Structure-activity relationships in the antiinflammatory steroids: a pattern-recognition approach.

A pattern-recognition technique has been used to determine structure-activity relationships for antiinflammatory steroids. Experimental results using the human vasoconstrictor test of McKenzie and Stoughton and the rat granuloma cotton pellet method of Meier were correlated with the various substructural descriptors. Steroids were classified into two categories according to potency, and a pattern-recognition method was applied to determine their relative ranking. The resulting structure-activity relationships obtained and the relative contributions of the various structural variables for both bioassays are discussed. A synergistic effect was predicted to be in operation between certain pairs of substituents.

Surface activities of barbital, phenobarbital, and pentobarbital and their interaction energies with phospholipid monolayers.

The adsorption free energies of barbital, phenobarbital, and pentobarbital at the air-water interface were estimated from plots of the surface pressure (pi less than or equal to 5 dynes/cm) against the bulk concentration. Their energies of interaction with dipalmitoylphosphatidylethanolamine and dipalmitoyllecithin monolayers spread at the air-water interface were estimated from the surface pressure increase with increasing concentrations of the subphase-injected barbituric acid derivatives. Adsorption free energies and interaction energies were barbital less than phenobarbital less than pentobarbital, which correlate with their nerve blocking concentration.

Kinetics and mechanisms of monolayer interactions V: surface activities of alkylamides, alkylmonocarboxylic acids, and alkylketones and their interaction energies with phospholipid monolayers.

The adsorption free energies of the C1-C6 alkylamides, C3-C8 alkylketones, and C1-C10 alkylmonocarboxylic acids at the air-water interface, estimated from plots of the surface pressure (less than or equal to 5 dynes/cm) versus the bulk concentration, were linear functions of the total surface area per molecule (square angstroms per molecule), with a slope 46% higher for the alkylamides and 25% lower for the alkylketones than that for the monocarboxylic acids. The interaction energies of alkylamides with dipalmitoyl lecithin and dipalmitoyl phosphatidylethanolamine spread at the air-water interface, estimated from the surface pressure increase with increasing concentrations of the injected C1-C5 compounds, were linear functions of the total surface area per molecule. The diffusion free energies, delta Gdif, of the alkylamides within a phospholipid bilayer, predicted from the permeability equation and their interaction energies with dipalmitoyl lecithin monolayers by assuming the additivity of their free energies of adsorption and dehydration at the solution-bilayer interface, agreed with the literature data.

Surface activities of procaine, lidocaine, and tetracaine and their interaction energies with phospholipid monolayers.

The free energies of adsorption of procaine, lidocaine, and tetracaine at the air--water interface were estimated from plots of surface pressure (pi less than or equal to 5 dynes/cm) against bulk concentration. Their interaction energies with dipalmitoylphosphatidylethanolamine and dipalmitoyllecithin monolayers, previously spread at the air--water interface, were estimated from the increase of surface pressure with increasing concentrations of the subphase-injected anesthetic. Free energies of adsorption and the interaction energies were in the order procaine less than lidocaine less than tetracaine and correlate with relative anesthetic potencies and the blocking of nerve conduction.

Interaction of doxorubicin with phospholipid monolayers.

The energies of interaction of doxorubicin hydrochloride and sodium 1,2,4-trihydroxy-9,10-dioxo-3-anthracenesulfonate with dipalmitoylphosphatidylethanolamine and dipalmitoyllecithin monolayers spread at the air-water interface were estimated from the increase in surface pressure with increasing concentrations of the subphase-injected compound. Their orders of magnitude were consistent with those of the energies of interaction of doxorubicin and acridines with double-stranded DNA, which suggests that the same type of van der Waals forces are operative.