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. 2023 May 15:86:117300.
doi: 10.1016/j.bmc.2023.117300. Epub 2023 Apr 27.

Dual targeted 2-Benzylideneindanone pendant hydroxamic acid group exhibits selective HDAC6 inhibition along with tubulin stabilization effect

Kapil Kumar  1 , Ranjana Das  1 , Barsha Thapa  1 , Bharti Rakhecha  2 , Sapna Srivastava  2 , Kumari Savita  1 , Monazza Israr  1 , Debabrata Chanda  3 , Dibyendu Banerjee  4 , Karuna Shanker  3 , D U Bawankule  3 , Benedetta Santini  5 , Maria Luisa Di Paolo  6 , Lisa Dalla Via  7 , Daniele Passarella  5 , Arvind Singh Negi  8
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Dual targeted 2-Benzylideneindanone pendant hydroxamic acid group exhibits selective HDAC6 inhibition along with tubulin stabilization effect

Kapil Kumar et al. Bioorg Med Chem. .

Abstract

Abnormal epigenetics has been recognised as an early event in tumour progression and aberrant acetylation of lysine in particular has been understood in tumorigenesis. Therefore, it has become an attractive target for anticancer drug development. However, HDAC inhibitors have limited success due to toxicity and drug resistance concerns. Present study deals with design and synthesis of bivalent indanone based HDAC6 and antitubulin ligands as anticancer agents. Two of the analogues 9 and 21 exhibited potent antiproliferative activities (IC50, 0.36-3.27 µM) and high potency against HDAC 6 enzyme. Compound 21 showed high selectivity against HDAC 6 while 9 exhibited low selectivity. Both the compounds also showed microtubule stabilization effects and moderate anti-inflammatory effect. Dual targeted anticancer agents with concomitant anti-inflammatory effects will be more attractive clinical candidates in future.

Keywords: Acute oral toxicity; Anticancer; Antiinflammatory; Histone deacetylases; Leukemia; Microtubules.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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