Inhibition of Cholesteryl Ester Transfer Protein by Rosenonolactone Derivatives.

Abstract

Several recent clinical trials have demonstrated that lower plasma cholesterol levels do indeed have a beneficial effect on events related to coronary heart diseases. (Fig. 1) were isolated from the culture of fungus strain F1064, that was isolated from a soil sample collected at Mt. Jiree, Kyun-815 gnamProvince, Korea. It was taxonomically identified as Trichothecium roseum by the method of Pitt and Hocking.9) A 2-ml portion of the seed culture was inoculated into a 1-liter baffled flask with four baffles containing 100 ml of production medium (soluble starch 2%, soytone 0,4%, pharmamedia 0.3%, K2HPO4 0.1%, 0.05%, NaCl 0.2%, CaCO3 0.3%, FeSO4-7H2O 0.002%, MnCl2-4H2O 0.001%, ZnSO4-7H2O 0.01%, CoCl2 0.005%). The fermentation was carried out for 5days at 26°C on a rotary shaker at 150 rpm. After fermentation at 26°C for 5days, the whole broth (800ml) was centrifuged to obtain the mycelial part which was extracted with 900ml of acetone. After filtration and concentration of the acetone extract, the resulting aqueous solution (100ml) was extracted twice with 500ml of chloroform. The extracts were concentrated in vacuo to dryness to give brown oily materials (1.5g).The oily material was applied to a silica gel column (30 g). The materials were eluted with a stepwise gradient of w-hexane-ethyl acetate. Active fractions were concentrated in vacuo to yield pale brown oily material

The biotransformation of the Diterpenoid, Rosenonolactone by Mucor Plumbeus

“…2 This structure possesses quaternary centres at C-4, C-9, C-10 and C-13 and consequently it is difficult using conventional chemical means, to functionalise rings A and C. A number of rosanes are biologically active and recently as a result of screening studies, it was concluded that rosenonolactone analogues may be good models for the design of new inhibitors of the cholesteryl ester transfer protein. 3 It was therefore of interest to examine the use of microbiological transformation in order to introduce hydroxyl groups into rings A and C.The fungus, Mucor plumbeus, has been used for the biotransformation of terpenoids. Incubation of rosenonolactone 1 with M.plumbeus for seven days on shake culture gave five metabolites which were separated by chromatography.…”

“…6β-Hydroxyrosenonolactone 2: m.p.185-187°C (lit., 4 180-181°C), (Found:M + 332.197 Calc. for C 20 H 28 0 4 M + 332.199), υ max /cm -l 3431, 1763, 1713, 1637; δH 0.97 (3H,s,H-17), 1.11(3H,s, H-20), 1.40(3H,s,H-18), 2.60(1H,dd, J 4.1 and 11.8 Hz, H-8), 2.88(1H,br.s.OH) (disappears on treatment with 2 H 2 0),3.96(1H,dd, J 1.9 and 4.9 Hz, H-6) (collapses to doublet J 4.9 Hz, on treatment with 2 H 2 0), 4.92 (lH,dd, J 10.7 and 0.9 Hz), 5.00 (lH,dd, J 17.5 and 0.9 Hz) (each H-16), 5.82 (lH,dd, J 10.7 and 17.5 Hz, H-15).15,16-Epoxyrosenonolactone 3: m.p, 168-172°C, (Found: M + 332.197 C 20 H 28 0 4 requires 332.199), υ max /cm -1 1756, 1714; δ H 0.86(3H,s, H-17), 0.92(3H,s, H-20), 1,11(3H,s, H-18), 2.62 (2H,d, J 3.2 Hz, H-16), 2.75(1H,t, J 3.2 Hz, H-15). 12α-Hydroxyrosenonolactone 4: m.p.…”

Stereospecific Inhibition of CETP by ChiralN,N-Disubstituted Trifluoro-3-amino-2-propanols

“…Support for this idea was recently obtained in a rabbit atherosclerosis model using a CETP inhibitor (). Several CETP inhibitors have been described, including monoclonal antibodies (), apolipoproteins ( , ), amphipathic peptides ( 5 , − , amphipathic small molecules such as cholesteryl sulfate and lipopolysaccharide that modify lipoprotein structure ( , ), as well as various small molecules including sterols, polycyclic natural products and heterocyles ( − ). Some compounds have been shown to irreversibly inactivate CETP following cysteine modification, suggesting that a cysteine residue may reside in or near the neutral lipid binding site ( 12 , 13 , 20−22 , 35 ).…”

New Diterpenes from Cultures of the Fungus Engleromyces goetzii and Their CETP Inhibitory Activity

“…This investigation led to the isolation and identification of one new cleistanthane-type diterpene named engleromycenolic acid A ( 1 ), one new rosane-type diterpene named engleromycenolic acid B ( 2 ) and one new natural rosane-type diterpene named engleromycenol ( 3 ), along with three known rosane-type diterpenes: rosololactone ( 4 ), rosenonolactone ( 5 ) and 7-deoxyrosenonolactone ( 6 ) [7]. Their structures (Fig.…”