Biomedical subjects

C J Quinn

Publications and source records attributed to C J Quinn.

9 recordsLinked to original sources

PubMed2004

Benzodioxocin-3-ones and N-acyl-3-amino-3-buten-2-ones: novel classes of cathepsin K cysteine protease inhibitors.

The design, synthesis, enzymologic, and protein mass spectrometric characterization of benzodioxocin-3-one and N-acyl-3-amino-3-buten-2-one inhibitors of the cysteine protease cathepsin K are described. The benzodioxocin-3-one ring system is chemically unstable giving rise to a mixture of N-acyl-3-amino-3-buten-2-one and hemiketals. This mixture of N-acyl-3-amino-3-buten-2-one and hemiketals potently inhibits recombinant, human cathepsin K (IC50 = 36 nM) by a time-independent, irreversible mechanism. Formation of a covalent adduct between cathepsin K and inhibitor has been confirmed by mass spectrometry.

Cathepsin K↗

PubMed2001

Azepanone-based inhibitors of human and rat cathepsin K.

The synthesis, in vitro activities, and pharmacokinetics of a series of azepanone-based inhibitors of the cysteine protease cathepsin K (EC 3.4.22.38) are described. These compounds show improved configurational stability of the C-4 diastereomeric center relative to the previously published five- and six-membered ring ketone-based inhibitor series. Studies in this series have led to the identification of 20, a potent, selective inhibitor of human cathepsin K (K(i) = 0.16 nM) as well as 24, a potent inhibitor of both human (K(i) = 0.0048 nM) and rat (K(i,app) = 4.8 nM) cathepsin K. Small-molecule X-ray crystallographic analysis of 20 established the C-4 S stereochemistry as being critical for potent inhibition and that unbound 20 adopted the expected equatorial conformation for the C-4 substituent. Molecular modeling studies predicted the higher energy axial orientation at C-4 of 20 when bound within the active site of cathepsin K, a feature subsequently confirmed by X-ray crystallography. Pharmacokinetic studies in the rat show 20 to be 42% orally bioavailable. Comparison of the transport of the cyclic and acyclic analogues through CaCo-2 cells suggests that oral bioavailability of the acyclic derivatives is limited by a P-glycoprotein-mediated efflux mechanism. It is concluded that the introduction of a conformational constraint has served the dual purpose of increasing inhibitor potency by locking in a bioactive conformation as well as locking out available conformations which may serve as substrates for enzyme systems that limit oral bioavailability.

Administration, Oral↗

PubMed2001

Cyclic ketone inhibitors of the cysteine protease cathepsin K.

Cathepsin K (EC 3.4.22.38), a cysteine protease of the papain superfamily, is predominantly expressed in osteoclasts and has been postulated as a target for the treatment of osteoporosis. Crystallographic and structure--activity studies on a series of acyclic ketone-based inhibitors of cathepsin K have led to the design and identification of two series of cyclic ketone inhibitors. The mode of binding for four of these cyclic and acyclic inhibitors to cathepsin K is discussed and compared. All of the structures are consistent with addition of the active site thiol to the ketone of the inhibitors with the formation of a hemithioketal. Cocrystallization of the C-3 diastereomeric 3-amidotetrahydrofuran-4-one analogue 16 with cathepsin K showed the inhibitor to occupy the unprimed side of the active site with the 3S diastereomer preferred. This C-3 stereochemical preference is in contrast to the X-ray cocrystal structures of the 3-amidopyrrolidin-4-one inhibitors 29 and 33 which show these inhibitors to prefer binding of the 3R diastereomer. The 3-amidopyrrolidin-4-one inhibitors were bound in the active site of the enzyme in two alternate directions. Epimerization issues associated with the labile alpha-amino ketone diastereomeric center contained within these inhibitor classes has proven to limit their utility despite promising pharmacokinetics displayed in both series of compounds.

Animals↗

PubMed2001

Molecular and morphological reassessment of relationships within the Vittadinia group of Astereae (Asteraceae).

Morphological and ITS (internal transcribed spacer) sequence data for 40 species of the Austral-Pacific genera Camptacra, Kippistia, Minuria, Peripleura, Tetramolopium, and Vittadinia as well as one semiherbaceous species of Olearia were subjected to cladistic analysis, separately and together. Minuria, Peripleura, and Tetramolopium are paraphyletic as currently defined. Tetramolopium vagans from Australia appears to represent an undescribed genus. Both Kippistia suadefolia and Peripleura diffusa show close affinity to Minuria species, and Minuria macrorhiza appears to contain two distinct but closely related species. Vittadinia and the remaining species of Tetramolopium and Peripleura form a strong affinity group. The distribution of indels and the combined analysis each provide evidence that the Hawaiian and Cook Island species of Tetramolopium are descended from New Guinea species. The combined analysis also suggests that the Cook Island species T. mitiaroense is sister to the Hawaiian clade. Olearia arguta groups strongly with Camptacra and shows no close affinity with either of the arborescent species of Olearia used to root these analyses. Marked homoplasy among morphological characters indicates why generic delimitation in the group has been problematic.

Journal Article↗

PubMed2000

The evolution of the atpbeta-rbcL intergenic spacer in the epacrids (Ericales) and its systematic and evolutionary implications.

