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

9-Trifluoromethyl-paullones with a carbon chain in the 2-position were synthesized by palladium-catalyzed coupling reactions of a 2-iodoprecursor with terminal alkenes or alkynes, respectively. The introduction of a 2-cyanoethyl substituent led to a significant enhancement of CDK1/cyclin B inhibiting property and in vitro antiproliferative activity.

[1]  Conrad Kunick,et al.  Synthese von 7,12‐Dihydro‐indolo[3,2‐d][1]benzazepin‐6‐(5H)‐onen und 6,11‐Dihydro‐thieno‐[3′,2′:2,3]azepino[4,5‐b]indol‐5(4H)‐on , 1992 .

[2]  H. A. Dieck,et al.  Palladium catalyzed synthesis of aryl, heterocyclic and vinylic acetylene derivatives , 1975 .

[3]  L Meijer,et al.  Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases. , 1999, Cancer research.

[4]  Conrad Kunick.  Synthese [b]‐kondensierter azepindione durch dealkoxycarbonylierung , 1991 .

[5]  Y. Tohda,et al.  A convenient synthesis of acetylenes: catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines , 1975 .

[6]  L. Meijer,et al.  Paullones, a series of cyclin-dependent kinase inhibitors: synthesis, evaluation of CDK1/cyclin B inhibition, and in vitro antitumor activity. , 1999, Journal of medicinal chemistry.

[7]  A. Kamb.  Cyclin-dependent kinase inhibitors and human cancer. , 1998, Current topics in microbiology and immunology.

[8]  M. Boyd,et al.  Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen , 1995 .

[9]  E. Corey,et al.  Reagent for the .alpha.,.beta. reduction of conjugated nitriles , 1975 .

[10]  A. Fattaey,et al.  CDK inhibition and cancer therapy. , 1999, Current opinion in genetics & development.

[11]  L Meijer,et al.  Cyclin-dependent kinases: initial approaches to exploit a novel therapeutic target. , 1999, Pharmacology & therapeutics.

[12]  D A Scudiero,et al.  Display and analysis of patterns of differential activity of drugs against human tumor cell lines: development of mean graph and COMPARE algorithm. , 1989, Journal of the National Cancer Institute.

[13]  D O Morgan,et al.  Cyclin-dependent kinases: engines, clocks, and microprocessors. , 1997, Annual review of cell and developmental biology.

[14]  D A Scudiero,et al.  The NCI anti-cancer drug screen: a smart screen to identify effectors of novel targets. , 1997, Anti-cancer drug design.

[15]  E. Sausville,et al.  Flavopiridol (L86 8275; NSC 649890), a new kinase inhibitor for tumor therapy. , 1996, International journal of oncology.