Design, synthesis and preliminary biological evaluation of 5,8-dihydropteridine-6,7-diones that induce apoptosis and suppress cell migration

被引：9

作者：

Geng, Peng-Fei ^{[1
,2
]}

Wang, Cong-Cong ^{[1
,2
]}

Li, Zhong-Hua ^{[1
,2
]}

Hu, Xiao-Ning ^{[1
,2
]}

Zhao, Tao-Qian ^{[1
,2
]}

Fu, Dong-Jun ^{[1
,2
]}

Zhao, Bing ^{[1
,2
]}

Yu, Bin ^{[1
,2
]}

Liu, Hong-Min ^{[1
,2
]}

机构：

[1] Zhengzhou Univ, Sch Pharmaceut Sci, Collaborat Innovat Ctr New Drug Res & Safety Eval, Key Lab Adv Drug Preparat Technol,Minist Educ, Zhengzhou 450001, Henan, Peoples R China

[2] Key Lab Henan Prov Drug Qual & Evaluat, Zhengzhou, Henan, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 143卷

基金：

中国国家自然科学基金;

关键词：

5,8-Dihydropteridine-6,7-dione; Antiproliferative activity; Colony formation; Migration; Apoptosis; ANTIPROLIFERATIVE AGENTS; DERIVATIVES; INHIBITORS; IDENTIFICATION; PTERIDINE;

D O I：

10.1016/j.ejmech.2017.11.009

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Pteridines are an important class of fused heterocycles found in natural products and drug molecules, and have shown diverse biological activities. A focused library of 5,8-dihydropteridine-6,7-dione derivatives were designed and evaluated for their antiproliferative activity against MGC-803, SGC-7901, A549 and PC-3 cancer cell lines. The SARs studies highlighted the importance of the piperazine substituted 5,8-dihydropteridine-6,7-dione frameworks for the activity and revealed essential structural elements. Among these compounds, compound 5n displayed the most potent and broad-spectrum antiproliferative inhibition against the tested cell lines and was sensitive to MGC-803 cell line, slightly more potent than 5-FU. Preliminary mechanistic studies showed that compound 5n could inhibit the colony formation and migration of MGC-803 cells. Besides, flow cytometry analysis showed that compound 5n concentration-dependently induced apoptosis of MGC-803 cells. Our studies suggest that the piperazine substituted 5,8-dihydropteridine-6,7-dione frameworks may be regarded as new chemotypes for designing effective antitumor agents targeting gastric cancer cells. (C) 2017 Published by Elsevier Masson SAS.

引用

页码：1959 / 1967

页数：9

共 19 条

[1]

Amjed A., 2015, RES J PHARM BIOL CHE, V6, P899

[2] Pterin chemistry and its relationship to the molybdenum cofactor [J].

Basu, Partha ;

Burgmayer, Sharon J. N. .

COORDINATION CHEMISTRY REVIEWS, 2011, 255 (9-10) :1016-1038

[3] Exploring 8-benzyl pteridine-6,7-diones as inhibitors of glutamate racemase (MurI) in Gram-positive bacteria [J].

Breault, Gloria A. ;

Comita-Prevoir, Janelle ;

Eyermann, Charles J. ;

Geng, Bolin ;

Petrichko, Randy ;

Doig, Peter ;

Gorseth, Elise ;

Noonan, Brian .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (23) :6100-6103

[4] Design and synthesis of novel 1,2,3-triazole-dithiocarbamate hybrids as potential anticancer agents [J].

Duan, Ying-Chao ;

Ma, Yong-Cheng ;

Zhang, En ;

Shi, Xiao-Jing ;

Wang, Meng-Meng ;

Ye, Xian-Wei ;

Liu, Hong-Min .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2013, 62 :11-19

[5] Synthesis and potential antiallergic activity of new pteridinones and related compounds [J].

Ferrand, G ;

Dumas, H ;

Depin, JC ;

Quentin, Y .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 1996, 31 (04) :273-280

[6] First synthesis and biological evaluation of 4-amino-2-aryl-6,9-dichlorobenzo[g]pteridines as inhibitors of TNF-α and IL-6 [J].

Guirado, Antonio ;

Lopez Sanchez, Jose I. ;

Ruiz-Alcaraz, Antonio J. ;

Garcia-Penarrubia, Pilar ;

Bautista, Delia ;

Galvez, Jesus .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2013, 66 :269-275

[7] New γ-fluoromethotrexates modified in the pteridine ring:: synthesis and in vitro immunosuppressive activity [J].

Kokuryo, Y ;

Nakatani, T ;

Kakinuma, M ;

Kabaki, M ;

Kawata, K ;

Kugimiya, A ;

Kawada, K ;

Matsumoto, M ;

Suzuki, R ;

Ohtani, M .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2000, 35 (05) :529-534

[8] Dendrimer-based multivalent methotrexates as dual acting nanoconjugates for cancer cell targeting [J].

Li, Ming-Hsin ;

Choi, Seok Ki ;

Thomas, Thommey P. ;

Desai, Ankur ;

Lee, Kyung-Hoon ;

Kotlyar, Alina ;

Holl, Mark M. Banaszak ;

Baker, James R., Jr. .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2012, 47 :560-572

[9] Identification of thiazolo[5,4-d]pyrimidine derivatives as potent antiproliferative agents through the drug repurposing strategy [J].

Li, Zhong-Hua ;

Zhang, Ji ;

Liu, Xue-Qi ;

Geng, Peng-Fei ;

Ma, Jin-Lian ;

Wang, Bo ;

Zhao, Tao-Qian ;

Zhao, Bing ;

Wei, Hao-Ming ;

Wang, Chao ;

Fu, Dong-Jun ;

Yu, Bin ;

Liu, Hong-Min .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2017, 135 :204-212

[10] Discovery of [1,2,3]Triazolo[4,5-d]pyrimidine Derivatives as Novel LSD1 Inhibitors [J].

Li, Zhong-Hua ;

Liu, Xue-Qi ;

Geng, Peng-Fei ;

Suo, Feng-Zhi ;

Ma, Jin-Lian ;

Yu, Bin ;

Zhao, Tao-Qian ;

Zhou, Zhao-Qing ;

Huang, Chen-Xi ;

Zheng, Yi-Chao ;

Liu, Hong-Min .

ACS MEDICINAL CHEMISTRY LETTERS, 2017, 8 (04) :384-389

← 1 2 →