Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor (original) (raw)
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Journal of Medicinal Chemistry, 2000
A new series of 2,6,9-trisubstituted purines, characterized by the presence of a common alkynyl substituent at C-2 and a range of different anilino/benzylamino groups at C-6, were synthesized. These compounds were evaluated for their capacity to inhibit cyclin-dependent kinase activity (CDK1-cyclin B) in vitro. Compounds 4e (N-6-p-Cl-benzylamino derivative) and 5e (N-6-m-Cl-anilino derivative) exhibited the strongest inhibitory activity with an IC 50 of 60 nM. The structure of compound 4b (N-6-p-methoxybenzylamino derivative) in complex with human CDK2 was determined by X-ray crystallography, revealing the molecular basis of inhibition by this molecule. Subsequent molecular modeling studies allowed us to rationalize the SAR observed for these compounds.
Journal of Medicinal Chemistry, 2014
Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O 6cyclohexylmethylguanine derivatives, revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a 'reverse' binding mode where the purine backbone has flipped 180°. This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these 'reverse' binding mode inhibitors to that of the parent 2-amino-6cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)purine derivative exhibited sub-micromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography.
Journal of Medicinal Chemistry
Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O6-cyclohexylmethylguanine derivatives, revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a 'reverse' binding mode where the purine backbone has flipped 180°. This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these 'reverse' binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited sub-mic...
Bioorganic & Medicinal Chemistry, 2010
A series of novel purine and pyrimidine derivatives were prepared and biologically evaluated for their in vitro anti-CDK2/cyclin A3 and antitumor activities in Ehrlich ascites carcinoma (EAC) cell based assay. The novel purine derivatives 13a,b demonstrated potent inhibitor activities with IC50 values of 14 ± 9 and 13 ± 9 μM, respectively. Additionally, compound 15a showed the highest potency (IC50 = 10 ± 6 μM) in EAC cell based assay. Molecular modeling study, including fitting to a 3D-pharmacophore model and their docking into cyclin dependant kinase2 (CDK2) active site showed high fit values and docking scores.The manuscript describes the investigation of a series of novel purine and pyrimidine derivatives, which were prepared in good yield by using diaminomaleonitrile and tosylisocyanate in acetonitrile. Molecular modeling studies, including fitting to a 3D-pharmacophore model their docking into cycline-dependent kinase2 (CDK2) active site were performed to understand the structural features of CDK2 inhibitors. Biological evaluation for both in vitro CDK2/cyclinA3 inhibition activity and antitumor activity in Ehrlich ascites carcinoma (EAC) cell based assay were also carried out.
Docking-Based Development of Purine-like Inhibitors of Cyclin-Dependent Kinase-2
Journal of Medicinal Chemistry, 2000
The cell division cycle is controlled by cyclin-dependent kinases (cdk), which consist of a catalytic subunit (cdk1-cdk8) and a regulatory subunit (cyclin A-H). Purine-like inhibitors of cyclindependent kinases have recently been found to be of potential use as anticancer drugs. Rigid and flexible docking techniques were used for analysis of binding mode and design of new inhibitors. X-ray structures of three (ATP, olomoucine, roscovitine) cdk2 complexes were available at the beginning of the study and were used to optimize the docking parameters. The new potential inhibitors were then docked into the cdk2 enzyme, and the enzyme/inhibitor interaction energies were calculated and tested against the assayed activities of cdk1 (37 compounds) and cdk2 (9 compounds). A significant rank correlation between the activity and the rigid docking interaction energy has been found. This implies that (i) the rigid docking can be used as a tool for qualitative prediction of activity and (ii) values obtained by the rigid docking technique into the cdk2 active site can also be used for the prediction of cdk1 activity. While the resulting geometries obtained by the rigid docking are in good agreement with the X-ray data, the flexible docking did not always produce the same inhibitor conformation as that found in the crystal.
