Colin William Smith

Preparation of some new benzylidenemalononitriles by an SNAr reaction: application to naphtho[1,2-b]pyran synthesis

The reaction of 4-fluoro-3-nitrobenzylidene malononitrile (3) with piperidine and 1-naphthol yields the addition-elimination product (9) rather than the expected naphtho[1,2-b]pyran (7). This reaction is extended to produce other 3,4-disubstituted benzylidenemalononitriles (10)-(13). These compounds are then reacted with 1-naphthol and 4-methylmorpholine producing the naphtho[1,2-b]pyrans (14)-(17)

The anti-rheumatic potential of a series of 2,4-di-substituted-4H-naphtho[1,2-b]pyran-3-carbonitriles

Abstract A new series of naphtho[1,2-b]pyran-3-carbonitriles with enhanced stability under acid conditions has been synthesised and examined for antiproliferative and anti-inflammatory activity. 4-(3-nitrophenyl)-2-(N-succinimido)-4H-naphtho[1,2-b]pyran-3-carbonitrile, 10, has proved to be acid stable and still retains biological activity.

LY290181, an Inhibitor of Diabetes-Induced Vascular Dysfunction, Blocks Protein Kinase C—Stimulated Transcriptional Activation Through Inhibition of Transcription Factor Binding to a Phorbol Response Element

Previous studies have shown that high glucose levels and diabetes induce an elevation in protein kinase C (PKC) activity in vascular cells and tissues susceptible to diabetic complications. In addition, PKC activation has been shown to modulate vascular cell growth, permeability, and gene expression, processes thought to be involved in the development of vascular complications. Using two in vivo model systems, we have identified a novel inhibitor of diabetic vascular dysfunction, LY290181. LY290181 prevented glucose-induced increases in blood flow and permeability in rat granulation tissue and corresponding vascular changes in the retina, sciatic nerve, and aorta of diabetic rats. Tested for its ability to inhibit PKC-regulated processes, LY290181 inhibited phorbol ester–stimulated plasminogen activator activity in a dose-dependent manner in bovine retinal endothelial cells and in human dermal fibroblasts. In addition, LY290181 inhibited phorbol ester–stimulated activation of the porcine urokinase plasminogen activator (uPA) promoter (−4600/+398) linked to the chloramphenicol acetyltransferase (CAT) reporter gene (p4660CAT). More detailed analysis of the uPA promoter revealed that LY290181 inhibited phorbol ester–stimulated activation of the uPA phorbol response element (−2458/−2349) located upstream of the thymidine kinase promoter (puPATKCAT). LY290181 appears to inhibit uPA promoter activation by blocking phorbol ester–stimulated binding of nuclear proteins to the uPA PEA3/12-O-tetradecanoylphorbol 13-acetate responsive element (TRE). These results suggest that LY290181 may inhibit diabetes-induced vascular dysfunction by inhibiting transcription factor binding to specific PKC-regulated genes involved in vascular function.

Semi-synthetic qualestatins: Squalene synthase inhibition and antifungal activity. The SAR of C6 and C7 modifications

Abstract We describe herein a protection/deprotection strategy that enables efficient transformation of natural Squalestatin S1 into C6 and C7 acyl analogues. We present the mammalian and fungal SQS enzyme activity and whole cell antifungal activity of the semi-synthetic Squalestatins.

A versatile synthesis of hydroxy-9,10-anthraquinone-2-carboxylic acids

Abstract Islandicin, a mould metabolite, can be synthesised in a few, robust, high yielding steps. This procedure can be further elaborated to give a variety of hydroxy-9,10-anthraquinone-2-carboxylic acids.

Five-membered heterocyclic amines as potential anti-rheumatoid arthritis agents.

Abstract 5-Amino-3-substituted-1,2,4-thiadiazoles have been found to reduce the inflammatory and arthritic symptoms in the adjuvant arthritis model of rheumatoid arthritis.

Synthesis of novel monocyclic squalestatin analogues as potential inhibitors of squalene synthase

Abstract The syntheses of two monocyclic 1,3-dioxane tricarboxylic acid analogues of the natural product squalestatin 1 are described herein. Their activity against both mammalian (rat liver) and fungal (Candida albicans) squalene synthase is also reported.

Anthraquinones related to rhein inhibit glucose uptake into chondrocytes. A mechanism for anti-osteoarthritis drugs?

Abstract Rhein has been shown to inhibit the uptake of glucose into Ehrlich Ascites tumor cells. In this paper we show that a wide range of antrhaquinones related to rhein can also inhibit glucose uptake into chondrocytes, many significantly more than the parent molecule.

2-Benzamido-4-phenylthiazoles as unexpected products of a novel rearrangement from the reaction of 2-bromo-1,3-bis(4-substituted)phenylpropane-1,3-diones and thiourea

A rearrangement leading to 2-benzamido-4-phenylthiazoles from the Hantzsch reaction under basic conditions is reported.