双靶向2-亚苄基茚满酮侧链异羟肟酸基团具有选择性抑制HDAC6的作用以及微管蛋白稳定效应。
Dual targeted 2-Benzylideneindanone pendant hydroxamic acid group exhibits selective HDAC6 inhibition along with tubulin stabilization effect.
作者信息
Kumar Kapil, Das Ranjana, Thapa Barsha, Rakhecha Bharti, Srivastava Sapna, Savita Kumari, Israr Monazza, Chanda Debabrata, Banerjee Dibyendu, Shanker Karuna, Bawankule D U, Santini Benedetta, Di Paolo Maria Luisa, Via Lisa Dalla, Passarella Daniele, Negi Arvind Singh
机构信息
CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India.
CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
出版信息
Bioorg Med Chem. 2023 May 15;86:117300. doi: 10.1016/j.bmc.2023.117300. Epub 2023 Apr 27.
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 (IC, 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.
异常表观遗传学已被认为是肿瘤进展的早期事件，尤其是赖氨酸的异常乙酰化在肿瘤发生过程中已得到认识。因此，它已成为抗癌药物开发的一个有吸引力的靶点。然而，由于毒性和耐药性问题，组蛋白去乙酰化酶（HDAC）抑制剂的成功有限。目前的研究涉及基于茚满酮的二价HDAC6和抗微管蛋白配体的设计与合成，作为抗癌剂。其中两个类似物9和21表现出强大的抗增殖活性（IC，0.36 - 3.27 μM）以及对HDAC 6酶的高效活性。化合物21对HDAC 6表现出高选择性，而9表现出低选择性。这两种化合物还显示出微管稳定作用和适度的抗炎作用。具有伴随抗炎作用的双靶点抗癌剂在未来将成为更具吸引力的临床候选药物。
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