2 + responses of 1 (C, 10 mm data from ref.[12]), 26 (D), 28 (E), and 37 (F). Ca 2 + responses areg iven as apercentage of the maximal response (E max )o forexin-A. The responses wereseparately normalized to the E max of orexin-A for each independent experiment beforeaveraging; n = 3-6.Scheme1.Synthesis of compounds 5-36:a)appropriate N,N-dimethylbenzamide, POCl 3 ,1,4-dioxane, mw,100 8C, 4-5 h, 22 %( 5), 18 %( 6), 44 %( 7), 31 %(8), 29 %( 9), 0% (11); b) 1) 2-chloro-N,N-diethylacetamide, POCl 3 ,1,4-dioxane, mw,1 00 8C, 2h,33%,2 )thioacetamide,E tOH, mw,1 20 8C, 30 min,7 1%;c )1)oxalyl chloride,t oluene, RT,1h, 2) appropriate amine, CH 2 Cl 2 ,10-30 min, 64 %( 14), 50 %( 15); d) 1) phosgene, toluene, 80 8C, overnight, 2) appropriate amine, 0 8C, 15-30 min, 35 %( 16), 9% (17), 49 %( 18), 84 %(19); e) 1) EDC·HCl,H OBt·H 2 O, DMF,08C, 15 min, RT,1h, 2) appropriate amined erivative, RT,1 -2.5 h, 79 %( 21), 85 %( 22), 88 %( 23), 49 %(24), 81 %( 25), 80 %( 26), 87 %( 28); f) NaOH, THF,MeOH,H 2 O, RT,30min, 98 %; g) benzoyl chloride, Et 3 N, CH 2 Cl 2 ,R T, 23 h, 59 %( 31), 22 %( 32); h) N,N-dimethylbenzamide, POCl 3 ,m w, 100 8C, 1-3 h, 2% (33), 3% (34), 23 %( 35), 48 %( 36).

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“…In medicinal chemistry, azulene is an unexplored scaffold; only one azulene-based drug, the antiulcer agent egualen sodium, is currently on the market. [15] In addition, there are a few other published examples of azulenes with application as anticancer [16][17][18] and antidiabetic [19] agents and in erectile dysfunction. [20] The study was initiated by developing general synthetic protocols to access 1,3,6trisubstituted azulenes.…”

Section: Introductionmentioning

confidence: 99%

Azulene-based compounds for targeting orexin receptors

Leino

Turku

Yli‐Kauhaluoma

et al. 2018

European Journal of Medicinal Chemistry

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A library of 70 000 synthetically accessible azulene-based compounds was virtually screened at the OX receptor. Based on the results, a series of azulene derivatives was synthesized and the binding to and activation of both orexin receptor subtypes were assessed. Two most promising binders were determined to have inhibition constants in the 3-9 μM range and two other compounds showed weak OX receptor agonism. Furthermore, three compounds exhibited a concentration-dependent potentiation of the response to orexin-A at the OX but not the OX receptors. Altogether this data opens new approaches for further development of antagonists, agonists, and potentiators of orexin response based on the azulene scaffold.

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Novel azulene-based derivatives as potent multi-receptor tyrosine kinase inhibitors

Cited by 23 publications

References 11 publications

In vitro and in vivo biological activities of azulene derivatives with potential applications in medicine

In vitro and in vivo biological activities of azulene derivatives with potential applications in medicine

Structure–Activity Relationships of 1‐Benzoylazulenes at the OX₁ and OX₂ Orexin Receptors

Azulene-based compounds for targeting orexin receptors

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Novel azulene-based derivatives as potent multi-receptor tyrosine kinase inhibitors

Cited by 23 publications

References 11 publications

In vitro and in vivo biological activities of azulene derivatives with potential applications in medicine

In vitro and in vivo biological activities of azulene derivatives with potential applications in medicine

Structure–Activity Relationships of 1‐Benzoylazulenes at the OX1 and OX2 Orexin Receptors

Azulene-based compounds for targeting orexin receptors

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Structure–Activity Relationships of 1‐Benzoylazulenes at the OX₁ and OX₂ Orexin Receptors