Filipin complex

The polyene macrolide filipin was isolated in 1955 from the cell culture filtrates of Sterptomyces filipinensis, and was later shown to be a mixture of four components [36]. Although too toxic for therapeutic use, the filipin complex has found widespread use as a histochemical stain for cholesterol and has even been used to quantitate cholesterol in cell membranes [37]. The flat structure of filipin III, the major component of the filipin complex, was assigned from a series of degradation studies [38]. Rychnovsky completed the structure determination by elucidating the relative and absolute stereochemistry [39]. The total synthesis plan for filipin III relied heavily on the cyanohydrin acetonide methodology discussed above. 

Next we will describe the synthesis of filipin III (114) in greater detail, to bring to light some of the issues that arise in the total synthesis of a complex polyene macrolide [7,8]. 

The macrolide antibiotic filipin interacts with 3-p-hydroxysterols such as cholesterol in the plasma membrane to form filipin-sterol complexes (59). Subsequently, the filamentous caveolin-l-coat rapidly disassembles, which... 

Organic molecules forming complexes with sodium ions in water, such as monensin, speed up ion transport by factors of about 10, molecules that form tunnels by factors of 10 ° and more. Scheme 2.7.1 depicts two typical structures of ion transport agents, namely monensin and filipin. Gramicidine, on the other hand, is thought to form a pore in membranes. The only clear-cut distinction between an ion pore and an ion transporter is that a pore can be closed and reopened by stopper molecules, whereas ion transport will always occur as long as complexation in membranes and decomplexation in water can occur. 

Freeze-fracture E.M. studies of natural and synthetic membranes treated with filipin, digitonin and tomatine revealed characteristic protuberances on the surfaces of membranes (52,53) but how these structures relate to the chemical complexes or to the formation of pores is not understood. 

Figure 3.7. Schematic representation of the cholesterol (C)-filipin (F) complex in a lipid bilayer, showing a cross-section through part of a...

Significant reduction in serum cholesterol levels can also be demonstrated in animals simultaneously fed polyenes and high sterol diets. Dogs appeared more able to maintain their serum cholesterol levels when fed sterols and filipin, amphotericin B or candicidin [145,535] but nystatin had no effect. The anti-hypercholesterolemic effect was not simply due to the prevention of sterol uptake [538,539]. A consequence of the excretion of sterol-polyene complexes in the faeces is the loss of bile salts (which are steroids) and this tends to remove sterol from the body. This resulted in increased hepatic synthesis, increased utilization of adipose fat and reduced sebum levels. Candicidin has been suggested as an antihypercholesterolemic agent in man [546]. 

C. H. Moeller and J. B. Mudd "Localization of Filipin - Sterol Complexes... 

Polyene antibiotics such as amphotericin, nystatin, or filipin are examples of inainly hydrophobic molecules that also have polar groups. In water, these cyclic molecules tend to aggregate to shield their hydrophobic surfaces from water. These compounds are readily incorporated into natural as well as model membranes and tend to aggregate in the bilayer, now in a reversed manner, i.e. shielding their polar groups from the hydrophobic interior of the membrane. The antibiotics form complexes with sterols and act as membrane active compounds in the sense that the bilayers become leaky [116,117]. 

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