Search

Utilizing structure-based drug design, a 4-aminoimidazole heterocyclic core was synthesized as a replacement for a 2-aminothiazole due to potential metabolically mediated toxicity. The synthetic route utilized allowed for ready synthesis of 1-substituted-4-aminoimidazoles. SAR exploration resulted in the identification of a novel cis-substituted cyclobutyl group that gave improved enzyme and cellular potency against cdk5/p25 with up to 30-fold selectivity over cdk2/cyclin E.

The design, synthesis, and biological evaluation of potent inhibitors of the TrkA kinase is presented. A homology model is created to aid in the enhancement of potency and selectivity of isothiazole inhibitors found during a high-throughput screen. Three different syntheses are utilized to make diverse analogs within this series. Aminoheterocycles are found to be good urea surrogates, whereas bicyclic substituents on the C3 thio group were found to be extremely potent TrkA inhibitors in kinase and cell assays.

High-throughput screening with cyclin-dependent kinase 5 (cdk5)/p25 led to the discovery of N-(5-isopropyl-thiazol-2-yl)isobutyramide (1). This compound is an equipotent inhibitor of cdk5 and cyclin-dependent kinase 2 (cdk2)/cyclin E (IC50 = ca. 320 nM). Parallel and directed synthesis techniques were utilized to explore the SAR of this series. Up to 60-fold improvements in potency at cdk5 and 12-fold selectivity over cdk2 were achieved.

Deuterium, the stable isotope of hydrogen, is known to medicinal chemists for its utility in mechanistic, spectroscopic, and tracer studies. In fact, well-known applications utilizing deuterium exist within every subdiscipline in pharmaceutical discovery and development. Recent emphasis on incorporation of deuterium into the active pharmaceutical ingredient has come about as a result of inquiries into the potential for substantial benefits of the deuterium kinetic isotope effect on the safety and disposition of the drug substance. This Perspective traces the author's experience in reviving and expanding this potential utility, first suggested many decades prior by the discoverer of this, the simplest of all isotopes.

2-Oxazolines have permeated numerous sub-disciplines in synthetic organic chemistry in the 100 years since their discovery. This versatile heterocycle has served as protecting group, coordinating ligand, and activating moiety, often exhibiting all of these characteristics in a single transformation. The well-defined reactivity of chiral oxazolines has given rise to numerous highly efficient strategies for asymmetric synthesis including their use as ligands in asymmetric catalysis. Various unique properties have dictated their use in a multitude of dissimilar applications: as monomers in polymer production, as moderators in analytical processes, and as conformationally rigid peptide mimics in medicinal chemistry. Even natural systems have chosen to incorporate oxazolines into their chemical arsenal, as evidenced by the rapidly growing number of identified natural products and their attendant pharmacological properties. Future studies will undoubtedly uncover unexpected properties and applications. The number of important publications detailing oxazoline-related chemistry is growing, suggesting that research in this area, as in synthetic organic chemistry in general, has yet to mature.

A novel substituted naphthalenone (TGG-II-23A) has been found that inhibits HIV-1 infection of CEM-SS cells at concentrations that are not cytotoxic. Time of addition experiments indicate that TGG-II-23A functions at a stage of the HIV-1 life cycle at or near reverse transcription. Cell free assays confirmed that TGG-II-23A inhibits HIV-1 reverse transcriptase. Similar to other non-nucleoside inhibitors, TGG-II-23A was specific for HIV-1 and failed to inhibit the replication of HIV-2. The binding site of TGG-II-23A appears to be in close proximity to that of the TIBO-like inhibitors, since a TIBO-resistant HIV-1 was also resistant to TGG-II-23A treatment. TGG-II-23A is a mixed non-competitive inhibitor that exhibits the same template:primer selectivity as other non-nucleoside inhibitors. TGG-II-23A therefore represents a new structural entry into the TIBO/Nevirapine class of inhibitors of HIV-1 reverse transcriptase.

An efficient synthesis of the phytoalexin, lacinilene C-7 methyl ether, via its probable biosynthetic precursor, 2-hydroxy-7-methoxycadalene is described. A related synthesis of a HIV-1 reverse-transcriptase inhibitor is briefly discussed.

A series of synthetic manipulations on the naphthalene nucleus, containing a 1-(2-oxazolinyl) moiety, is described. Nucleophilic additions afford both regio- and stereoselective products in the 1- and 4-positions. The latter is oxidatively transformed in the 4-keto system 4 which can undergo various substitutions as well as carbonyl transpostions

An efficient synthesis of the phytoalexin, lacinilene C-7 methyl ether, via its probable biosynthetic precursor, 2-hydroxy-7-methoxycadalene is described. A related synthesis of a HIV-1 reverse-transcriptase inhibitor is briefly discussed.

A series of synthetic manipulations on the naphthalene nucleus, containing a 1-(2-oxazolinyl) moiety, is described. Nucleophilic additions afford both regio- and stereoselective products in the 1- and 4-positions. The latter is oxidatively transformed in the 4-keto system 4 which can undergo various substitutions as well as carbonyl transpostions

Mitogen-activated protein kinase phosphatase-4 (MKP-4) is a dual specificity phosphatase, which acts as a negative regulator of insulin-stimulated pathways [1]. Here, we describe expression, purification, and biochemical characterization of MKP-4. We used the Baculovirus expression system and purification with a combination of affinity and gel filtration chromatography to generate pure MKP-4 and MKP-4/p38 complex. Both MKP-4 and the MKP-4/p38 complex exhibited moderate activity toward the surrogate substrates p-nitrophenyl phosphate, 6, 8-difluoro-4-methylumbelliferyl phosphate, and 3-O-methylfluorescein phosphate. The phosphatase activity could be inhibited by peroxovanate, a potent inhibitor of protein tyrosine phosphatases. We further determined kinetic parameters for the MKP-4 and the MKP-4/p38 by using spectrophotometric and fluorescence intensity methods. The MKP-4/p38 complex was found to provide substantially higher phosphatase activity than MKP-4 alone, similar to what has been shown for MKP-3. Our data allow the configuration of screens for modulators of MKP-4 activity.