Design, synthesis and evaluate of novel dual FGFR1 and HDAC inhibitors bearing an indazole scaffold

Liu, Jian; Qian, Chengbo; Zhu, Yehua; Cai, Jianping; He, Yuhang; Li, Jie; Wang, Tianlin; Zhu, Haohao; Li, Zhi; Li, Wei; Hu, Lihong

doi:10.1016/j.bmc.2017.12.041

Cited by 52 publications

(19 citation statements)

References 29 publications

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“…Heteroaromatic compounds are key precursors in natural products and pharmaceuticals . Of these, indazoles have drawn much interest because of their wide range of potent bioactivity in the pharma sector, for example, as antimicrobial, antiinflammatory, HIV protease inhibitor, and promising anticancer agents . They have also been used as bacterial gyrase B inhibitors and selective estrogen receptors .…”

Section: Methodsmentioning

confidence: 99%

“…[1][2][3][4] Of these, indazoles have drawn much interest because of their wide range of potent bioactivity in the pharma sector, [5, 6] fore xample, as antimicrobial, [7] antiinflammatory, [8,9] HIV proteaseinhibitor, [10] and promising anticancer agents. [11,12] They have also been used as bacterial gyrase Bi nhibitors [13] and selectivee strogen receptors. [14] Commercially important drugss uch as MK-4827 (anticancer activity) [15] and pazopanib (tyrosinek inase inhibitor,v otrient) [16,17] incorporate indazole as ab asic scaffold.Functionalization of 2H-indazolesl eads to formation of privileged structural motifs that can be transformed into diverse scaffoldsi na grochemicals and pharmaceuticals.…”

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confidence: 99%

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Continuous‐Flow Visible Light Organophotocatalysis for Direct Arylation of 2H‐Indazoles: Fast Access to Drug Molecules

et al. 2019

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A continuous‐flow homogeneous photocatalytic method has been devised for the direct arylation of 2H‐indazoles. This visible‐light‐promoted approach directly accesses a wide range of structurally diverse C3‐arylated scaffolds of biological interest in a fast (1 min), single‐step reaction by using eosin Y as an organophotocatalyst. Furthermore, a microreactor technology is also employed for the fast synthesis of liver X receptor inhibitor drugs with very good yields under metal‐free conditions, whereas the reported methods required multiple steps and much longer reaction times (18–24 h).

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Continuous‐Flow Visible Light Organophotocatalysis for Direct Arylation of 2H‐Indazoles: Fast Access to Drug Molecules

et al. 2019

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“…Recently, the combination composed of HDAC6 and TK inhibitors was proven to be effective against breast cancer, suggesting the possible development of hybrid compounds able to interact with both targets . Compound 56 (IC 50 FGFR1 = 2.9 nM) (Figure ) has been previously reported by Liu et al as novel and selective second generation TKi and resulted in the starting point for the design of the first series of HDAC6/FGFR1 dual inhibitors . The 56 /FGFR1 cocrystal structure revealed that the N ‐ethyl‐4‐phenylpiperazine moiety extended out of the solvent‐exposed region.…”

Section: The Mtdl Approachmentioning

confidence: 99%

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

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“…Therefore, FGFR has emerged as an attractive target for cancer therapy. Recently in 2018, Liu et al . developed the first dual FGFR‐1/ HDAC‐6 inhibitor 54c using their previously reported FGFR‐1 potent inhibitor 54a as a surface recognition capping group that was attached to benzohydroxamic acid scaffold as in the reported HDAC‐6 inhibitor nexturastat 54b (Figure ).…”

Section: Design Of Dual Protein Tyrosine Kinase (Ptk) Hdac Inhibitorsmentioning

confidence: 99%

Chimeric HDAC inhibitors: Comprehensive review on the HDAC‐based strategies developed to combat cancer

Hesham

Lasheen

Abouzid

2018

Medicinal Research Reviews

120

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Recently, molecular hybridization paradigm became an interesting and smart way to defeat the multifaceted cancer disease by a single molecular entity that acts via several mechanisms just like a magic bullet. Also, HDAC is an important epigenetic target in drug discovery, and the HDAC inhibitors showed successful pattern as cytotoxic agents. Because of their flexible structure activity relationship, it was easy to link them to other anticancer scaffolds. So, many dual action HDAC inhibitors have been developed and most of these hybrids have higher potency than the constituting parents in fighting of the cancer cells. This review describes potential applications of chimeric HDAC inhibitors, which simultaneously modulate not only HDAC but also multiple targets, in treatment of relapsing and drug-resistant cancers. We have nearly collected most of the reported dual action HDAC inhibitors yet to provide a comprehensive guide for the drug discovery process for developing more efficient anticancer agents.

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Design, synthesis and evaluate of novel dual FGFR1 and HDAC inhibitors bearing an indazole scaffold

Cited by 52 publications

References 29 publications

Continuous‐Flow Visible Light Organophotocatalysis for Direct Arylation of 2H‐Indazoles: Fast Access to Drug Molecules

Continuous‐Flow Visible Light Organophotocatalysis for Direct Arylation of 2H‐Indazoles: Fast Access to Drug Molecules

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Chimeric HDAC inhibitors: Comprehensive review on the HDAC‐based strategies developed to combat cancer

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