The biological activity and chemistry of the southern African Combretaceae

The improved multigram-scale syntheses of the important 8-styrylxanthine A(2A) adenosine receptor antagonist MSX-2 (8), its water-soluble prodrug MXS-3 (9), and KW-6002 (16) are described. N-Alkylation reactions at different positions of uracil derivatives were optimized. Two different methods for xanthine formation from 6-amino-5-cinnamoylaminouracil precursors were investigated, (a) the elimination of water by alkaline catalysis and (b) hexamethyldisilazane as a condensing agent; the latter was found to be superior. The photosensitivity of 8-styrylxanthines was studied. The (E)-configurated stryrylxanthine MSX-2 (8) isomerized in diluted solution, and the resulting (Z)-isomer (10a) was isolated and characterized. Furthermore, we describe for the first time that solid 8-styrylxanthines can dimerize upon exposition to daylight or irradiation with UV light. The resulting cyclobutane derivatives with head-to-tail (syn) configuration exhibited a considerably lower A(2A) adenosine receptor affinity than their parent compounds. The dimerization product of MSX-2 was a moderately potent nonselective A(1) and A(2A) antagonist (K(i)(A(1)) = 273 nM, K(i) (A(2A)) = 175 nM) while the dimer of the related compound KW-6002 was inactive at A(1) and only weakly active at A(2A) adenosine receptors (K(i) = 1.57 microM). The light sensitivity of 8-styrylxanthine derivatives, not only in solution, but also in the solid state, has to be considered when using those compounds as pharmacological tools or drugs.

Multigram-Scale Syntheses, Stability, and Photoreactions of A2A Adenosine Receptor Antagonists with 8-Styrylxanthine Structure: Potential Drugs for Parkinson's Disease

Three phenolic acid derivatives from stromata of Epichloe typhina on Phleum pratense

Nine unexpected new flavonol glycoside cyclodimers in the truxinate (1–7, biginkgosides A–G, respectively) or truxillate [biginkgosides H (8) and I (9)] forms were isolated as minor components from the extract of Ginkgo biloba leaves. The new dimers possess an unusual cyclobutane ring formed by a [2+2]-cycloaddition between two symmetric (for compounds 1–5 and 7–9) or nonsymmetric (for 6) flavonol coumaroyl glucorhamnosides. A plausible biosynthetic pathway for these new compounds based on the frontier molecular orbital theory of cycloaddition reactions is briefly discussed. An antineuroinflammatory screening revealed that biginkgosides E (5) and H (8) inhibited nitric oxide production in lipopolysaccharide-activated BV-2 microglial cells, with IC50 values of 2.91 and 17.23 μM, respectively. Additionally, biginkgoside F (6) showed a significant neuroprotective effect (34.3% increase in cell viability at 1 μM) against Aβ25–35-induced cell viability decrease in SH-SY5Y neuroblastoma cells.

Biginkgosides A–I, Unexpected Minor Dimeric Flavonol Diglycosidic Truxinate and Truxillate Esters from Ginkgo biloba Leaves and Their Antineuroinflammatory and Neuroprotective Activities

A methanol extract of everlasting flowers of Helichrysum arenarium L. Moench (Asteraceae) was found to inhibit the increase in blood glucose elevation in sucrose-loaded mice at 500 mg/kg p.o. The methanol extract also inhibited the enzymatic activity against dipeptidyl peptidase-IV (DPP-IV, IC50 = 41.2 μg/ml), but did not show intestinal α-glucosidase inhibitory activities. From the extract, three new dimeric dihydrochalcone glycosides, arenariumosides V–VII (2–4), were isolated, and the stereostructures were elucidated based on their spectroscopic properties and chemical evidence. Of the constituents, several flavonoid constituents, including 2–4, were isolated, and these isolated constituents were investigated for their DPP-IV inhibitory effects. Among them, chalconaringenin 2′-O-β-D-glucopyranoside (16, IC50 = 23.1 μM) and aureusidin 6-O-β-D-glucopyranoside (35, 24.3 μM) showed relatively strong inhibitory activities.

/pdf/dipeptidyl-peptidase-iv-inhibitory-activity-of-dimeric-y3qxxwhji7.pdf

Dipeptidyl peptidase-IV inhibitory activity of dimeric dihydrochalcone glycosides from flowers of Helichrysum arenarium

1H NMR spectra of photodimers of cinnamic acid, chalcone and related compounds were analysed, and the spectral parameters and all the coupling constants were obtained A clear differentiation among the head-to-head and head-to-tail stereoisomers can be obtained by considering the values of K, L, M and N parameters The different types of hh and ht isomers can be immediately assigned by considering the relative values of the three-bond couplings An authentic example of an A2B2 spin system is reported

G. Montaudo

Papers

Photodimers of cinnamic acid and related compounds. A stereochemical study by NMR