ABSTRACT: Polyether glycosidic ionophores and macrocyclic glycosides are of great interest, especially for the medicinal and pharmaceutical industries. These biologically active natural sur- factants are good prospects for the future chemical preparation of compounds useful as antibiotics, anticancer agents, or in indus- try. More than 300 interesting and unusual natural surfactants are described in this review article, including their chemical struc- tures and biological activities. Paper no. L9676 in Lipids 40, 219–248 (March 2005). The diversity of natural surfactants and their biomedical activ- ity has recently been partly reviewed in some articles (1–6) and books (7–10). Polyether glycosidic ionophores and macro- cyclic glycosides are a large group of structurally related polyketide natural surfactants (2,11–13). The polyether glyco- sidic ionophores are characterized by multiple tetrahydrofuran and tetrahydropyrane (or more) rings connected by aliphatic bridges, direct C–C linkage, or spiro-linkages, and they also contain one or more sugar moieties. Other features include a free carboxyl function, many lower alkyl groups, and a variety of functional oxygen groups. These structural features enable the molecule to form a cyclic conformation with the oxygen functions at the center and the alkyl groups on the outer sur- face. Accordingly, this conformation results in lipid solubility, even for the salt forms, enabling transport of cations across lipid membranes (14–16). The term ionophore was first used by Pressman et al. to describe compounds that can transport ions across artificial or natural membranes (17). The polyethers are sometimes referred to as carboxylic acid ionophores to dis- tinguish some antibiotics from other compounds showing ionophoretic activity (18,19). Individual polyether ionophores exhibit varying specificities for cations (20,21). Many macrolide glycosides are well-established antimicro- bial agents in both clinical and veterinary medicine (22–25). These agents can be administered orally and are generally used to treat infections in the respiratory tract, skin and soft tissues, and genital tract caused by Gram-positive organisms, such as Mycoplasma species, and by certain susceptible Gram-nega- tive and anaerobic bacteria (26–28). The macrolide class is large and structurally diverse (2,12,29–31). Macrolides are produced by the fermentation of microorganisms and/or are found in marine invertebrates, such as sponges, bryozoa, or marine cyanobacteria, and in dinofla- gellate species belonging to the genera Amphidinium, Gam- bierdiscus, Prymnesium, and Protoceratium (32–34). Addition- ally, structural modifications using both chemical and microbi- ological means have yielded biologically active semisynthetic derivatives. The term macrolide was introduced in 1957 by Woodward (35) to denote the class of substances produced by Streptomyces species containing a macrocyclic lactone ring. The generalized structure is a highly substituted monocyclic lactone (aglycone) to which is attached one or more saccha- rides glycosidically linked to hydroxyl groups on either the aglycone or another saccharide (12,30). The aglycones are de- rived via similar polyketide biosynthetic pathways and thus share many structural features in terms of pattern and stereo- chemistry of substituents (36, and references cited). Traditional macrolide antibiotics are divided into three families according to the size of the aglycone, which can be 12-, 14-, or 16-mem- bered, but more recently macrolides with 30–72-membered macrolactone glycosides have been isolated (2,12,29–31). Be- cause one or more amino sugars are usually present, these com- pounds are basic and can form acid addition salts. In addition, one or more neutral sugars are often present. The saccharides share some common features: They tend to be highly deoxy- genated and N- and/or O-methylated, and the amino groups are located at either position 3 or 4. The most common macrocyclic glycosides are given below. POLYETHER GLYCOSIDIC IONOPHORES Ionophores are used as food antibiotics throughout the world in the beef and poultry industries. The efficiency of cattle pro- duction is increased by altering rumen fermentation and con- trolling the protozoa that cause coccidiosis. Ionophores act by Copyright © 2005 by AOCS Press 219 Lipids, Vol. 40, no. 3 (2005) *Address correspondence at Department of Organic Chemistry, P.O. Box 39231, Hebrew University, Jerusalem 91391, Israel. E-mail: dvalery@cc.huji.ac.il or devalery@gmail.com Abbreviations: EC 50 , the median effect concentration, being a statistically-derived concentration of a substance that can be expected to cause (i) an adverse reaction in 50% of organisms or (ii) a 50% reduction in growth or in the growth rate of or- ganisms; ED 50 (effective dose 50 ), the amount of material required to produce a specified effect in 50% of an animal population; GI, growth inhibition; GI 50 , the concentration needed to reduce the growth of treated cells to half that of untreated (i.e., control) cells; HSV-1, herpes simplex virus type 1; IC, inhibitory concentra- tion; IC 50 , concentration at which growth or activity is inhibited by 50% (applies to ligand and growth inhibition); %ILS, percent increase in life span; LC 50 for drugs with a cytotoxic effect, the concentration of drug at which 50% of cells die (a 50% reduction in the measured protein at the end of the drug treatment as com- pared with that at the beginning); LD 50 , (lethal dose 50 ), the dose of a chemical that kills 50% of a sample population; log IC (log EC), IC (or EC) in a log 10 scale (a log 10 scale is frequently used when x values are a serial dilution, as a better es- timate of the SE is obtained); log GI 50 , log concentrations that reduced cell growth to 50% of the level at the start of the experiment; log 10 RC 50 , root elongation half inhibition concentration (mol/L) in logarithmic form; LD, lethal dose; LD 50 , the dose at which 50% of test subjects die; LPS, lipopolysaccharide; MIC, minimal inhibitory concentration; RC 50 , concentration at which there is a 50% reduction in the number of offspring as compared with controls; TRAP, tartrate-resistant acid phosphatase; VZV, varicella-zoster virus. REVIEW Astonishing Diversity of Natural Surfactants: 2. Polyether Glycosidic Ionophores and Macrocyclic Glycosides Valery M. Dembitsky* Department of Organic Chemistry and School of Pharmacy, Hebrew University, Jerusalem, Israel