Roger John Griffin

Structure-Based Design of a Potent Purine-Based Cyclin-Dependent Kinase Inhibitor

Aberrant control of cyclin-dependent kinases (CDKs) is a central feature of the molecular pathology of cancer. Iterative structure-based design was used to optimize the ATP- competitive inhibition of CDK1 and CDK2 by O6-cyclohexylmethylguanines, resulting in O6-cyclohexylmethyl-2-(4′- sulfamoylanilino)purine. The new inhibitor is 1,000-fold more potent than the parent compound (Ki values for CDK1 = 9 nM and CDK2 = 6 nM versus 5,000 nM and 12,000 nM, respectively, for O6-cyclohexylmethylguanine). The increased potency arises primarily from the formation of two additional hydrogen bonds between the inhibitor and Asp 86 of CDK2, which facilitate optimum hydrophobic packing of the anilino group with the specificity surface of CDK2. Cellular studies with O6-cyclohexylmethyl-2-(4′- sulfamoylanilino) purine demonstrated inhibition of MCF-7 cell growth and target protein phosphorylation, consistent with CDK1 and CDK2 inhibition. The work represents the first successful iterative synthesis of a potent CDK inhibitor based on the structure of fully activated CDK2–cyclin A. Furthermore, the potency of O6-cyclohexylmethyl-2-(4′- sulfamoylanilino)purine was both predicted and fully rationalized on the basis of protein–ligand interactions.

The role of inhibitors of poly(ADP-ribose) polymerase as resistance-modifying agents in cancer therapy

Poly(ADP-ribose) polymerase (PARP) plays an important role in a number of cellular processes including DNA repair. Since poly(ADP-ribosyl)ation occurs in response to radiation- or drug-induced DNA damage, inhibitors of the enzyme may enhance the antitumour activity of radiotherapy or cytotoxic drug treatment. In this review the development of PARP inhibitors is discussed, and structure-activity relationships amongst inhibitors of the enzyme are presented. Studies to date regarding the in vitro and in vivo activity of PARP inhibitors, as resistance modifying agents in cancer therapy, are also overviewed.

4-Alkoxy-2,6-diaminopyrimidine derivatives: Inhibitors of cyclin dependent kinases 1 and 2

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.

The medicinal chemistry of the azido group

Publisher Summary This chapter describes physico-chemical and biological properties of the azido functionality of interest to the medicinal chemist, and examples of biologically active azides appearing in the scientific literature up to early 1993. It is of interest to note that the popularity of the azido group as a photoactivatable substituent is derived, in part, from the synthetic accessibility of azido-substituted derivatives of the natural substrate or drug, and the ease with which retention of high receptor affinity, a prerequisite in the design of such molecules, may be achieved. Indeed, on more than one occasion, the introduction of an azido group for the purpose of conducting photolabelling experiments has afforded a derivative with intrinsically interesting biological properties compared with the parent compound. Once thought to exist as a cyclic structure, the azido group in organic azides is now known to be linear, this being first demonstrated with the determination of the X-ray crystal structure of cyanuric triazide.

Synthesis of water-soluble prodrugs of the cytotoxic agent Combretastatin A4

Water-soluble phosphate and glycine carbamate prodrugs of the cytotoxic agent Combretastatin A4 (1) have been prepared. The phosphate prodrug was degraded slowly in plasma at 37°C. The degradation was accelerated by the addition of alkaline phosphatase.