- Synthesis and biological evaluation of seliciclib derivatives as potent and selective CDK9 inhibitors for prostate cancer therapy
-
Seliciclib is a cyclin-dependent kinase (CDK) inhibitor that has been assayed in phase II clinical trials as an anticancer agent. This paper describes the synthesis of novel derivatives of seliciclib with improved potency, metabolic stability, aqueous solubility, and anti-proliferative activity. The new derivatives showed a novel CDKs selectivity profile. Replacement of ethyl alcohol at position 2 of purine with dimethylaminopropyl and fluorination of benzyl at position 6 of purine of seliciclib resulted in the formation of a derivative that potently and selectively inhibited CDK9 (26?nM vs. CDK9 and > 60-fold selectivity vs. CDK2/5/7). In comparison to seliciclib, this derivative shows lower metabolic clearance (25% lower in Clint), higher aqueous solubility and is more cytotoxic in androgen-independent prostate cancer cells. Graphic abstract: [Figure not available: see fulltext.].
- Alsfouk, Aisha A.,Alshibl, Hanan M.,Altwaijry, Najla A.,Alsfouk, Bshra A.,Al-Abdullah, Ebtehal S.
-
-
Read Online
- Adamantane-substituted purines and their β-cyclodextrin complexes: Synthesis and biological activity
-
Cyclin-dependent kinases (CDKs) play an important role in the cell-division cycle. Synthetic inhibitors of CDKs are based on 2,6,9-trisubstituted purines and are developed as potential anticancer drugs; however, they have low solubility in water. In this
- ?melík, Richard,Kry?tof, Vladimír,Rouchal, Michal,Rudolfová, Jana,Vícha, Robert,Vojá?ková, Veronika
-
-
- Synthesis and pharmacophore modelling of 2,6,9-trisubstituted purine derivatives and their potential role as apoptosis-inducing agents in cancer cell lines
-
Twelve compounds were obtained by a three step synthetic procedure using microwave irradiation in a pivotal step. All compounds were evaluated in vitro to determine their potential effect on cell toxicity by the MTT method and flow cytometry analysis on four cancer cells lines and Vero cells. Three out of twelve compounds were found to be promising agents compared to a known and effective anticancer drug, etoposide, in three out of four cancer cell lines assayed with considerable selectivity. Preliminary flow cytometry data suggests that compounds mentioned above induce apoptosis on these cells. The main structural requirements for their activity for each cancer cell line were characterized with a preliminary pharmacophore model, which identified aromatic centers, hydrogen acceptor/donor center and a hydrophobic area. These features were consistent with the cytotoxic activity of the assayed compounds.
- Calderón-Arancibia, Jeannette,Espinosa-Bustos, Christian,Ca?ete-Molina, álvaro,Tapia, Ricardo A.,Faúndez, Mario,Torres, Maria Jose,Aguirre, Adam,Paulino, Margot,Salas, Cristian O.
-
p. 6808 - 6826
(2015/05/06)
-
- The first iron(III) complexes with cyclin-dependent kinase inhibitors: Magnetic, spectroscopic (IR, ES+ MS, NMR, 57Fe M?ssbauer), theoretical, and biological activity studies
-
The first FeIII complexes 1-6 with cyclin-dependent kinase (CDK) inhibitors of the type [Fe(Ln)Cl3]·nH2O (n=0 for 1, 1 for 2, 2 for 3-6; L1-L6=C2- and phenyl-substituted CDK inhibitors derived from 6-benzylamino-9-isopropylpurine), have been synthesized and characterized by elemental analysis, IR, 57Fe Mo?ssbauer, 1H and 13C NMR, and ES+ mass spectroscopies, conductivity and magnetic susceptibility measurements, and thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The study revealed that the compounds are mononuclear, tetrahedral high-spin (S=5/2) FeIII complexes with an admixture of an S=3/2 spin state originating probably from five-coordinated FeIII ions either connecting with a bidentate coordination mode of the CDK inhibitor ligand or relating to the possibility that one crystal water molecule enters the coordination sphere of the central atom in a portion of molecules of the appropriate complex. Nearly spin-only value of the effective magnetic moment (5.82μeff/μB) was determined for compound 1 due to absence of crystal water molecule(s) in the structure of the complex. Based on NMR data and DFT calculations, we assume that the appropriate organic ligand is coordinated to the FeIII ion through the N7 atom of a purine moiety. The cytotoxicity of the complexes was tested in vitro against selected human cancer cell lines (G-361, HOS, K-562 and MCF-7) along with the ability to inhibit the CDK2/cyclinE kinase. The best cytotoxicity (IC50: 4-23μM) and inhibition activity (IC50: 0.02-0.09μM) results have been achieved in the case of complexes 2-4, and complexes 3, 4 and 6, respectively. In addition, the X-ray structure of 2-chloro-6-benzylamino-9-isopropylpurine, i.e. a precursor for the preparation of L1, L4 and L5, is also described.
- Trávní?ek, Zdeněk,Popa, Igor,?ajan, Michal,Zbo?il, Radek,Kry?tof, Vladimír,Mikulík, Ji?í
-
scheme or table
p. 405 - 417
(2011/12/22)
-
- Practical synthesis of roscovitine and CR8
-
Roscovitine and CR8 are potent inhibitors of cyclin-dependent kinases. A scalable synthesis of both inhibitors is described. In the case of CR8, the biarylmethylamine moiety was obtained as a stable and high-purity salt.
