Thio- and oxoflavopiridols, cyclin-dependent kinase 1-selective inhibitors: synthesis and biological effects.

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Kim KS, Sack JS, Tokarski JS, Qian L, Chao ST, Leith L, Kelly YF, Misra RN, Hunt JT, Kimball SD, Humphreys WG, Wautlet BS, Mulheron JG, Webster KR

Thio- and oxoflavopiridols, cyclin-dependent kinase 1-selective inhibitors: synthesis and biological effects.

J Med Chem. 2000 Nov 2;43(22):4126-34.

PubMed ID
11063609 [ View in PubMed
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Abstract

Flavopiridol analogues, thio- and oxoflavopiridols which contain a sulfur (16) or oxygen (18) atom linker between a chromone ring and the hydrophobic side chain, are selective cyclin-dependent kinase 1 (CDK1) inhibitors with an IC(50) of 110 and 130 nM. These analogues were prepared from key intermediate 7 by substituting the ethyl sulfoxide. Enantio pure intermediate piperidone 10 was obtained from the racemic piperidone 8 via a very efficient "dynamic kinetic resolution" in 76% yield. Hydrophobic side chains such as chlorophenyl or tert-butyl produced potent CDK1 inhibitory activity, while hydrophilic side chains such as pyrimidine or aniline caused a severe reduction in CDK inhibitory activity. These analogues are competitive inhibitors with respect to ATP, and therefore activity was dependent upon the CDK subunit without being affected by the cyclin subunit or protein substrate. Thio- and oxoflavopiridols 16 and 18 are not only selective within the CDK family but also discriminated between unrelated serine/threonine and tyrosine protein kinases. CDK1 selective thio- and oxoflavopiridol analogues inhibit the colony-forming ability of multiple human tumor cell lines and possess a unique antiproliferative profile in comparison to flavopiridol.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AlvocidibCyclin-dependent kinase 1IC 50 (nM)30830Details
AlvocidibCyclin-dependent kinase 2IC 50 (nM)170830Details
AlvocidibCyclin-dependent kinase 4IC 50 (nM)100830Details
OlomoucineCyclin-dependent kinase 1IC 50 (nM)7000830Details
OlomoucineCyclin-dependent kinase 2IC 50 (nM)7000830Details