Cyclin dependent kinase inhibitors synthesis

W.G., Marathe, P., Bursuker, I., Kellar, K.A., Roongta, U., Batorsky, R., Mul-heron, J.G., Bol, D., Fairchild, C. R., Lee, F. Y., Webster, K. R. Discovery of amino-thiazole inhibitors of cyclin-dependent kinase 2 synthesis, X-ray crystallographic analysis and biological activities. Journal of Medicinal Chemistry 2002, 45, 3905-3927. 

A new solid-phase synthesis of families of asymmetrically disubstituted furazano[3,4-h]-pyrazines, which overcomes selectivity problems found in solution, has been achieved by stepwise displacement of the two chlorine atoms of 5,6-dichlorofurano[3,4-b]pyrazines with nucleophiles <02TL4741>. Pyrazolo[3,4-fe]quinoxalines as a new class of cyclin-dependent kinase inhibitors have been described <02BMC2177>. 

Figure 8.10 Some bioisosteric replacements for carboxylic acids (top) (Carini, D.J., et al. Nonpeptide angiotensin II receptor antagonists The discovery of a series of A-(Biphenylmethyl) imidazoles as potent, orally active antihypertensives. J. Med. Chem. 1991, 34, 2525-2547), esters (middle) (Kim, K.S., et al. Discovery of aminothiazole inhibitors of cyclin-dependent kinase 2 Synthesis, X-ray crystallographic analysis, and biological activities. /. Med. Chem. 2002, 45, 3905-3927.), and amides (bottom) (Black, W.C., et al. Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K. Bioorg. Med. Chem. Lett. 2005,15,4741 744.) The clinical candidate odanacatib (bottom right) incorporates a trifluoroethylamine amide isostere. (Gauthier, J.Y., et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett. 2008,18,923-928.)...

Kim, K.S., et al. Discovery of aminothiazole inhibitors of cyclin-dependent kinase 2 Synthesis, X-ray crystallographic analysis, and biological activities. J. Med. Chem. 2002, 45, 3905-3927. 

Cyclin-dependent kinases (CDKs) play a key role in regulating cell cycle machinery. This family of kinases requires association with a cyclin regulatory subunit for activity. Different CDK/cyclin pairs are active during each phase of the cell cycle. Negishi cross-coupling reactions were the key steps in the synthesis of [l,3,5]triazine-pyridine biheteroaryls 161 as a novel series of potent cyclin-dependent kinase inhibitors. ... 

In 1998-99, she worked on the synthesis of cyclin-dependent kinase (CDK) inhibitors, under the direction of Professor Miguel F. Brana at University San Pablo (CEU, Spain). 

Treatment of dihydropyran-2-one with tosylmethyl isocyanide in the presence of DBU provides the tetrahydro-pyran-2-one 1020, an intermediate during the synthesis of cyclin-dependant kinase 2 inhibitors (Equation 398)... 

Tu S, Zhang J, Zhu X et al (2006) New potential inhibitors of cyclin-dependent kinase 4 design and synthesis of pyrido[2, 3-d]pyrimidine derivatives under microwave irradiation. Bioorg Med Chem Lett 16 3578-3581... 

Raynaud and co-workers recently reported the optimization of inhibitors of cyclin-dependent kinase-2 (CDK-2), based on a purine scaffold (Scheme 7). The synthesis... 

F.I. Raynaud, P.M. Fischer, B.P. Nutley, P.M. Goddard, D.P. Lane and P. Workman, Cassette dosing pharmacokinetics of a library of 2,6,9-trisubstituted purine cyclin-dependent kinase 2 inhibitors prepared by parallel synthesis, Mol. Cancer Then, 2004, 3, 353. 

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 43 4126-34. 

Figure 1 Overview of the different phases of the cell cycle. Quiescent cells are in GO phase and reenter the cell cycle at Gl during which cells prepare for DNA synthesis. After passing the restriction point in late Gl cells are committed to enter S phase, during which DNA replication occurs. Cells in G2 phase prepare for mitosis (M phase). Cell cycle progression is controlled by various positive and negative cell cycle regulatory proteins including cyclins (A, B, D, E) cyclin dependent kinases (cdk 1,2, 4, 6) cdk inhibitors (p15, p16, p18, p19, p21, p27, p57), retinoblastoma (Rb) and p53.

P. Worland, S.P. Seitz, Synthesis and biological evaluation of 1 -aryl-4,5-dihydro-lH-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of cyclin-dependent kinases,/. Med. Chem. 2004, 47(24), 5894-5911. 

Carini et al. converted 8-bromobenzo[c]carbazole to the corresponding aryl derivatives 56, which are selective inhibitors of cyclin dependent kinase 4 [100], and Nicolaou employed a 4-bromoindole to craft 57 in a model study towards the synthesis of diazonamide A [101]. 

Cyclin-dependent kinase inhibition by flavoalkaloids 12MRM632. Design and synthesis of bicycUc azasugars, carbasugars and related molecules as glycosidase inhibitors 13CSR5102. 

Recently, other groups have used this facile and mild tin-mediated Fukuyama indole synthesis. For example, a new route to the general core of the paullones 40, potential cyclin-dependent kinase (CDK) inhibitors that are particularly efficient against three disease-relevant kinases was reported. ... 

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