Novel Acetylenic Acids from the Root Bark of Paramacrolobium caeruleum: Inhibitors of 3-Hydroxy-3-methyl-glutaryl Coenzyme A Reductase

Abstract

hSTRACT.-The n-hexane extract of the root bark of Paramurrolobirtmcmleum, collected in Kenya, yielded eleven long chain fatty acids, of which acids la, 2a, 6a, 7a, 9a, and lOaare novel. These acetylenic acids are among the first natural products isolated from plants that have been shown to inhibit the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme responsible for the formation of mevalonate in the rate-determining step of cholesterol biosynthesis.The leading cause of death in the Western world is coronary artery disease, and there is considerable evidence in support of a direct correlation between the incidence of this widespread disorder and elevated levels of plasma cholesterol ( 1,2). As a large proportion of the total cholesterol in the body is accounted for by de novo synthesis (3) in the liver and intestine, the search for drugs to control cholesterol biosynthesis has long been pursued as a means of regulating plasma cholesterol levels. The major rate-limiting step in the biosynthesis of cholesterol is the reduction of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate, which is catalyzed by the enzyme HMG-CoA reductase (4). Considerable success has been achieved in the search for naturally occurring inhibitors of HMG-CoA reductase from microbial sources. In a study of 8000 strains of microorganisms ( 5 ) , two potent, low toxicity inhibitors, ML-236B (compactin) and monacolin K, were discovered in the cultured broth of the fungi Penicillium citrinum (6) and Monascus ruber (7), respectively. Monacolin K is identical to mevinolin, which was isolated independently (8) from another fungus, Aspergillus terreus, and shown to be a very potent inhibitor of HMG-CoA reductase (Ki of 0.6 nm).As part of a feasibility study, a search for inhibitors of HMG-CoA reductase in terrestrial plants was carried out on approximately 600 plant extracts using a bioassay-directed screen with enzyme isolated from rat liver (9,17). Ten extracts were found with IC,, values less than 100 ug/ml and one of these, the hexane extract of the Kenyan plant Paranacrolobium caeruleum (Taub) Leonard (Fabaceae), was selected for fractionation; the results are presented in this paper. RESULTS AND DISCUSSIONReversed-phase (CIS) Si gel column chromatography of the n-hexane extract of the r w t bark of P. caeruleurn afforded several fractions showing substantial activity in HMG-CoA reductase (HMGR) assays. These fractions after preparative thin-layer chromatography (ptlc) and reversed-phase high performance liquid chromatography (rp-hplc) provided ten straight chain C,, acids, including oleic and stearic, and a C14 acid. The eleven identified acids (Figure 1) are: (Z)-7-octadecen-9-ynoic [la), (E)-7-octadecen-9-ynoic [2a), 9-octadecynoic [3a), 7,9-octadecadiynoic [ha}, 7,9-tetradecadiynoic [5a), (E)-5-octadecen-7,9-diynoic [6a), (Z)-5-octadecen-7,9-diynoic [7a), stearic [Sa), 3-( 1,3-dodecadiynyl)-6-0xiranebutanoic [9a}, 6-hydroxy-7,9-octadecadiynoic Elk), and (Z)-9-octadecenoic(oleic) acid Ella}.A mol...

Synthesis of Naturally Occurring Polyynes

“…Several acetylenic fatty acids, such as 121 , have been isolated from the root bark of the legume Paramacrolobium caeruleum and shown to inhibit the activity of a HMG‐CoA reductase 109. The enantiospecific synthesis of diyne alcohol 121 has been reported by Mhaskar and Lakshminarayana,110 who used a Sharpless epoxidation to introduce the stereogenic center in ( R )‐ 122 (Scheme ).…”

Hypolipidaemic Activity in Rats of Bergenin, the Major Constituent of Flueggea microcarpa

“…A survey of lipid-lowering and cholesterol-lowering agents reveals a great deal of structural diversity, from simple acetylenic fatty acids (Patil et al, 1989) to afphapyrones (Alberts et al, 1980), furochromones (Gammil et a f . , 1983), flavonoids (Choi et al, 1991;Masquelier, 1980), phenol glucosides (Arichi et al, 1982) and also the steroids (Bajaj and Dev, 1982) belong to this group of bioactive agents.…”

Bioactivity guided fractionation and hypolipidemic property of a novel HMG-CoA reductase inhibitor from Ficus virens Ait

“…The fraction F18 was identified as Octadecanyl-O-α-D-glucopyranosyl (6′ → 1″)-O-α-D-glucopyranoside. This is a new and completely different structure than the other inhibitors isolated from various plants such as tocotrienol from barley [ 52 ], kakkalide and irisolidone from flower of Pueraria thunbergiana [ 53 ], camphene, a plant-Derived monoterpene [ 54 ], daidzein from Pueraria thunbergiana [ 55 ], acetylenic acids from the root bark of Paramacrolobium caeruleum [ 56 ], and flavonoids from the buds of Rosa damascena [ 57 ].…”