Uncarinic acid

In traditional systems of medicine, species of Uncaria have been used for the treatment of neurotoxicity. Bioactivity-guided fractimiation of U. rhynchophylla led to the discovery of pentacychc triterpene esters, namely uncarinic acid A and B [38,37]. Literature demonstrates that these compounds inhibit the growth of human cancer cell lines A-549, HCT-15, MCF-7, HT-1197, and phosphohpase Cyl, an enzyme which induces proliferation of human cancer cells [38,37]. The studies on cDNA microarray revealed that hyperin (3.5) isolated from stems of U. rhynchophylla, down regulated SNU-668 human gastric cancer cells. 

The structural diversity has been found in many other species of Uncaria including U. elliptica (44 compounds), U. attemata (34 compounds), and U. rhynchophylla (33 compounds). The chemical diversity of these species is as complex as U. tomentosa. For instance, U. elliptica possesses several ajmalicinine derivatives, corynoxines, rauniticines, and D-secoalkaloids. In addition to the compounds present in U. tomentosa, U. elliptica also possesses uncarinic acids and uncaric acids. 

Uncaria spp. also contain pentacyclic triterpenoids, mostly of the ursane type. Uncarinic acids A-E (1.14—1.18) which include both ursane- and oleanane-type skeletons are prevalent among 16 different species that have important pharmacological activities. Phosphatidylinositol-specific phospholipase C plays a cmcial role in DNA synthesis and cell proliferation. This... 

In 1966, Johns and Lamberton [45] showed that equilibration of uncarine C and uncarine D in acidic and basic solutions resulted in C-3 isomerizations. Further investigations [46,47] revealed that equilibration of e.g. uncarine C in an aqueous acetic acid solution (50%) resulted in four isomers, namely uncarine C (64), D (65), E (66) and F (67), Fig. 

The presence of an oxindole nucleus in mitraphylline is established by the results of zinc dust distillation. The basic products include isoquinoline and 3,4-diethylpyridine, while the neutral fraction affords 3-spirocyclopropano-oxindole (IV), mp 179°-181° (55, 56). This degradation product is of the greatest importance in this series of alkaloids it was first obtained from the calcium oxide distillation of rhynchophyllic acid (19), and has since been obtained by zinc dust distillation of uncarine-A (58), by hydrogenation and pyrolysis of uncarine-A methiodide (59), and by zinc dust distillation of formosanine (uncarine-B) (60). The structure of this neutral degradation product was first proposed by Wenkert and Reid (61), who pointed out that its properties were very similar to those... 

The stem, wood, and bark of Uncaria kawaJcamii contain the two isomeric alkaloids, uncarine-A and uncarine-B, C21H24N2O4 (30, 31), the highest proportion of alkaloids (1.48%) occurring in the bark (31). Uncarine-B has been identified with formosanine (28, 33), which was isolated earlier from Ourouparia formosana (21, 32). The chemical behavior of uncarine-A and formosanine is identical in all respects, and their relationship as stereoisomers is shown by their ready interconversion and equilibration, which frequently hinders the separation and purification of individual isomers. Thus, uncarine-A in hot dilute acetic acid yields formosanine, and the reverse transformation can be achieved by heating formosanine with ether, until it has all been isomerized into the more soluble uncarine-A. Some formosanine is even obtained when uncarine-A is recovered from its hydrochloride, or from the hydrochloride of the related amino acid, by methylation with diazomethane (59). 

Final confirmation of these structures for formosanine and uncarine-A is afforded by their total synthesis (50). The keto ester 36, prepared earlier together with its C-20 epimer in connection with the synthesis of akuammigine and tetrahydroalstonine (q.v.), was reduced catalytical-ly to the lactone ester 37 which was further reduced (NaBH ) to the lactol ester 38. Polyphosphoric acid converted 38 into 3-iso-19-epiaj-malicine (39) which reacted with i-butyl hypochlorite to give the chloro-indolenine 40. Treatment of 40 with aqueous methanolic acid then gave a mixture of formosanine (31) and uncarine-A (32) (50). 

These four stereoisomers can be equilibrated in acetic acid solution and any one isomer rapidly gives a mixture of all four isomers. In P3U idine solution the equilibrium is slowly attained and only traces of uncarines-D and -F, for example, are produced from either uncarine-C or uncarine-E. 

The oxidative transformation of tetrahydroalstonine into its oxindole analogs, unsuccessfully attempted on previous occasions (see comment above), has now been achieved. Tetrahydroalstonine was oxidized with lead tetraacetate to its 7-acetoxyindolenine derivative, which was then converted by treatment with methanolic acetic acid into a mixture of oxindoles all four possible stereoisomers, uncarines C-F, were obtained, and were isolated by preparative thin-layer chromatography (44). 

---