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.
Isatin derivatives with activity against apoptosis-resistant cancer cells
Evdokimov, Nikolai M.,Magedov, Igor V.,McBrayer, Dominic,Kornienko, Alexander
, p. 1558 - 1560 (2016)
In a search of small molecules active against apoptosis-resistant cancer cells, a series of isatin-based heterocyclic compounds were synthesized and found to inhibit proliferation of cancer cell lines resistant to apoptosis. The synthesis of these compounds involved a condensation of commercially available, active methylene heterocycles with isatin proceeding in moderate to excellent yields. The heterocyclic scaffolds prepared in the current investigation appear to be a useful starting point for the development of agents to fight cancers with apoptosis resistance, and thus, associated with dismal prognoses.
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.
Indirubin derivatives protect against endoplasmic reticulum stress-induced cytotoxicity and down-regulate CHOP levels in HT22 cells
Kosuge, Yasuhiro,Saito, Hiroaki,Haraguchi, Tatsuki,Ichimaru, Yoshimi,Ohashi, Sachiyo,Miyagishi, Hiroko,Kobayashi, Shunsuke,Ishige, Kumiko,Miyairi, Shinichi,Ito, Yoshihisa
, p. 5122 - 5125 (2017)
Indirubin and its derivatives have been reported to exhibit anti-cancer and anti-inflammatory activities. Recently, some of its derived analogs have been shown to have neuroprotective potential. Endoplasmic reticulum (ER) stress has been demonstrated to contribute to the pathogenesis of various neurodegenerative diseases, whereas the effects of indirubin derivatives on ER stress-induced cell death have not been addressed. In the present study, a series of 44 derivatives of indirubin was prepared to search for a novel class of neuroprotective agents against ER stress-induced neuronal death. The MTT reduction assay indicated that tunicamycin (TM), an inducer of ER stress, significantly decreased the viability of hippocampal neuronal HT22 cells. Among the compounds tested, eight showed significant inhibitory activity against TM-induced cell death. Western blot analysis showed that application of these analogs to the cells simultaneously with TM reduced the TM-induced expression of CHOP, an established mediator of ER stress. Our results suggest that the preventive effect of these indirubin derivatives against ER stress-induced neuronal death may be due, at least in part, to attenuation of the CHOP-dependent signaling system.
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 new indirubin derivatives and their in vitro anticancer activity
Nguyen, Dan Trong,Truong, Giang Nguyen,Van Vuong, Truong,Van, Tai Nguyen,Manh, Cuong Nguyen,Dao, Cuong To,Thuy, Thuy Dinh Thi,Van, Chinh Luu,Khac, Vu Tran
, p. 1083 - 1092 (2019)
The opening of epoxy rings from (2′Z)-N-1-(oxiran-2-ylmethyl)indirubin (2) and (2′Z-3′E)-indirubin-3?-[O-oxiran-2-ylmethyl)oxime] (6) with thiols gave 17 new derivatives of indirubin in good yields. Their structures were elucidated by 1D-, 2D-NMR and HRMS
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.
A tunable synthesis of indigoids: Targeting indirubin through temperature
Cheek, Joshua T.,Horner, John S.,Kaller, Kaylie S.,Kinsey, Ally L.,Shriver, James A.,Sterrenberg, Summer R.,Van Vors, Madison K.,Wang, Katelyn R.
, p. 5407 - 5414 (2022/03/01)
The spontaneous conversion of 3-indoxyl to indigo is a well-established process used to produce indigo dyes. It was recently shown that some indoles, when reacted with molybdenum hexacarbonyl and cumyl peroxide, proceed through an indoxyl intermediate to produce significant amounts of indirubin through a competing mechanism. Modulation of this system to lower temperatures allows for careful tuning, leading to selective production of indirubins in a general process. A systematic assay of indoles show that electron deficient indoles work well when substituted at the 5 and 7 positions. In contrast, 6-substituted electron rich indoles give the best results whereas halogeno indoles work well in all cases. This process shows broad functional group tolerance for generally reactive carbonyl-containing compounds such as aldehydes and carboxylic acids. This journal is
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.
