Synthesis and Biological Evaluation of Novel 2-Amino-1,4-Naphthoquinone Amide-Oxime Derivatives as Potent IDO1/STAT3 Dual Inhibitors with Prospective Antitumor Effects

被引:4
作者
Huang, Ri-Zhen [1 ]
Liang, Qiao-Ling [1 ]
Jing, Xiao-Teng [2 ,3 ]
Wang, Ke [1 ]
Zhang, Hui-Yong [1 ]
Wang, Heng-Shan [2 ]
Ma, Xian-Li [1 ]
Wei, Jian-Hua [1 ]
Zhang, Ye [1 ]
机构
[1] Guilin Med Univ, Guangxi Engn Res Ctr Pharmaceut Mol Screening & Dr, Sch Pharm, Guangxi Key Lab Drug Discovery & Optimizat, Guilin 541199, Peoples R China
[2] Guangxi Normal Univ, Collaborat Innovat Ctr Guangxi Ethn Med, Sch Chem & Pharmaceut Sci, State Key Lab Chem & Mol Engn Med Resources, Guilin 541004, Peoples R China
[3] Guilin Normal Coll, Dept Chem & Pharmaceut Sci, Xinyi Rd 15, Guilin 541001, Peoples R China
来源
MOLECULES | 2023年 / 28卷 / 16期
基金
中国国家自然科学基金; 中国博士后科学基金;
关键词
indoleamine 2,3-dioxygenase 1; signal transducer and activator of transcription 3; dual inhibitors; naphthoquinone-oxime derivatives; anticancer agents; INDOLEAMINE 2,3-DIOXYGENASE; CANCER-IMMUNOTHERAPY; STAT3; IDO1; DISCOVERY; CHALLENGES; GROWTH; INDOLEAMINE-2,3-DIOXYGENASE; OPPORTUNITIES; SUPPRESSION;
D O I
10.3390/molecules28166135
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Indoleamine-2,3-dioxygenase 1 (IDO1) and signal transducer and activator of transcription 3 (STAT3) have emerged as significant targets in the tumor microenvironment for cancer therapy. In this study, we synthesized three novel 2-amino-1,4-naphthoquinone amide-oxime derivatives and identified them as dual inhibitors of IDO1 and STAT3. The representative compound NK3 demonstrated effective binding to IDO1 and exhibited good inhibitory activity (hIDO1 IC50 = 0.06 mu M), leading to its selection for further investigation. The direct interactions between compound NK3 and IDO1 and STAT3 proteins were confirmed through surface plasmon resonance analysis. A molecular docking study of compound NK3 revealed key interactions between NK3 and IDO1, with the naphthoquinone-oxime moiety coordinating with the heme iron. In the in vitro anticancer assay, compound NK3 displayed potent antitumor activity against selected cancer cell lines and effectively suppressed nuclear translocation of STAT3. Moreover, in vivo assays conducted on CT26 tumor-bearing Balb/c mice and an athymic HepG2 xenograft model revealed that compound NK3 exhibited potent antitumor activity with low toxicity relative to 1-methyl-L-tryptophan (1-MT) and doxorubicin (DOX). Overall, these findings provided evidence that the dual inhibitors of IDO1 and STAT3 may offer a promising avenue for the development of highly effective drug candidates for cancer therapy.
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页数:16
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共 43 条
  • [1] Big opportunities for small molecules in immuno-oncology
    Adams, Jerry L.
    Smothers, James
    Srinivasan, Roopa
    Hoos, Axel
    [J]. NATURE REVIEWS DRUG DISCOVERY, 2015, 14 (09) : 603 - 622
  • [2] Microwave irradiation: A facile, scalable and convenient method for synthesis of N-phthaloylamino acids
    Al-Hazimi, Hassan M.
    El-Faham, Ayman
    Ghazzali, Mohamed
    Al-Farhan, Khalid
    [J]. ARABIAN JOURNAL OF CHEMISTRY, 2012, 5 (03) : 285 - 289
  • [3] Polypharmacology: Challenges and Opportunities in Drug Discovery
    Anighoro, Andrew
    Bajorath, Juergen
    Rastelli, Giulio
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (19) : 7874 - 7887
  • [4] A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy
    Awuah, Samuel G.
    Zheng, Yao-Rong
    Bruno, Peter M.
    Hemann, Michael T.
    Lippard, Stephen J.
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2015, 137 (47) : 14854 - 14857
  • [5] Understanding the tumor immune microenvironment (TIME) for effective therapy
    Binnewies, Mikhail
    Roberts, Edward W.
    Kersten, Kelly
    Chan, Vincent
    Fearon, Douglas F.
    Merad, Miriam
    Coussens, Lisa M.
    Gabrilovich, Dmitry I.
    Ostrand-Rosenberg, Suzanne
    Hedrick, Catherine C.
    Vonderheide, Robert H.
    Pittet, Mikael J.
    Jain, Rakesh K.
    Zou, Weiping
    Howcroft, T. Kevin
    Woodhouse, Elisa C.
    Weinberg, Robert A.
    Krummel, Matthew F.
    [J]. NATURE MEDICINE, 2018, 24 (05) : 541 - 550
  • [6] Discovery and structure-activity relationships of phenyl benzenesulfonylhydrazides as novel indoleamine 2,3-dioxygenase inhibitors
    Cheng, Ming-Fu
    Hung, Ming-Shiu
    Song, Jen-Shin
    Lin, Shu-Yu
    Liao, Fang-Yu
    Wu, Mine-Hsine
    Hsiao, Wenchi
    Hsieh, Chia-Ling
    Wu, Jian-Sung
    Chao, Yu-Sheng
    Shih, Chuan
    Wu, Su-Ying
    Ueng, Shau-Hua
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2014, 24 (15) : 3403 - 3406
  • [7] Targeting the IDO1/TDO2-KYN-AhR Pathway for Cancer Immunotherapy - Challenges and Opportunities
    Cheong, Jae Eun
    Sun, Lijun
    [J]. TRENDS IN PHARMACOLOGICAL SCIENCES, 2018, 39 (03) : 307 - 325
  • [8] Couzin-Frankel J., 2013, SCIENCE, V342, P1432, DOI DOI 10.1126/SCIENCE.342.6165.1432
  • [9] Recent Update on Development of Small-Molecule STAT3 Inhibitors for Cancer Therapy: From Phosphorylation Inhibition to Protein Degradation
    Dong, Jinyun
    Cheng, Xiang-Dong
    Zhang, Wei-Dong
    Qin, Jiang-Jiang
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2021, 64 (13) : 8884 - 8915
  • [10] Discovery of Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) and Histone Deacetylase (HDAC) Dual Inhibitors
    Fang, Kun
    Dong, Guoqiang
    Li, Yu
    He, Shipeng
    Wu, Ying
    Wu, Shanchao
    Wang, Wei
    Sheng, Chunquan
    [J]. ACS MEDICINAL CHEMISTRY LETTERS, 2018, 9 (04): : 312 - 317