Naturally Occurring Pentacyclic Triterpenes as Inhibitors of Glycogen Phosphorylase: Synthesis, Structure−Activity Relationships, and X-ray Crystallographic Studies

Abstract

Twenty-five naturally occurring pentacyclic triterpenes, 15 of which were synthesized in this study, were biologically evaluated as inhibitors of rabbit muscle glycogen phosphorylase a (GPa). From SAR studies, the presence of a sugar moiety in triterpene saponins resulted in a markedly decreased activity ( 7, 18- 20) or no activity ( 21, 22). These saponins, however, might find their value as potential natural prodrugs which are much more water-soluble than their corresponding aglycones. To elucidate the mechanism of GP inhibition, we have determined the crystal structures of the GPb-asiatic acid and GPb-maslinic acid complexes. The X-ray analysis indicates that the inhibitors bind at the allosteric activator site, where the physiological activator AMP binds. Pentacyclic triterpenes represent a promising class of multiple-target antidiabetic agents that exert hypoglycemic effects, at least in part, through GP inhibition.

URSOLIC ACID AND CIS-TILIROSIDE PRODUCED BY Merremia tomentosa AFFECT OVIPOSITION OF Leucoptera coffeella ON COFFEE PLANTS

“…Substances like asiatate and maslinate, which are structurally similar to ursolate, as well as (S)-3-(1-methylethyl) 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methylpyridine-3,5,6-tricarboxylate (W1807), 4-[2,4-bis-(3-nitrobenzoylamino)phenoxy]phthalic acid (Novo4j) and 1-(2-chloro-4-fluorobenzoyl)-3-(5-hydroxy-2-methoxy-phenyl)urea (AVE#21), 21 inhibit the enzyme by binding to this allosteric site, which was chosen to carry out the study on the interaction of these compounds with the glycogen phosphorylase in complexes 2QN1 and 2QN2. Other substances structurally similar to ursolate and active against insects according to the literature were also docked to the allosteric site of the enzyme (Figure 2).…”

Crystal structure of benzyl-2-oxo-oleanic acid, C37H52O4

“…It has been reported to exhibits pharmacological activities, such as anti-tumor, anti-viral, anti-HIV and anti-HCV activities [1,2]. Because of its wide biological activities and its potential applications, the extraction, synthesis and biological activity of oleanic acid and its derivatives have attracted much attention [3][4][5][6][7].Inthis paper, we report the crystal structure of the title compound, whose synthetic protocolhas been alreadyreported elsewhere [7]. In the molecule of thetitle compound (Fig.…”

Tethered derivatives of d-glucose and pentacyclic triterpenes for homo/heterobivalent inhibition of glycogen phosphorylase

“…The residue was purified by column chromatography. (16). Prepared from 4 (0.13 g, 0.27 mmol) and 7 (0.10 g, 0.27 mmol) according to General procedure IVa.…”

“…[13][14][15] X-Ray crystallographic studies revealed the molecular basis of their inhibitory effect, demonstrating that pentacyclic triterpenes such as asiatic and maslinic acids bind to GP at the allosteric site. 16 Oleanolic acid (1, OA), ursolic acid (2, UA) and maslinic acid (3,MA) have recently attracted much attention due to their broad biological activities such as protection of the liver against toxic injury, anti-inflammation, anti-HIV, antitumor, antioxidation, anti-hyperglycemia and cardiovascular activities. 17 Inhibitors having the potential to bind to more than one site of an enzyme may be significantly more efficient than those with a single binding group (for some tentatively selected examples of bi-or trivalent enzyme inhibitors see ref.…”