160807-49-8Relevant articles and documents
Studies on the acetylation and NMR reassignment of indirubin derivatives
Cuong, Nguyen Manh,Tai, Bui Huu,Hoan, Dang Hoang
, p. 99 - 105 (2010)
The analysis of 1D- and 2D-NMR spectroscopic data confirmed that the amino N-1' protons of indirubin and indirubin-3'-oxime resonate at a higher frequency than N-1 protons. The amino N-1' protons in both indirubin and indirubin-3'-oxime are not favourable for acetylated reaction due to their intramolecular hydrogen bonding with the amide carbonyl group. The new N-1-acetylindirubin-3'-acetoxime has been synthesised using acetic anhydride. The reassignment of the NMR data of indirubin, indirubin-3'-oxime and N-1-acetylindirubin was confirmed with the aid of DEPT, HSQC, HMBC and NOESY methods.
The synthesis, antileukemic activity, and crystal structures of indirubin derivatives
Li, Chunmin,Go, Yunhong,Mao, Zihua,Koyano, Kazuo,Kai, Yasushi,Kanehisa, Nobuko,Zhu, Qingtai,Zhou, Zhonghua,Wu, Souyu
, p. 1621 - 1627 (1996)
In order to search for a new kind of antileukemic drug, we synthesized four indirubin derivatives, including indirubin monooxime (IM), indirubin monooxime O-methyl ether (IMME), N1-methylindirubin monooxime O-methyl ether (MIMME), and indirubin monooxime O-ethyl ether (IMEE). Their antileukemic activities in vivo and in vitro were tested; some of these compounds showed good activities. Their molecular and crystal structures were determined by an X-ray diffraction method. The results revealed that all four indirubin derivatives are planar, and have a tendency to form a big π-system. The molecular structures also showed that oximation of indirubin resulted in only a slight change in the antileukemic activity. On the other hand, the amido moiety in the compounds may play an important role in the activity of the indirubin monooxime derivatives. This conclusion was supported by the calculation results of the electrostatic-potential (esp) derived charge distribution of the indirubin derivatives, which were obtained using an ab initio molecular orbital of the basis set (3-21G), taking the electronic correlation into account at the MP2 level.
Discovery of orally active indirubin-3′-oxime derivatives as potent type 1 FLT3 inhibitors for acute myeloid leukemia
Choi, Jungil,Han, Sun-Young,Heo, Jeong Doo,Jeong, Pyeonghwa,Kim, Jiheon,Kim, Na Yoon,Kim, Yong-Chul,Kim, Yoon-Gyoon,Lee, Hyo Jeong,Lee, Je-Heon,Lee, Jungeun,Lee, So-Deok,Moon, Yeongyu,Park, Hyun Woo,Park, Jiyeon,Shin, Ji Eun
, (2020)
FMS-like receptor tyrosine kinase-3 (FLT3) is expressed on acute leukemia cells and is implicated in the survival, proliferation and differentiation of hematopoietic cells in most acute myeloid leukemia (AML) patients. Despite recent achievements in the development of FLT3-targeted small-molecule drugs, there are still unmet medical needs related to kinase selectivity and the progression of some mutant forms of FLT3. Herein, we describe the discovery of novel orally available type 1 FLT3 inhibitors from structure-activity relationship (SAR) studies for the optimization of indirubin derivatives with biological and pharmacokinetic profiles as potential therapeutic agents for AML. The SAR exploration provided important structural insights into the key substituents for potent inhibitory activities of FLT3 and in MV4-11 cells. The profile of the most optimized inhibitor (36) showed IC50 values of 0.87 and 0.32 nM against FLT3 and FLT3/D835Y, respectively, along with potent inhibition against MV4-11 and FLT3/D835Y expressed MOLM14 cells with a GI50 value of 1.0 and 1.87 nM, respectively. With the high oral bioavailability of 42.6%, compound 36 displayed significant in vivo antitumor activity by oral administration of 20 mg/kg once daily dosing schedule for 21 days in a mouse xenograft model. The molecular docking study of 36 in the homology model of the DFG-in conformation of FLT3 resulted in a reasonable binding mode in type 1 kinases similar to the reported type 1 FLT3 inhibitors Crenolanib and Gilteritinib.
