Synthesis and Biological Evaluation of Novel 2-Aroyl Benzofuran-Based Hydroxamic Acids as Antimicrotubule Agents

被引:3
作者
Mariotto, Elena [1 ,2 ]
Canton, Martina [1 ,2 ]
Marchioro, Chiara [1 ,2 ]
Brancale, Andrea [3 ]
Hamel, Ernest [4 ]
Varani, Katia [5 ]
Vincenzi, Fabrizio [5 ]
De Ventura, Tiziano [6 ]
Padroni, Chiara [7 ]
Viola, Giampietro [1 ,2 ]
Romagnoli, Romeo [6 ]
机构
[1] Univ Padua, Dept Womans & Childs Hlth, Hematooncol Lab, Padua, Italy
[2] Fdn Citta Speranza, Ist Ric Pediat IRP, Lab Expt Pharmacol, I-35128 Padua, Italy
[3] Univ Chem & Technol Prague, Dept Organ Chem, Prague 16628, Czech Republic
[4] NCI, Mol Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA
[5] Univ Ferrara, Dept Translat Med & Romagna, I-44121 Ferrara, Italy
[6] Univ Ferrara, Dept Chem Pharmaceut & Agr Sci, I-44121 Ferrara, Italy
[7] Evotec Co, Aptuit, Med Chem Dept, Integrated Drug Discovery, I-37135 Verona, Italy
关键词
dual-target inhibitors; anticancer agents; benzo[b]furan; tubulin; histone deacetylase (HDAC); HISTONE DEACETYLASE INHIBITORS; TUBULIN POLYMERIZATION; CANCER; COLCHICINE; BINDING; ANALOGS; RESISTANCE; INDUCTION; MECHANISM; STRATEGY;
D O I
10.3390/ijms25147519
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
Because of synergism between tubulin and HDAC inhibitors, we used the pharmacophore fusion strategy to generate potential tubulin-HDAC dual inhibitors. Drug design was based on the introduction of a N-hydroxyacrylamide or a N-hydroxypropiolamide at the 5-position of the 2-aroylbenzo[b]furan skeleton, to produce compounds 6a-i and 11a-h, respectively. Among the synthesized compounds, derivatives 6a, 6c, 6e, 6g, 11a, and 11c showed excellent antiproliferative activity, with IC50 values at single- or double-digit nanomolar levels, against the A549, HT-29, and MCF-7 cells resistant towards the control compound combretastatin A-4 (CA-4). Compounds 11a and 6g were also 10-fold more active than CA-4 against the Hela cell line. When comparing the inhibition of tubulin polymerization versus the HDAC6 inhibitory activity, we found that 6a-g, 6i, 11a, 11c, and 11e, although very potent as inhibitors of tubulin assembly, did not have significant inhibitory activity against HDAC6.
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页数:35
相关论文
共 82 条
[1]  
Amnekar RV, 2018, Journal of Clinical Epigenetics, V04, DOI [10.21767/2472-1158.100093, DOI 10.21767/2472-1158.100093]
[2]   Polypharmacology: Challenges and Opportunities in Drug Discovery [J].
Anighoro, Andrew ;
Bajorath, Juergen ;
Rastelli, Giulio .
JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (19) :7874-7887
[3]  
[Anonymous], 2019, Schrodinger Release 2018-2
[4]   New thiazole-2(3H)-thiones containing 4-(3,4,5-trimethoxyphenyl) moiety as anticancer agents [J].
Ansari, Mahsa ;
Shokrzadeh, Mohammad ;
Karima, Saeed ;
Rajaei, Shima ;
Fallah, Marjan ;
Ghassemi-Barghi, Nasrin ;
Ghasemian, Majid ;
Emami, Saeed .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2020, 185
[5]   Comprehensive review for anticancer hybridized multitargeting HDAC inhibitors [J].
Bass, Amr K. A. ;
El-Zoghbi, Mona S. ;
Nageeb, El-Shimaa M. ;
Mohamed, Mamdouh F. A. ;
Badr, Mohamed ;
Abuo-Rahma, Gamal El-Din A. .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2021, 209
[6]   Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer [J].
Beljkas, Milan ;
Ilic, Aleksandra ;
Cebzan, Alen ;
Radovic, Branko ;
Djokovic, Nemanja ;
Ruzic, Dusan ;
Nikolic, Katarina ;
Oljacic, Slavica .
PHARMACEUTICS, 2023, 15 (11)
[7]   Romidepsin: a novel histone deacetylase inhibitor for cancer [J].
Bertino, Erin M. ;
Otterson, Gregory A. .
EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2011, 20 (08) :1151-1158
[8]   Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis [J].
Blauvelt, Andrew ;
Kempers, Steven ;
Lain, Edward ;
Schlesinger, Todd ;
Tyring, Stephen ;
Forman, Seth ;
Ablon, Glynis ;
Martin, George ;
Wang, Hui ;
Cutler, David L. ;
Fang, Jane ;
Kwan, Min-Fun R. .
NEW ENGLAND JOURNAL OF MEDICINE, 2021, 384 (06) :512-520
[9]   Design, synthesis and biological evaluation of novel 2,4-thiazolidinedione derivatives able to target the human BAG3 protein [J].
Budassi, Federica ;
Marchioro, Chiara ;
Canton, Martina ;
Favaro, Annagiulia ;
Sturlese, Mattia ;
Urbinati, Chiara ;
Rusnati, Marco ;
Romagnoli, Romeo ;
Viola, Giampietro ;
Mariotto, Elena .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2023, 261
[10]   Tubulin: A Target for Antineoplastic Drugs into the Cancer Cells but also in the Peripheral Nervous System [J].
Canta, Annalisa ;
Chiorazzi, Alessia ;
Cavaletti, Guido .
CURRENT MEDICINAL CHEMISTRY, 2009, 16 (11) :1315-1324