- Oumata, Nassima,Ferandin, Yoan,Meijer, Laurent,Galons, Herve
-
experimental part
p. 641 - 644
(2010/04/22)
-
- 6,9-DISUBSTITUTED 2- TRANS-(4- AMINOCYCLOHEXYL) AMINO]PURINES
-
The present invention provides novel compounds of formula (I) wherein R is selected from the group consisting of R2, R2NH-, or H2N-R3- wherein R2 is selected from the group consisting of C1-C8 alkyl and formula (II), wherein Z is selected from the group c
- -
-
-
- 6,9,-disubstituted 2-[trans-(4-aminocyclohexyl) amino] purines
-
The present invention provides novel compounds of the formula (I) wherein R is selected from the group consisting of R2, R2NH—, or H2N—R3— wherein R2 is selected from the group consisting of C1-C8alkyl and ?wherein Z is selected from the group consisting of phenyl, heterocycle and cycloalkyl, each R4 is independently hydrogen or C1-C4alkyl, and n is an integer 1-8; wherein each C1-C8alkyl and Z is optionally substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of Ha1, OH, and C1-C4alkyl; R3 is C1-C8alkylene; and R1 is selected from the group consisting of cyclopentyl and isopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof. In addition, the present invention provides a method of inhibiting cell cycle progression. More specifically, the present invention provides a method of inhibiting cyclin dependent kinases, particularly cdk-2. The present invention also provides a method of preventing apoptosis in neuronal cells and a method of inhibiting the development of neoplasms. In addition, the present invention provides a composition comprising an assayable amount of a compound of Formula (I) in admixture or otherwise in association with an inert carrier. The present invention also provides a pharmaceutical composition comprising an effective inhibitory amount of a compound of Formula (I) in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.
- -
-
-
- Purine derivatives having, in particular, antiproliferative properties, and their biological uses
-
This invention provides 2-, 6, and 9-substituted purine derivatives having, in particular, antiproliferative properties, and suitable for use as pharmaceutical compositions and herbicidal compositions. Also provided are pharmaceutical compositions and her
- -
-
-
- Cyclin dependent kinase inhibitor
-
The present invention is based on the method of treating a patient suffering from leukemia comprising administering a therapeutically effective amount of the compound 2-([(3-hydroxypropyl)amino]-6-benzylamino)-9-isopropylpurine or a pharmaceutically accep
- -
-
-
- Synthesis and biological activities of C-2, N-9 substituted 6- benzylaminopurine derivatives as cyclin-dependent kinase inhibitor
-
In this study, C-2, N-9 substituted 6-benzylaminopurine derivatives were synthesized and their inhibitory effects on cyclin-dependent kinase (CDK2) were evaluated. The effect of substituents at the C-2 and N-9 positions of substituted purine was investigated. Among the compounds tested, compound 7b- iii (6-benzylamino-2-thiomorpholinyl-9-isopropylpurine) was the most active inhibitor (IC50 = 0.9 μM). Compound 7b-iii showed 10-fold higher activity compared to olomoucine and almost the same activity as roscovitine. Results from structure-activity relationship studies should allow the design of more potent and selective CDK inhibitors, which may provide an effective therapy for cancer or other CDK dependent diseases.
- Oh, Chang-Hyun,Lee, Su-Chul,Lee, Ki-Soo,Woo, Eun-Rhan,Hong, Chang Yong,Yang, Boem-Seok,Baek, Dae Jin,Cho, Jung-Hyuck
-
p. 187 - 190
(2007/10/03)
-
- Cytokinin-derived cyclin-dependent kinase inhibitors: Synthesis and cdc2 inhibitory activity of olomoucine and related compounds
-
Cyclin-dependent kinases (cdk) have recently raised considerable interest in view of their essential role in the regulation of the cell division cycle. The structure-activity relationships of edk inhibition showed that the 1, 3, and 7 positions of the purine ring must remain free, probably for a direct interaction, in which it behaves as a hydrogen bond acceptor. Olomoucine (6-(benzylamino)-2-[(2-hydroxyethyl)amino]-9-methylpurine, OC), roscovitine (6-(benzylamino)2(R)-[[1-(hydroxymethyl)propyl]amino]-9- isopropylpurine), and other N6,2,9-trisubstituted adenines were found to exert a strong inhibitory effect on the p34(cdc2)/cyclin B kinase. Removal or change of the side chain at position 2 or the hydrophobic group at position 9 dramatically decreased the inhibitory activity of olomoucine or roscovitine. Inhibition of cdk with OC and related compounds clearly arrests cell proliferation of many tumor cell lines at G1/S and G2/M transitions and also triggers apoptosis in the target tumor cells in vitro and in vivo. Thus, from a pharmacological point of view, OC may represent a model compound for a new class of antimitotic and antitumor drugs.
- Havlí?ek, Libor,Hanu?, Jan,Vesely, Jaroslav,Leclerc, Sophie,Meijer, Laurent,Shaw, Gordon,Strnad, Miroslav
-
p. 408 - 412
(2007/10/03)
-
