Hypocholesterolemic Activity of N-(Ferrocenylmethyl) piperidine

Abstract

The search for new hypocholesterolemic agents has resulted in the discovery of many active compounds in the last few years. I t is highly probable that the majority of these affect cholesterol biosynthesis in some way. In particular, several have been reported which inhibit one of the later reactions in the sequence (1-3).The purpose of the present paper is to report the investigation of a member of a series of new hypocholesterolemic agents having ferrocene as a component of their structure. The results of this study show that this compound, N -( ferrocenylmethyl) piperidine, causes abnormal quantities of a compound resembling 7-dehydrocholesterol to acumulate in serum and liver, and probably acts by inhibiting 7-dehydrocholesterol reductase. Very little work has been reported on the pharmacological activity of ferrocene compounds, although it has been suggested that ferrocene or ferrocene derivatives could be used as hematinic agents (4, 5).Experimental Methods. Animal studies. The chemical was adsorbed on silica gel from an acetone solution and mixed with ground rodent mash on a roller mill to give a concentration of 0.007%. Groups of six male weanling rats (Harlan Wistar strain, Harlan Industries, Cumberland, In.) were maintained on the experimental diet for 1 week, then killed and blood and liver samples were collected.Andytical. A modification ( 6 ) of the method of Sperry and Webb (7) was used for the determination of "fast-acting" sterols and cholesterol. This method takes advantage of the fact that the so-called "fast-acting" sterols give full color development in 12 min at O", whereas cholesterol does not react at all in this time. After standing at 25" for an additional 30 min, the absorbancy is again determined. After a suitable correction for the contribution of " fast-acting" sterols to the latter reading, the amount of cholesterol can be determined. Materials absorbing at 28 1.5 mp were determined spectrophotometrically by measuring the absorbancy in ethanol of nonsaponifiable material from serum and liver. Correction for extraneous absorption was made using a three-point procedure (8) with selected wavelengths of 276.5, 281.5, and 284.5 mp. The reference material for "fast-acting" sterols and the 281.5 mp determination was 7-dehydrocholesterol.A spectrophotometric assay (9) was used to determine inhibition of the enzymatic reduction of 7-dehydrocholesterol in vitro.Each flask contained 13,OOOg rat liver supernate equivalent to 0.25 g of liver, 0.75 pmoles of 7-dehydrocholesterol, 1.7 pmoles of NADP, 30 pmoles of nicotinamide, 15 pmoles of glucose-6-phosphate, and 70 pmoles of Tris-maleate buffer, pH 7.2. The total volume was 1.0 ml and the incubations were carried out in duplicate at 37" for 2 hr under nitrogen.

Biological properties of transition-metal organometallic compounds. 3. .beta.-Ferrocenylalanine

“…The compounds investigated included dl-1, five DLhalophenylalanines (p-F, 2; m-F, 3; o-F, 4; p-Cl, 5; p-Br, 6), L-/3-(2-pyridyl)alanine (7), and DL-/3-(6-methyl-2pyridyl)alanine (8).…”