ABSTRACT
The need for new therapies to treat systemic fungal infections continues to rise. Naturally occurring hexapeptide echinocandin B (1) has shown potent antifungal activity via its inhibition of the synthesis of beta-1,3 glucan, a key fungal cell wall component. Although this series of agents has been limited thus far based on their physicochemical characteristics, we have found that the synthesis of analogues bearing an aminoproline residue in the 'northwest' position imparts greatly improved water solubility (> 5 mg/mL). The synthesis and structure-activity relationships (SAR) based on whole cell and upon in vivo activity of the series of compounds are reported.
Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Fungal Proteins , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/pharmacology , Peptides , Acute Disease , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Amphotericin B/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemistry , Candida/drug effects , Candidiasis, Vulvovaginal/drug therapy , Candidiasis, Vulvovaginal/microbiology , Disease Models, Animal , Dose-Response Relationship, Drug , Echinocandins , Female , Mice , Microbial Sensitivity Tests , Peptides, Cyclic/chemistry , Proline/chemistry , Solubility , Structure-Activity Relationship , Yeasts/drug effectsABSTRACT
The preparation is described by several Nalpha-9-fluorenylmethyloxycarbonylamino acids and derivatives bearing tert.-butyl type side-chain protection of amine, carboxyl, guanido, hydroxyl, imidazol, and sulfhydryl functionalities. Physicochemical properties of these compounds have been determined. Cleavage of the Fmoc group by various amines appears to depend on the base strength and steric hindrance. Premature deblocking of Fmoc group by amine on solid support is very slow and may be negligible under the conditions of solid-phase synthesis.
Subject(s)
Amino Acids/chemical synthesis , Fluorenes/chemical synthesis , Butanols , Chemical Phenomena , ChemistryABSTRACT
The synthesis of the protected polypeptide precursor of [1-beta-mercapto-beta,beta-diethylpropionic acid,2-(3,5-dibromo-L-tyrosine)]oxytocin was performed in a stepwise manner by solution techniques. This analog of oxytocin has two modifications, each of which taken alone gives analogs which inhibit some of the pharmacological responses to oxytocin. The S-ethylcarbamoyl protecting groups of beta-Mpa(beta-Et2)(Ec)-Dbt-Ile-Gln-Asn-Cys(Ec)-Pro-Leu-Gly-NH2 were removed in refluxing liquid NH3, and the resulting disulfhydryl compound was oxidatively cyclized in H2O-MeOH with ICH2CH2I. Purification was effected by partition chromatography and gel filtration. The analog possesses antioxytocic (pA2 = 7.08) and antiavian vasodepressor (pA2 = 7.38) activities but has neither agonist nor antagonist activity in the rat pressor assay. These potencies are close to those exhibited by [1-beta-mercaptopropionic acid,2-(3,5-dibromo-L-tyrosine)]oxytocin but different from those of [1-beta-mercapto-beta,beta-diethylpropionic acid]oxytocin.
Subject(s)
Oxytocin/analogs & derivatives , Animals , Blood Pressure/drug effects , Chickens , Depression, Chemical , Female , In Vitro Techniques , Male , Oxytocin/chemical synthesis , Oxytocin/pharmacology , Rats , Uterine Contraction/drug effectsABSTRACT
[1-Beta-Mercaptopropionic acid,2-(3,5-dibromo-L-tyrosine)]oxytocin was synthesized from a protected polypeptide intermediate that had been prepared by the condensation of S-ethylcarbamoyl-beta-mercaptopropionyl-3,5-dibromotyrosine with H-Ile-Gln-Asn-Cys(Ec)-Pro-Leu-Gly-NH2, using dicyclohexylcarbodiimide in dimethylformamide. The ethylcarbamoyl (Ec) protecting groups were removed by refluxing NH3, and the resulting disulfhydryl peptide was oxidatively cyclized to the corresponding disulfide by ICH2CH2I. Purification of the analog was effected by partition chromatography and gel filtration. The analog possesses antioxytocic (pA2 = 7.05) and antiavian vasodepressor (pA2 = 7.44) activities but has neither agonist nor antagonist activity in the rat pressor assay.
Subject(s)
Oxytocin/analogs & derivatives , Oxytocin/antagonists & inhibitors , Animals , Blood Pressure/drug effects , Chickens , Depression, Chemical , Female , In Vitro Techniques , Oxytocin/chemical synthesis , Oxytocin/pharmacology , Rats , Sulfhydryl Compounds/chemical synthesis , Sulfhydryl Compounds/pharmacology , Tyrosine/chemical synthesis , Tyrosine/pharmacology , Uterine Contraction/drug effectsABSTRACT
A randomized double-blind left-right comparative trial was carried out between a new steroid Desoximetason 0,25% (Ibaril) and fluocinolone acetonide 0,025% cream. Evaluation of symptoms on 50 patients suffering from endogenous eczema was recorded after 1, 2, 3 and 4 weeks. There was a significantly better effect of Ibaril compared to Fluocinolone-acetonide as judged by the observer during the 1st, 3rd and 4th week of treatment. After the 2nd week treatment Ibaril showed a better effect, however, a significancy could not be established.