Journal of medicinal chemistry, 2016
Purines and related heterocycles substituted at C-2 with 4'-sulfamoylanilino and at C-6 with a variety of groups have been synthesized with the aim of achieving selectivity of binding to CDK2 over CDK1. 6-Substituents that favour competitive inhibition at the ATP binding site of CDK2 were identified and typically exhibited 10-80-fold greater inhibition of CDK2 compared to CDK1. Most impressive was 4-((6-([1,1'-biphenyl]-3-yl)-9H-purin-2-yl)amino) benzenesulfonamide (73) that exhibited high potency towards CDK2 (IC50 0.044 μM), but was ~ 2000-fold less active towards CDK1 (IC50 86 μM). This compound is therefore a useful tool for studies of cell cycle regulation. Crystal structures of inhibitor-kinase complexes showed that the inhibitor stabilizes a glycine-rich loop conformation that shapes the ATP ribose binding pocket, and that is preferred in CDK2, but has not been observed in CDK1. This aspect of the active site may be exploited for the design of inhibitors that distingu...
Annals of the New York Academy of Sciences, 1999
The frequent deregulation of cell cycle progression in cancer 1 has prompted an active search for kinase inhibitors with high affinity and specificity for cyclin-dependent kinases (Cdks). Three major classes of Cdk-targeting drugs have been identified to date, including butyrolactone I, 2 polyhydroxylated flavones such as flavopiridol, 3 and substituted purines. 4 The first substituted purine derivative acting as a selective Cdk inhibitor, olomoucine, has been identified from screening against Cdk1/cyclin B complex. 5 Olomoucine competitively inhibits Cdk1, Cdk2, Cdk5, and, to a lesser extent, Erk1. 5 Recent results have pointed to unexpected pharmacologic properties of 2,6,9trisubstituted purines derived from the olomoucine lead structure. 6,7 To investigate the question in more detail, we developed a program for synthesis and evaluation of new compounds in this series. Twenty-seven derivatives were synthesized and assayed for specific inhibition of Cdk1/cyclin B from starfish oocytes and human recombinant Cdk5/p35 complex. In agreement with earlier results, 5 data showed that a strong correlation exists between inhibitory efficiencies against Cdk1 and Cdk5. In contrast, all compounds were only marginally active against Erk1 and Erk2 kinases. One compound in the series, ML-1437, proved much more active than olomoucine against purified Cdk1/cyclin B, Cdk5/p35, and Cdk2/cyclin E. It also showed pronounced cytotoxicity against human cervix carcinoma HeLa cells in vitro, even on short exposure. Growing IMR-90 (human normal fibroblasts), LoVo (human colon adenocarcinoma), and SQ-20B (human head and neck squamous carcinoma) cells gave similar results, but drug resistance increased rapidly as cells (SQ-20B and IMR-90) reached confluence. These results suggest that the affinity for Cdks and the cytotoxic potential of the drugs are interrelated (FIG. 1, TABLE 1). With the exception of pronounced lengthening of S phase transit during early-S in synchronized HeLa cells, ML-1437 at subtoxic concentration proved unable to produce reversible arrest of the cell cycle progression. When observed, arrest in the G1 and G2 phases of the cell cycle correlated with induced cell death, and chronic exposure to lethal doses of the drug resulted in massive micronucleation in relation to mitotic cell death, with no evidence of endoreduplication (polyploidization) or apd
Tetrahedron Letters, 2001
Purine bound resins 1a-c were obtained by the reaction of 6-thiopurines 2 or 6-chloropurines 3-5 with Merrifield-Cl or -SH resins (DMF, 70°C, base). S-Oxidation of resins 1c and reaction of the desired sulfone with p-methoxybenzylamine to give 6, proved effective for release of the purine from the resin and simultaneous C-6 substitution. Reaction of resin 1c with pyrrolidine and pyrrolidine-2-methanol prior to S-oxidation led to the C-2 amine substituted resin bound purines 8 and 9. Activation of sulfur in these intermediates, followed by reaction with Ar-CH 2 -NH 2 gave the 2,6,9-trisubstituted purines 10-14 in 42-60% yields.