Tony Raynham

The identification of α-ketoamides as potent inhibitors of hepatitis c virus nS3-4a proteinase

Peptides based upon the non-prime side residues of the NS4A-4B cleavage site of hepatitis C virus (HCV) NS3-4A proteinase containing an α-ketoamide moiety in place of the scissile amide bond are potent inhibitors of this enzyme.

Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.

VEGF (vascular endothelial growth factor) plays an essential role in angiogenesis during development and in disease largely mediated by signalling events initiated by binding of VEGF to its receptor, VEGFR2 (VEGF receptor 2)/KDR (kinase insert domain receptor). Recent studies indicate that VEGF activates PKD (protein kinase D) in endothelial cells to regulate a variety of cellular functions, including signalling events, proliferation, migration and angiogenesis. To better understand the role of PKD in VEGF-mediated endothelial function, we characterized the effects of a novel pyrazine benzamide PKD inhibitor CRT5 in HUVECs (human umbilical vein endothelial cells). The activity of the isoforms PKD1 and PKD2 were blocked by this inhibitor as indicated by reduced phosphorylation, at Ser916 and Ser876 respectively, after VEGF stimulation. The VEGF-induced phosphorylation of three PKD substrates, histone deacetylase 5, CREB (cAMP-response-element-binding protein) and HSP27 (heat-shock protein 27) at Ser82, was also inhibited by CRT5. In contrast, CRT6, an inactive analogue of CRT5, had no effect on PKD or HSP27 Ser82 phosphorylation. Furthermore, phosphorylation of HSP27 at Ser78, which occurs solely via the p38 MAPK (mitogen-activated protein kinase) pathway, was also unaffected by CRT5. In vitro kinase assays show that CRT5 did not significantly inhibit several PKC isoforms expressed in endothelial cells. CRT5 also decreased VEGF-induced endothelial migration, proliferation and tubulogenesis, similar to effects seen when the cells were transfected with PKD siRNA (small interfering RNA). CRT5, a novel specific PKD inhibitor, will greatly facilitate the study of the role of PKD signalling mechanisms in angiogenesis.

THE SYNTHESIS OF NOVEL AMINO ACIDS VIA HYDROBORATION-SUZUKI CROSS COUPLING

Abstract The Garner aldehyde-derived methylene alkene has been hydroborated using 9-BBN and the resulting organoborane employed in palladium-catalysed Suzuki coupling reactions to produce, after hydrolysis-oxidation, a range of novel amino acids as their N-BOC protected derivatives.

Solution and solid-Phase synthesis of potent inhibitors of hepatitis C Virus NS3 proteinase

A versatile route for the synthesis of homochiral alpha-ketoamide analogues of amino acids is described. Incorporation of this functionality into peptide sequences using either solution or solid-phase chemistry resulted in potent inhibitors of the Hepatitis C Virus NS3 proteinase.

Synthesis and structure-activity relationships for 1-(4-(piperidin-1-ylsulfonyl)phenyl)pyrrolidin-2-ones as novel non-carboxylate inhibitors of the aldo-keto reductase enzyme AKR1C3

High expression of the aldo-keto reductase enzyme AKR1C3 in the human prostate and breast has implicated it in the development and progression of leukemias and of prostate and breast cancers. Inhibitors are thus of interest as potential drugs. Most inhibitors of AKR1C3 are carboxylic acids, whose transport into cells is likely dominated by carrier-mediated processes. We describe here a series of (piperidinosulfonamidophenyl)pyrrolidin-2-ones as potent (<100 nM) and isoform-selective non-carboxylate inhibitors of AKR1C3. Structure-activity relationships identified the sulfonamide was critical, and a crystal structure showed the 2-pyrrolidinone does not interact directly with residues in the oxyanion hole. Variations in the position, co-planarity or electronic nature of the pyrrolidinone ring severely diminished activity, as did altering the size or polarity of the piperidino ring. There was a broad correlation between the enzyme potencies of the compounds and their effectiveness at inhibiting AKR1C3 activity in cells.

Completely diastereoselective aziridination of α,β-unsaturated acids via intramolecular reaction of 3-acetoxyaminoquinazolin-4(3H)-ones

(R)-3-Amino-2-[1-(2-hydroxyethoxy)ethyl]quinazolin-4(3H)-one 10 was prepared in 62% yield without the need for chromatography and O-cinnamoylated; reaction with lead tetra-acetate gave aziridine 12 as a single diastereoisomer in quantitative yield which was converted into the β-amino acid ester 15 corresponding to overall enantioselective addition of ammonia to the double bond of cinnamic acid.

exo-Glycal approaches to C-linked glycosyl amino acid synthesis

Two novel routes to C-linked glycosyl amino acids are described; the first involves elaboration of an exo-glycal and subsequent Ramberg–Backlund rearrangement of a sulfone intermediate to give, after functional group manipulation, a protected C-glycosyl serine, while the second uses hydroboration–Suzuki coupling of the same exo-glycal to produce ultimately the corresponding C-glycosyl asparagine analogue.

Ring-opening of chiral N-(3,4-dihydro-4-oxoquinazolin-3-yl)-substituted aziridines (Q∗-substituted aziridines): access to Q∗-free chirons

Abstract The presence of the quinazolin-4(3H)-one ring (Q∗) in N-(Q∗)-aziridines facilitates ring-opening by nucleophiles: removal of the Q∗ group from enantiopure ring-opened products gives useful chirons.

Acid-catalysed ring-opening of N-(3, 4-dihydro-4-oxoquinazolin-3-yl)-substituted aziridines: aziridine ring-opening with retention of configuration

Abstract The presence of the quinazolin-4(3H)-one (Q) ring in 1-(Q)-2-vinylaziridine (2) can be used to control the stereochemistry of the 3-membered ring-opening; participation by the quinazolinone carbonyl oxygen brings about ring-opening with retention of configuration.

Asymmetric synthesis of amines using a chiral, non-racemic, cyclic sulphinamide.

Abstract The homochiral cyclic sulphinamide S(S)R-(+)-1 has been employed in the asymmetric synthesis of α-methylbenzylamine via the benzylidene sulphinamide R(S)Ri-(−)-3. Following diastereoselective reduction and hydrolysis S(S)R-(+)-1 can be recycled in one step from the sulphinic acid 6.