Sequence data from the noncoding region separating the plastid genes atpbeta and rbcL were gathered for 27 epacrid taxa, representing all previously recognized infrafamilial groups, and four outgroup taxa (Ericaceae), to address several persistent phylogenetic questions in the group. Parsimony analyses were conducted on these data, as well as on a complementary rbcL sequence dataset assembled from the literature and the combined dataset. The atpbeta-rbcL spacer was notable for the high frequency of insertion-deletion mutations (indels); their distributions were coded as binary characters and included as a adjunct matrix in some of the analyses. The phylogenetic patterns derived from the spacer and rbcL data and the combined analyses, both including and excluding the indel data, concur in resolving seven major lineages corresponding to the tribes of Crayn et al. (1998, Aust. J. Bot. 46, 187-200), viz. Prionoteae, Archerieae, Oligarrheneae, Cosmelieae, Richeeae, Epacrideae, and Styphelieae. The relationships of the tribes and within Styphelieae, however, are not convincingly resolved. Minor conflicts in the positions of some taxa between the spacer and the rbcL trees are poorly supported. Among epacrids, the spacer region provided more cladistically informative characters than rbcL and resulted in trees with lower homoplasy. Further, the spacer data, when analyzed alone and when combined with rbcL, resolved several clades that could not be retrieved on rbcL data alone and provided increased support for many other relationships. The evolution of a putative three-base inversion associated with a hairpin secondary structure in the spacer region is discussed in the light of the inferred phylogeny.

Classification↗

PubMed2000

Relationships within Cupressaceae sensu lato: a combined morphological and molecular approach.

Parsimony analysis of matK and rbcL sequence data, together with a nonmolecular database, yielded a well-resolved phylogeny of Cupressaceae sensu lato. Monophyly of Cupressaceae sensu stricto is well supported, and separate northern and southern hemisphere subclades are resolved, with Tetraclinis within the northern subclade; there is no support for any of the tribes sensu Li. Taxodiaceae comprise five separate lineages. Chamaecyparis nootkatensis falls within Cupressus, clustering with a robust clade of New World species. Libocedrus Florin is paraphyletic and should incorporate Pilgerodendron. Evolution of several characters of wood and leaf anatomy and chemistry is discussed in light of this estimate of the phylogeny; numerous parallelisms are apparent. A new infrafamilial classification is proposed in which seven subfamilies are recognized: Callitroideae Saxton, Athrotaxidoideae Quinn, Cunninghamioideae (Sieb. & Zucc.) Quinn, Cupressoideae Rich. ex Sweet, Sequoioideae (Luerss.) Quinn, Taiwanioideae (Hayata) Quinn, Taxodioideae Endl. ex K. Koch. The rbcL sequence for Taxodium distichum is corrected, and the implications for a previously published estimate of the minimum rate of divergence of the gene since the Miocene are highlighted.

Journal Article↗

PubMed1998

Identification of ceramide-phosphorylethanolamine in oomycete plant pathogens: Pythium ultimum, Phytophthora infestans, and Phytophthora capsici.

Cellular lipids were extracted from three species of Oomycete plant pathogens (Pythium ultimum, Phytophthora infestans, and Ph. capsici) and analyzed via normal-phase high-performance liquid chromatography with flame-ionization detection. The most abundant polar lipids in each of the three species were the polar membrane lipids, phosphatidylethanolamine (PE), phosphatidylcholine, and a phosphosphingolipid that eluted soon after PE. Structural analysis via mass spectrometry and nuclear magnetic resonance spectrometry revealed that the phosphosphingolipid was ceramide phosphorylethanolamine (Cer-PE). The most abundant molecular species of Cer-PE in P. ultimum had a molecular weight of 670.5, contained an unusual 19-carbon branched triunsaturated sphingoid (C19-delta 4, 8, 10, 9-methyl long-chain base) and palmitic acid as the amide-linked fatty acid. The most abundant molecular species of Cer-PE in Ph. infestans had a molecular weight of 714.5, contained a common 16-carbon 1,3 di-OH sphingoid, and erucic (cis 13-docosenoic, C22-delta 13) acid as the amide-linked fatty acid. The Cer-PE in Ph. capsici comprised a mixture of each of the two molecular species found in P. ultimum and Ph. infestans.

Ceramides↗

PubMed1996

Cystoid macular edema.

Cystoid macular edema (CME) may develop in association with a wide variety of ocular conditions. It is the result of cystic accumulation of extracellular intraretinal fluid in the outer plexiform and inner nuclear layers of the retina, as a result of breakdown of the blood-retinal barrier. It is most common following intraocular surgery, and in patients with venous occlusive disease, diabetic retinopathy, and posterior segment inflammatory conditions. A variety of approaches to the treatment of CME have been attempted, with a variable degree of success. These options have included topical and oral steroids, nonsteroidal anti-inflammatory agents, and laser photocoagulation treatment. The exact cause of CME and the effective treatment of this condition have remained elusive.

Cataract Extraction↗

PubMed1993

Rosid affinities of Surianaceae: molecular evidence.

Nucleotide sequences of the chloroplast gene, rbcL, were obtained for Suriana maritima, Cadellia pentastylis, Guilfoylia monostylis, Stylobasium australe, Quassia amara, Brucea mollis, Cupaniopsis anacardioides, Mangifera indica, Connarus conchocarpus, and Comesperma ericinum. Phylogenetic analyses of these, along with published sequences of representatives of rosid families, support the monophyly of the Surianaceae sensu Cronquist and provide evidence of an affinity with the Polygalaceae and Fabaceae. These conclusions are discussed in the light of available morphological data.

Chloroplasts↗