Percy S. Manchand

Inhibitory effect of curcumin and some related dietary compounds on tumor promotion and arachidonic acid metabolism in mouse skin

Topical application of curcumin, the major yellow pigment in turmeric and curry, has a potent inhibitory effect on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion in mouse skin. The structurally related compounds chlorogenic acid, caffeic acid and ferulic acid are less potent inhibitors. Curcumin is a potent inhibitor of TPA-induced ornithine decarboxylase activity and inflammation in mouse skin whereas chlorogenic acid, caffeic acid and ferulic acid are only weakly active or inactive. Curcumin is a potent inhibitor of arachidonic acid-induced inflammation in vivo in mouse skin, and this compound is also a potent inhibitor of epidermal lipoxygenase and cyclooxygenase activity in vitro. Although chlorogenic acid is only weakly active as an inhibitor of epidermal lipoxygenase activity and TPA-induced ear inflammation, it is more active than caffeic acid and ferulic acid. The inhibitory effects of curcumin, chlorogenic acid, caffeic acid and ferulic acid on TPA-induced tumor promotion in mouse skin parallel their inhibitory effects on TPA-induced epidermal inflammation and epidermal lipoxygenase and cyclooxygenase activities. Examination of the structural features of curcumin required for its biological activity indicate that free hydroxyl groups on the benzene rings are not required for inhibition of TPA-induced ornithine decarboxylase activity and inflammation in mouse skin.

Salvinorin, a new trans-neoclerodane diterpene from Salvia divinorum(Labiatae)

Salvinorin, isolated from Salvia divinorum, has been shown by spectroscopic and X-ray-crystallographic methods to be a trans-neoclerodane diterpene of structure (1). Crystals of compound (1) are orthorhombic, space group P212121 with a= 6.368(2), b= 11.338(3), c= 30.710(6)A, and Z= 4. The structure was refined by leastsquares to R 0.052 and R′ 0.056.

Highly active analogs of 1α,25-dihydroxyvitamin D3 that resist metabolism through C-24 oxidation and C-3 epimerization pathways

The secosteroid hormone 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] is metabolized in its target tissues through modifications of both the side chain and the A-ring. The C-24 oxidation pathway, the main side chain modification pathway is initiated by hydroxylation at C-24 of the side chain and leads to the formation of the end product, calcitroic acid. The C-23 and C-26 oxidation pathways, the minor side chain modification pathways are initiated by hydroxylations at C-23 and C-26 of the side chain and lead to the formation of the end product, calcitriol lactone. The C-3 epimerization pathway, the newly discovered A-ring modification pathway is initiated by epimerization of the hydroxyl group at C-3 of the A-ring to form 1alpha,25(OH)(2)-3-epi-D(3). A rational design for the synthesis of potent analogs of 1alpha,25(OH)(2)D(3) is developed based on the knowledge of the various metabolic pathways of 1alpha,25(OH)(2)D(3). Structural modifications around the C-20 position, such as C-20 epimerization or introduction of the 16-double bond affect the configuration of the side chain. This results in the arrest of the C-24 hydroxylation initiated cascade of side chain modifications at the C-24 oxo stage, thus producing the stable C-24 oxo metabolites which are as active as their parent analogs. To prevent C-23 and C-24 hydroxylations, cis or trans double bonds, or a triple bond are incorporated in between C-23 and C-24. To prevent C-26 hydroxylation, the hydrogens on these carbons are replaced with fluorines. Furthermore, testing the metabolic fate of the various analogs with modifications of the A-ring, it was found that the rate of C-3 epimerization of 5,6-trans or 19-nor analogs is decreased to a significant extent. Assembly of all these protective structural modifications in single molecules has then produced the most active vitamin D(3) analogs 1alpha,25(OH)(2)-16,23-E-diene-26,27-hexafluoro-19-nor-D(3) (Ro 25-9022), 1alpha,25(OH)(2)-16,23-Z-diene-26,27-hexafluoro-19-nor-D(3) (Ro 26-2198), and 1alpha,25(OH)(2)-16-ene-23-yne-26,27-hexafluoro-19-nor-D(3) (Ro 25-6760), as indicated by their antiproliferative activities.