Synthesis of methoxy- and bromo-substituted indirubins and their activities on apoptosis induction in human neuroblastoma cells
Saito, Hiroaki,Tabata, Keiichi,Hanada, Satoshi,Kanda, Yuko,Suzuki, Takashi,Miyairi, Shinichi
, p. 5370 - 5373 (2011)
This paper reports the synthesis of methoxy- and bromo-indirubins, and their antiproliferative activities in human neuroblastoma. Among 20 compounds, 5'-methoxyindirubin induced cell death in human neuroblastoma cells (IMR-32, SK-N-SH and NB-39) without inhibiting normal cells (NHDF and HUVEC). Typical morphologic features of apoptosis were observed in 5′-methoxyindirubin- treated cells by Hoechst 33342 staining. Additional studies by flow cytometry support apoptosis induction. These data suggest that 5′-methoxyindirubin might be an effective drug for treatment of neuroblastoma.
Design, synthesis and biological evaluation of bisindole derivatives as anticancer agents against Tousled-like kinases
Lee, Sung-Bau,Chang, Ting-Yu,Lee, Nian-Zhe,Yu, Zih-Yao,Liu, Chi-Yuan,Lee, Hsueh-Yun
, (2021/10/20)
This study presents the design, synthesis, and characterization of bisindole molecules as anti-cancer agents against Tousled-like kinases (TLKs). We show that compound 2 composed of an indirubin-3′-oxime group linked with a (N-methylpiperidin-2-yl)ethyl moiety possessed inhibitory activity toward both TLK1 and TLK2 in vitro and diminished the phosphorylation level of the downstream substrate anti-silencing function 1 (ASF1) in replicating cells. The treatment of compound 2 impaired DNA replication, slowed S-phase progression, and triggered DNA damage response in replicating cells. Structure optimization further discovered six derivatives exhibiting potent TLK inhibitory activity and revealed the importance of the tertiary amine-containing moiety of the side chain. Moreover, the derivatives 6, 17, 19, and 20 strongly suppressed the growth of triple-negative breast cancer MDA-MB-231 cells, non-small cell lung cancer A549 cells, and colorectal cancer HCT-116 cells, while normal lung fibroblast MRC5 and IMR90 cells showed a lower response to these compounds. Taken together, this study identifies tertiary amine-linked indirubin-3′-oximes as potent anticancer agents that inhibit TLK activity.
Indirubin Derivatives as Dual Inhibitors Targeting Cyclin-Dependent Kinase and Histone Deacetylase for Treating Cancer
An, Jianxiong,Cao, Zhuoxian,Gu, Zhicheng,He, Bin,Li, Yan,Li, Yongjun,Lin, Hening,Lin, Shuxian,Liu, Ting,Wang, Jie,Wang, Pan,Yang, Fenfen,Zhao, Yonglong
, p. 15280 - 15296 (2021/10/25)
To utilize the unique scaffold of a natural product indirubin, we herein adopted the strategy of combined pharmacophores to design and synthesize a series of novel indirubin derivatives as dual inhibitors against cyclin-dependent kinase (CDK) and histone deacetylase (HDAC). Among them, the lead compound 8b with remarkable CDK2/4/6 and HDAC6 inhibitory activity of IC50 = 60.9 ± 2.9, 276 ± 22.3, 27.2 ± 4.2, and 128.6 ± 0.4 nM, respectively, can efficiently induce apoptosis and S-phase arrest in several cancer cell lines. In particular, compound 8b can prevent the proliferation of a non-small-cell lung cancer cell line (A549) through the Mcl-1/XIAP/PARP axis, in agreement with the unique modes of action of the combined agents of HDAC inhibitors and CDK inhibitors. In an A549 xerograph model, compound 8b showed significant antitumor efficacy correlated with its dual inhibition. Our data demonstrated that compound 8b as a single agent could be a promising drug candidate for cancer therapy in combination with CDK and HDAC inhibitors.
