Synthesis and activity of 2,6,9-trisubstituted purines

Schow, Steven R.; Mackman, Richard L.; Blum, Cheri L.; Brooks, Eric E.; Horsma, Amy G.; Joly, Alison; Kerwar, S.S.; Lee, Gavin; Shiffman, Dov; Nelson, Marek G.; Wang, Fudi; Wick, Michael M.; Zhang, Xiaoming; Lum, Robert T.

doi:10.1016/s0960-894x(97)10076-2

Cited by 67 publications

(27 citation statements)

References 6 publications

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“…The best The 9-position of the purines is very restrictive towards substitution in terms of CDK inhibition. Only small aliphatic and alicyclic groups, optionally containing hydroxyl groups [77], are tolerated. The 9-isopropyl group appears to be optimal.…”

Section: Purinesmentioning

confidence: 99%

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Inhibitors of Cyclin-Dependent Kinases as Anti-Cancer Therapeutics

Fischer

Lane²

2000

CMC

141

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Initiation, progression, and completion of the cell cycle are regulated by various cyclin-dependent kinases (CDKs), which are thus critical for cell growth. Tumour development is closely associated with genetic alteration and deregulation of CDKs and their regulators, suggesting that inhibitors of CDKs may be useful anticancer therapeutics. Indeed, early results suggest that transformed and normal cells differ in their requirement for e.g. cyclin/CDK2 and that it may be possible to develop novel antineoplastic agents devoid of the general host toxicity observed with conventional cystostatic drugs. Numerous active-site inhibitors of CDKs have been studied; the main limitation with these ATP antagonists is kinase specificity for CDKs. However, screening of compound collections, as well as rational design based on enzyme-ligand complex crystal structures, are now yielding pre-clinical candidates, particularly certain purine and flavonoid analogues, with impressive potency and selectivity. Natural CDK inhibitors (CKIs), e.g. the tumour suppressor gene products p16 INK4 , p21 WAF1 , and p27 KIP1 , form the starting point for the design of mechanism-based CDK inhibitors. A number of these small proteins have been dissected and inhibitory lead peptides amenable to peptidomimetic development have been identified. Conversion of these peptides into pharmaceutically useful molecules is greatly aided by the recent elucidation of CKI/CDK crystal and solution structures. Additional interaction sites on CDKs being exploited for the purposes of inhibitor design include: phosphorylation/dephosphorylation sites, macromolecular substrate binding site, CKS regulatory subunit binding sites, cyclin-binding site, cellular localisation domain, and destruction box. Finally, progress has recently been made in the application of antisense technology in order to target CDK activity.

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Section: Purinesmentioning

confidence: 99%

“…The routes commonly used [79,76,69,80,77] for the synthesis of 2,6,9-trisubstituted purines in many sterically hindered and poorly nucleophilic alkyl-and aryl amines. The 2-fluoro group (9.8, X = F) renders the purine 2-position much more electrophilic and has been found to be more versatile for the final amination step.…”

Section: Purinesmentioning

confidence: 99%

Inhibitors of Cyclin-Dependent Kinases as Anti-Cancer Therapeutics

Fischer

Lane²

2000

CMC

141

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“…Moderate in vitro inhibitory activity against CDK5 and CDK1 was observed but were found to be inactive against Glycogen Synthase Kinase (GSK3) [80]. Optimized N-6 anilino/benzylamino inhibitors discovered for the most part through screening of large libraries of 2,6,9-trisubstituted purines are reported [76,81,[83][84][85][86][87][88][89][90]. From the HN N N N N N H HO (18) crystal structure of the initial lead compound NU2058 (21) with CDK2 (IC 50 = 12 μM) it was determined that (21) binds in the ATP site in yet another orientation.…”

Section: Purine Derivativesmentioning

confidence: 99%

Inhibitors of Cyclin Dependent Kinases: Useful Targets for Cancer Treatment

Sharma¹,

Sharma²,

Tyagi³

2008

CCDT

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Cancer drug discovery is one of the most rapidly changing areas of pharmaceutical research. Uncontrolled proliferation is a hallmark of cancer cells. Over the past two decades, it has become increasingly clear that in many human cancers, hyperactivity of Cyclin Dependent Kinases (CDKs) is one of the mechanisms underlying the physiological hyper-proliferation. CDKs are serine/threonine protein kinases, which play an important role in cell-cycle regulation. Their sequential activation ensures, the correct timing and ordering of events required for cell cycle progression. Therefore, inhibition of CDKs, through the insertion of small molecules into its ATP binding pocket has emerged as a potential therapy method for cancers. Consequently, a number of small molecules with CDK inhibitory properties have been developed. Many of these have been evaluated as potent inhibitors and some are currently in clinical-trials for various types of cancer. This review reports various CDK inhibitors, natural as well as small molecules, along with their reported activities for various CDKs. It will highlight the potential for the development of novel anti-cancer molecules.

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“…The preparation of combinatorial purine librairies using solid-phase methods has been recently reported [8][9][10] . We have previously described [11] the synthesis and CDK1/cyclin B inhibitory activity of various C2-amino ethanol substituted purines, as well as C2 alkynylated purines like 4 [12,13] with potent anti-CDK activity in vitro.…”

Section: J Heterocyclic Chem 38 299 (2001)mentioning

confidence: 99%