The structure of cleomeolide, an unusual bicyclic diterpene from cleome viscosa L. (capparaceae)

Abstract A bicyclic diterpene cleomeolide (1) C20H30O3 has been isolated from Cleome viscosa L. (Capparaceae), and its stereostructure established by chemical, spectral and X-ray crystallographic means. Crystals of 1 belong to space group P21 with a = 10.329(2)A, b = 12.468(3)A, c= 7.356(2)A,β = 109.98°, and Z = 2. The structure was solved by a multiple solution procedure and refined by full matrix least-squares to give R = 0.041 and wR = 0.051. Oxidation of 1 gave the ketone 4, which on treatment with methanolic KOH led to a facile transannular reaction to give the lactone 6

Synthesis of 3,4,5-Trimethoxybenzaldehyde

Abstract The copper [I]-catalyzed exchange of bromine by methoxide in 5-bromovanillin and in 3,5-dibromo-4-hydroxybenzaldehyde provides an efficient method for preparing 3,5-dimethoxy-4-hydroxybenzaldehyde, from which 3,4,5-trimethoxybenzaldehyde is obtained by methylation with dimethylsulfate.

The structure of corylifuran, A clerodane-type diterpene from Croton corylifolius lam

The structure and stereochemistry of corylifuran, a clerodane-type diterpene from Croton corylifolius Lam, have been determined as 2 by chemical and spectroscopic data and X-ray crystallographic analysis.

Characterization of five 19-nor-analogs of 1α,25(OH)2-Vitamin D3 with 20-cyclopropyl-modified side-chains: implications for ligand binding and calcemic properties ☆

The steroid hormone 1alpha,25(OH)(2)-Vitamin D(3) [1alpha,25(OH)(2)D(3)] exerts a wide variety of biological actions through one or more receptors/binding proteins. The nuclear Vitamin D receptor (VDR) when bound to its natural ligand, 1alpha,25(OH)(2)D(3), can stimulate transcription of a wide variety of genes. The synthesis of 1alpha,25(OH)(2)D(3) analogs allows the study of structure-function relationships between ligand and the VDR. 1alpha,25(OH)(2)D(3) is a conformationally flexible molecule; specifically the side-chain of the hormone can display a large variety of shapes for its receptor. Here, we describe and analyze the properties of 10 1alpha,25(OH)(2)D(3) analogs modified at the side-chain of which five lack carbon-19 (19-nor) but have a novel 20-cyclopropyl functionality. Analog NG [20,21-methylene-23-yne-26,27-F(6)-19-nor-1alpha,25(OH)(2)D(3)] possesses a respectable binding affinity for the VDR and exhibits a high transcriptional activity (EC(50) approximately 10pM), while retaining low induction of hypercalcemia in vivo in the mouse, making it a primary candidate for further analyses of its anti-proliferative and/or cell differentiating properties.

X-Ray structure and absolute stereochemistry of stemarin, a diterpene with a new skeleton

The structure and absolute stereochemistry of stemarin, a novel tetracyclic diterpene isolated from Stemodia maritima L. and shown to possess a new skeleton, were determined with the aid of spectral and X-ray crystallographic analyses.

The structure of crotonitenone, a novel casbane diterpene from Croton nitens Sw. (Euphorbiaceae)

A novel casbane diterpene, crotonitenone {(E)-(1R*,5S*,7R*,11S*,14S*)-5-hydroxy-3,7,11,15,15-pentamethylbicyclo[12.1.0]pentadec-2-ene-4,8-dione}(7), C20H32O3, has been isolated from Croton nitens(Euphorbiaceae) and its structure and relative stereochemistry have been established by chemical, spectral, and X-ray crystallographic means. Crystals of (7) are monoclinic, space group P21, with a= 12.446(1), b= 13.285(1), c= 5.872(1)A, β= 97.02(1)°, and Z= 2. The structure was refined by least squares to R 0.040 and R′ 0.038.

Synthesis of an orally active PAF antagonist of the N-[4-(3-pyridinyl) butyl]pentadienamide class

The PAF antagonist [R-(E,E)]-5-(4-methoxyphenyl)-N-[1-methyl-4-(3-pyridinyl)butyl]-2,4-decadienamide (2) was synthesized from (S)-α-methyl-3-pyridinebutanol (14), which was obtained either from ethyl lactate or by enantioselective kinetic hydrolysis of its racemate using the lipase derived from Pseudomonaas cepacia (syn. P. fluorescens). Mesylation of 14, followed by azide displacement and hydrogenation, produced amine (7), which was coupled with the p-nitrophenol ester (8) to give 2. The direct coupling of (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid (27) with azide (24) in the presence of tri-n-butylphosphine also gave 2. Acid (27) was prepared by a vinylogous Reformatsky reaction between ketone (25) and methyl 4-bromocrotonate