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This paper reports a study of the chemistry of valinomycin, enniatins and related membrane-active depsipeptides that increase alkali metal ion permeability of model and biological membranes. The antimicrobial activity of these compounds and their effect on membranes has been correlated with their cation-complexing ability. The complexing reaction has been studied by spectropolarimetric and conductimetric methods. Nuclear magnetic resonance, optical rotatory dispersion, and infrared spectrophotometric studies have revealed the coexistence of conformers of the cyclodepsipeptides in solution and have led to elucidation of the spatial structure of valinomycin, enniatin B and their K(+) complexes. The effect of the conformational properties of the cyclodepsipeptides on their complexation efficiency and selectivity, surface-active properties and behavior towards phospholipid monolayers, bimolecular phospholipid membranes and a number of biological membrane systems has been ascertained. The studies have clearly shown the feasibility of using cyclodepsipeptides with predetermined structural and conformational parameters as chemical tools for membrane studies. it is suggested that the principle of conformation-dependent cation binding through iondipole interactions may possibly lie at the basis of the mode of action of systems governing the natural ion permeability in biological membranes.

trans-l,5-cyclodecadiene (85) has recently been reported 1731. The interaction of a double bond with a cationic center across the ring is well established in this and other ring systemsL741. A similar behavior with a thiiranium ion, however, is unprecedented and particularly surprising in the case of the strongly bridging methylthio group, since all evidence regarding such ions points toward little charge being developed o n carbon (Section 3.1). It is not known whether one or both of the stereoisomeric cis-decalins are formed. Compound (88) would arise from attack on the trans double bond of (85) which has been[73] J. . -____shown to be the preferred reaction site with addends not involving a carbonium ion intermediate. However, o n the basis of the considerably faster rate of sulfenyl chloride addition to cis-butene compared to its tmns-isomer "71 one would expect preferential attack at the cis double bond of (85) and subsequent formation of decalin (87).The possibility of initial 1,2-addition, as in the case of conjugated dienes, and transannular post-isomerization to (87) or (88) must also be considered. It is, therefore, tempting to suggest transition state (86b) which is strongly reminiscent of the intermediate (52) previously proposed for the rearrangement of the 1,2-adducts from methanesulfenyl chloride and conjugated dienes. Inspection of a model shows that C-1 and C-6 in (866) can approach sufficiently closely for the lobe of the p orbital on C-1 to overlap with the electron deficient orbital on C-6.The basic principles of the topochemical approach to the investigation of the structurefunction relation in peptide systems are formulated. This approach makes use of the new possibility of transforming natural peptides, consisting in the modification of the molecule as a whole alid utilization of the resultant analogs to elucidate the boundaries of the stereoelectronic complementarity of the biologically active peptide to the corresponding receptor. In particular, on the example of depsipepfide antibiotics and their topochemical analogs the fruitfulness of using such compounds as tools in elucidating the physicochemical basis of functioning of biological membranes is shown. The topochemical principle has also been applied in preparing speciJic competitive inhibitors of proteolytic enzymes, whose study may shed light on the nature of the forces binding the substrate to the contact site of the corresponding enzyme.

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