220036-08-8Relevant articles and documents
NU-6027 Inhibits Growth of Mycobacterium tuberculosis by Targeting Protein Kinase D and Protein Kinase G
Kidwai, Saqib,Bouzeyen, Rania,Chakraborti, Sohini,Khare, Neha,Das, Sumana,Gosain, Tannu Priya,Behura, Assirbad,Meena, Chhuttan Lal,Dhiman, Rohan,Essafi, Makram,Bajaj, Avinash,Saini, Deepak Kumar,Srinivasan, Narayanaswamy,Mahajan, Dinesh,Singh, Ramandeep
, (2019)
Tuberculosis (TB) is a global health concern, and this situation has further worsened due to the emergence of drug-resistant strains and the failure of BCG vaccine to impart protection. There is an imperative need to develop highly sensitive, specific dia
Cyclin dependent kinase inhibitors
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Page/Page column 9-10, (2010/02/05)
A range is disclosed of pyrimidine derivatives (I) which can act as inhibitors of cyclin dependent kinases (CDK's) and which thereby can provide useful therapeutic compounds for use in treatment of tumours or other cell proliferation disorders. The compounds of this invention bind to CDK molecules in a manner that appears to differ from that of known CDK inhibitors such as olomoucine and roscovitine. In formula (I), X is O, S or CHRxwhere Rxis H or C1-4alkyl; D is H or NZ1Z2where Z1and Z2are each independently H, C1-4alkyl, C1-4hydroxyalkyl, optionally substituted aryl or optionally substituted aralkyl; A is selected from H, C1-4alkyl, C1-4alkoxy, hydroxy, CH2(CH2)nOH (n=1-4), and NRa1Ra2where Ra1and Ra2are each independently H or C1-4alkyl; Y is or includes an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring; D′ is H or NZ3Z4where Z3and Z4are each independently H, C1-4alkyl, C1-4hydroxyalkyl, optionally substituted aryl or optionally-substituted aralkyl; E is selected from NO, NO2, N═N—Ar where Ar is an optionally substituted aryl or optionally substituted aralkyl, NRe1Re2or Nre1Nre2Re3(Re1, Re2and Re3each being independently H, C1-4alkyl, C1-4hydroxyalkyl, an optionally substituted aryl or an optionally substituted aralkyl), C(Re)═U (Rebeing hydrogen, C1-4alkyl or substituted alkyl, e.g. hydroxyalkyl, or an unsubstituted or substituted aryl or aralkyl, e.g. benzyl, and U being selected from O, Nre′, NORe′ and N—NRe′Re″ where Re′ and Re″ are each independently H, C1-4alkyl or CONH2), T, CH2T, CHT2and CT3, where T is a halide I, Br, Cl or F.
4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2.
Mesguiche, Veronique,Parsons, Rachel J,Arris, Christine E,Bentley, Johanne,Boyle, F Thomas,Curtin, Nicola J,Davies, Thomas G,Endicott, Jane A,Gibson, Ashleigh E,Golding, Bernard T,Griffin, Roger J,Jewsbury, Philip,Johnson, Louise N,Newell, David R,Noble, Martin E M,Wang, Lan Z,Hardcastle, Ian R
, p. 217 - 222 (2007/10/03)
The cyclin dependent kinase (cdk) inhibitor NU6027, 4-cyclohexylmethoxy-5-nitroso-pyrimidine-2,6-diamine (IC(50) vs cdk1/cyclinB1=2.9+/-0.1 microM and IC(50) vs cdk2/cyclinA3=2.2+/-0.6 microM), was used as the basis for the design of a series of 4-alkoxy-2,6-diamino-5-nitrosopyrimidine derivatives. The synthesis and evaluation of 21 compounds as potential inhibitors of cyclin-dependent kinases 1 and 2 is described and the structure-activity relationships relating to NU6027 have been probed. Simple alkoxy- or cycloalkoxy-groups at the O(4)-position were tolerated, with the 4-(2-methylbutoxy)-derivative (IC(50) vs cdk1/cyclinB1=12+/-2 microM and cdk2/cyclinA3=13+/-4 microM) retaining significant activity. Substitutions at the N(6) position were not tolerated. Replacement of the 5-nitroso substituent with ketone, oxime and semicarbazone groups essentially abolished activity. However, the derivative bearing an isosteric 5-formyl group, 2,6-diamino-4-cyclohexylmethoxy-pyrimidine-5-carbaldehyde, showed modest activity (IC(50) vs cdk1/cyclinB1=35+/-3 microM and cdk2/cyclinA3=43+/-3 microM). The X-ray crystal structure of the 5-formyl compound bound to cdk2 has been determined to 2.3A resolution. The intramolecular H-bond deduced from the structure with NU6027 bound to cdk2 is not evident in the structure with the corresponding formyl compound. Thus the parent compound, 4-cyclohexylmethoxy-5-nitrosopyrimidine-2,6-diamine (NU6027), remains the optimal basis for future structure-activity studies for cyclin-dependent kinase inhibitors in this series.
Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles
Arris, Christine E.,Boyle, F. Thomas,Calvert, A. Hilary,Curtin, Nicola J.,Endicott, Jane A.,Garman, Elspeth F.,Gibson, Ashleigh E.,Golding, Bernard T.,Grant, Sharon,Griffin, Roger J.,Jewsbury, Philip,Johnson, Louise N.,Lawrie, Alison M.,Newell, David R.,Noble, Martin E. M.,Sausville, Edward A.,Schultz, Robert,Yu, Wyatt
, p. 2797 - 2804 (2007/10/03)
Substituted guanines and pyrimidines were tested as inhibitors of cyclin B1/CDK1 and cyclin A3/CDK2 and soaked into crystals of monomeric CDK2. O6- Cyclohexylmethylguanine (NU2058) was a competitive inhibitor of CDK1 and CDK2 with respect to ATP (K(i) values: CDK1, 5 ± 1 μM; CDK2, 12 ± 3 μM) and formed a triplet of hydrogen bonds (i.e., NH-9 to Glu 81, N-3 to Leu 83, and 2-NH2 to Leu 83). The triplet of hydrogen bonding and CDK inhibition was reproduced by 2,6-diamino-4-cyclohexylmethyloxy-5-nitrosopyrimidine (NU6027, K(i) values: CDK1, 2.5 ± 0.4 μM; CDK2, 1.3 ± 0.2 μM). Against human tumor cells, NU2058 and NU6027 were growth inhibitory in vitro (mean GI50 values of 13 ± 7 μM and 10 ± 6 μM, respectively), with a pattern of sensitivity distinct from flavopiridol and olomoucine. These CDK inhibition and chemosensitivity data indicate that the distinct mode of binding of NU2058 and NU6027 has direct consequences for enzyme and cell growth inhibition.
