James Garner

Cantharidin analogues: synthesis and evaluation of growth inhibition in a panel of selected tumour cell lines

Diels-Alder addition of furans (furan, furfuryl alcohol, and 3-bromofuran) to maelic anhydride yields three distinct 5,6-dehydronorcantharidins. Hydrogenation of (4,10-dioxatricyclo[5.2.1.0]decane-3,5-dione) (4a), in dry ethanol affords the monoester (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic aid monoethyl ester) (6). Subsequent transesterification affords a series of monoesters (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid monomethyl ester (7)), 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid monopropyl ester (8), (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid monohexyl ester (9)) and differentially substituted diesters (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-ethyl ester 3-isopropyl ester) (10), and (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-ethyl ester 3-phenyl ester) (11). Analogues were firstly screened for their ability to inhibit protein phosphatases 1 (PP1) and 2A (PP2A) as the lead compounds cantharidin (1) and norcantharidin (2) are known PP1 and PP2A inhibitors. Only analogues 4a, 6-8 displayed good PP1 and PP2A inhibition (PP1 IC(50)s=2.0, 2.96, 4.71, and 4.82 microM, respectively; PP2A IC(50)s=0.2, 0.45, 0.41, and 0.47 microM, respectively). All analogues were also screened for their anti-cancer potential against a panel of tumour cell lines, HL60, L1210, SW480, WiDr, HT29, HCT116, A2780, ADDP, and 143B, producing GI(50) values ranging from 6 microM to >1000 microM. Analogues possessing good PP1 and/or PP2A inhibition also returned moderate to good anti-cancer activity. Analogues with substituents directly attached to the intact bicyclo[2.2.1]heptane skeleton were poor to moderate anti-cancer agents. This correlates well with their lack of PP1 or PP2A activity. Analogues capable of undergoing a facile ring opening of the anhydride or with a single carboxylate were good PP1 and PP2A inhibitors, largely correlating to the observed anti-cancer activity in all cases, except 11. Analogue 11, whist neither a PP1 nor a PP2A inhibitor shows anti-cancer activity comparable to 1 and 2. We believe that intracellular esterases generate the corresponding dicarboxylate, which is a potent PP1 and PP2A inhibitor, and that it is this species which is responsible for the observed anti-cancer activity.

Tetraallylstannane and Weinreb amides: a simple ‘green’ route to N-protected homoallylic alcohols and allyl ketones

Abstract We have explored the addition of tetraallylstannane ( 7 ) to a variety of N -protected Weinreb amides ( N -phthalimido and N -benzyl). Reactions were conducted in methanol and the ionic liquid, butylmethylimidazole tetrafluoroborate (bmim[BF 4 ]), yields of the corresponding N -protected allylketones were moderate to good. Allylation of the corresponding aminoaldehydes gave excellent yields of homoallylic alcohols (68–94%) and moderate to good diastereoselectivities (50–86%).

Synthesis, molecular modeling and biological activity of methyl and thiomethyl substituted pyrimidines as corticotropin releasing hormone type 1 antagonists.

Four small, targeted libraries of differentially substituted amino pyrimidines were synthesized in moderate to good yields. Excellent regiochemistry was observed for substitution at C2/C4 with selectivity > 50:1 noted. All analogues were screened for their ability to interact with CRH1 and CRH2 receptors. In all instances only poor agonistic and/or antagonistic behaviour was noted at CRH2. However, several compounds were potent and selective CRH1 antagonists, most notably 13a Ki = 39 nM. Additionally we have utilized these data and that recently reported by others to refine our original CRH1 pharmacophore (J Med. Chem., 1999, 42, 2351-2357).

Identification of Aminopyrimidine Regioisomers via Line Broadening Effects in 1H and 13C NMR Spectroscopy

Substituted mono- and diamino-pyrimidines were synthesized as part of our medicinal chemistry programmes. Primary amines substituted at the 4-position exhibited room-temperature line broadening effects in both 1H and 13C NMR spectroscopy due to the presence of rotamers, but these effects were not observed for substituents in the 2-position. This provided a simple diagnostic tool for the identification of regioisomers, a determination which would otherwise have required two-dimensional experiments.

Viability Study for an Unattended UF6 Cylinder Verification Station: Phase I Final Report

............................................................................................................................................ iii Executive Summary ............................................................................................................................ v Acknowledgments ......................................................................................................................... xxiii Acronyms and Abbreviations ......................................................................................................... xxv

Corticotrophin Releasing Hormone: Chemistry and Recent Developments

Corticotrophin Releasing Hormone [CRH; also known as Corticotrophin Releasing Factor (CRF)], a 41-amino-acid hormone, is one of the body’ major modulators of the stress response. CRH coordinates the endocrine, autonomic, and behavioural responses to stress through actions in both the brain and the periphery activating the ‘fight or flight’ response. CRH is also implicated in various neurological disorders including Alzheimer’s, Parkinson’s, and anorexia nervosa, and it has been described as a biological clock controlling the length of gestation in humans and other higher-order primates. In the past decade there has been an enormous effort expended in the design and development of new therapeutic agents targetting CRHs in the central nervous and peripheral systems. In this review, we examine the chemistry and recent developments in this exciting field.