2-Substituted paullones: CDK1/cyclin B-inhibiting property and in vitro antiproliferative activity

Kunick, Conrad; Schultz, Christiane; Lemcke, Thomas; Zaharevitz, Daniel; Gussio, Rick; Jalluri, Ravi; Sausville, Edward A.; Leost, Maryse; Meijer, Laurent

doi:10.1016/s0960-894x(00)00048-2

Cited by 69 publications

(48 citation statements)

References 11 publications

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“…Indirubin derivatives can inhibit CDK and GSK-3 kinases (10,25,28) and possess antitumor activity (28). (iii) Group three consisted of the paullones, which were originally discovered by screening the National Cancer Institute Human Tumor Cell Line Anti-Cancer Drug Screen data for compounds with patterns of activity similar to those of the known CDK inhibitor flavopiridol (42) and which are also inhibitors of CDKs and GSK-3 kinases (23,26,42). Our laboratory has already shown that flavopiridol inhibits CRK3 and causes cell cycle arrest at the G 2 /M phase of the cell cycle in L. mexicana (16).…”

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confidence: 99%

Inhibitors of Leishmania mexicana CRK3 Cyclin-Dependent Kinase: Chemical Library Screen and Antileishmanial Activity

Grant

Dunion

Yardley

et al. 2004

Antimicrob Agents Chemother

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The CRK3 cyclin-dependent kinase of Leishmania has been shown by genetic manipulation of the parasite to be essential for proliferation. We present data which demonstrate that chemical inhibition of CRK3 impairs the parasite's viability within macrophages, thus further validating CRK3 as a potential drug target. A microtiter plate-based histone H1 kinase assay was developed to screen CRK3 against a chemical library enriched for protein kinase inhibitors. Twenty-seven potent CRK3 inhibitors were discovered and screened against Leishmania donovani amastigotes in vitro. Sixteen of the CRK3 inhibitors displayed antileishmanial activity, with a 50% effective dose (ED 50 ) of less than 10 M. These compounds fell into four chemical classes: the 2,6,9-trisubstituted purines, including the C-2-alkynylated purines; the indirubins; the paullones; and derivatives of the nonspecific kinase inhibitor staurosporine. The paullones and staurosporine derivatives were toxic to macrophages. The 2,6,9-trisubstituted purines inhibited CRK3 in vitro, with 50% inhibitory concentrations ranging from high nanomolar to low micromolar concentrations. The most potent inhibitors of CRK3 (compounds 98/516 and 97/344) belonged to the indirubin class; the 50% inhibitory concentrations for these inhibitors were 16 and 47 nM, respectively, and the ED 50 s for these inhibitors were 5.8 and 7.6 M, respectively. In culture, the indirubins caused growth arrest, a change in DNA content, and aberrant cell types, all consistent with the intracellular inhibition of a cyclin-dependent kinase and disruption of cell cycle control. Thus, use of chemical inhibitors supports genetic studies to confirm CRK3 as a validated drug target in Leishmania and provides pharmacophores for further drug development.

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confidence: 99%

Inhibitors of Leishmania mexicana CRK3 Cyclin-Dependent Kinase: Chemical Library Screen and Antileishmanial Activity

Grant

Dunion

Yardley

et al. 2004

Antimicrob Agents Chemother

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“…Introduction of additional substituents or the replacement of the lactam structure did not yield more active compounds, although substituents of the benzazepine scaffold especially at position 2 are tolerated. [164] Enzyme kinetic and molecular modeling studies revealed that paullones interact with the ATP binding pocket. Further targets of this substances were identified in subsequent studies and, besides the CDKs, GSK3a and b were inhibited in the nanomolar range.…”

Section: Paullonesmentioning

confidence: 99%

Small Molecules as Inhibitors of Cyclin‐Dependent Kinases

2003

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Cell division (mitosis) is one of the basic requirements for multicellular oranisms. The capability of a cell to replicate enables a complex assembly to be created. Faulty regulation of the control mechanism in the cell cycle leads to an excessive cell proliferation and is the cause of cancer. The key position of the cyclin-dependent kinases (CDKs) and their direct partners, as well as the fact that the majority of malign illnesses show defects in at least one of these key players of the cell cycle, is of great interest for the development of low-molecular-weight CDK inhibitors. In this Review an overview of the different structural classes of ATP-competitive inhibitors of CDKs are given, whose devlopment was aimed at battling cancer. The Review shows how far the development of selective CDK inhibitors has progressed and to what extent the expectations for such drugs have so far been fulfilled.

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“…Owing to the importance of N-heterocycles, individual role of indole and azepine in cancer prevention, and ring fusion concepts, development of indole-fused azepines may be of critical importance toward the potential success in cancer drug discovery. In addition, considering potency and in vitro cell line selectivity, several indole-fused azepines including paullones [9][10][11][12][13][14] open a new venture for the discovery of novel potential anticancer agents. Although several…”

Section: Introductionmentioning

confidence: 99%

Determination of 5h-Benzo[2,3][1,4]oxazepino[5,6-B]indoles in Rat Plasma by Reversed-Phase High-Performance Liquid Chromatographic-Ultraviolet Method: Application to Pharmacokinetic Studies

Singh

Raj

Rai

et al. 2017

Asian J Pharm Clin Res

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Objective: Recently, we reported newly synthesized 5H-benzo [2,3] [1,4]oxazepino [5,6-b]indole) derivatives and proved their cytotoxicity against hepatocellular carcinoma specific Hep-G2 cell lines. We attempted herein to describe a reversed-phase high-performance liquid chromatographic method for the determination of three most active compounds 6a, 10a, and 15a in rat plasma to predict their pharmacokinetics parameters before in vivo study. Methods:A rapid and sensitive reversed-phase high-performance liquid chromatographic was employed for the determination of 6a, 10a, and 15a in rat plasma. Each compound was separated by a gradient elution of acetonitrile and water with 1 mL/min flow rate. The detector was set at 270, 285, and 275 nm for 6a, 10a, and 15a and the recorded elution times were 2.00, 2.87, and 1.88 min, respectively. Results:The calibration curve was linear with R 2 of 0.938, 0.875, and 0.923 over the concentration range of 0.1-50 µg/mL. The inter-and intraday variations of the assay were lower than 12.26%; the average recovery of 6a, 10a, and 15a was 97.31, 92.56, and 95.23 % with relative standard deviation of 2.12%, 3.25%, and 2.28%, respectively. The C max and T max were ~ 46.34, 18.56, and 25.65 µg/mL and 2.0, 4.0, and 4.0 h for 6a, 10a, and 15a, respectively, which indicate a robust method of detection in the present experiment. Conclusion:The study suggests that all of the three compounds have a lower rate of absorption, higher volume of distribution, and lower clearance rate, indicating good therapeutic response for in vivo activity.

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2-Substituted paullones: CDK1/cyclin B-inhibiting property and in vitro antiproliferative activity

Cited by 69 publications

References 11 publications

Inhibitors of Leishmania mexicana CRK3 Cyclin-Dependent Kinase: Chemical Library Screen and Antileishmanial Activity

Inhibitors of Leishmania mexicana CRK3 Cyclin-Dependent Kinase: Chemical Library Screen and Antileishmanial Activity

Small Molecules as Inhibitors of Cyclin‐Dependent Kinases

Determination of 5h-Benzo[2,3][1,4]oxazepino[5,6-B]indoles in Rat Plasma by Reversed-Phase High-Performance Liquid Chromatographic-Ultraviolet Method: Application to Pharmacokinetic Studies

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