In the course of a screening program for HIV-1 protease inhibiting activity, six new homologues of 3-alkanoyl-5-hydroxymethyl tetronic acids (1~6) and the known natural product resistomycin (7) were isolated from cultures of the Actinomycete strain DSM7357. The substituted tetronic acids belong to a recently described structural class of secondary metabolites. The HIV-1 activity of resistomvcin (7) has not been reoorted before.Human immunodeficiencyvirus (HIV) is the etiological agent responsible for the development of acquired immunodeficiency syndrome (AIDS) in man. Replication of HIV depends on the cleavage of two viral polyproteins by a virally-encoded protease (HIV-1 protease) to yield structural proteins and essential viral enzymes1}. Inhibition of this enzymeresults in the formation of immature viral particles and hence suppression of infection in vitro. Several synthetic transition state mimetics of this aspartyl protease have been designed, which display potent antiviral activity, and which are currently in clinical evaluation2). The availability of structural information through X-ray analysis allowed the rational design and optimization of enzyme inhibitors. The identification of natural HIV-1 protease inhibitors could be a further important Scheme 1. Chemical structures of six new homologues of 3-alkanoyl-5-hydroxymethyl tetronic acid (1~6).step leading to a therapeutic agent against AIDS3).In the course of a screening program for inhibitors of HIV-1 protease an Actinomycete strain (DSM 7357) was found which produced six new 3-alkanoyl-5-hydroxymethyl tetronic acid homoScheme 2. Chemical structure of resistomycin (7).
The structures of six novel spirodihydrobenzofuranlactams I~VI (1~6) were determined by spectroscopic methods.Six novel spirodihydrobenzofuranlactams I~VI (16 ) (Fig. 1) have been identified in extracts of two different Stachybotrys species as antagonists of endothelin and as inhibitors of HIV-1 protease. In a recently published paper1} we described the fermentation, isolation and biological properties of these secondary metabolites 1~6. Besides this novel class of the spirodihydrobenzofurans including the lactams 1~4, 6 and the imide 5 the known spirodihydrobenzofuranalcohol L-67 1 7762) was isolated. This inositol-phosphate phosphatase and HIV-1 protease
Six novel spirodihydrobenzofuranlactams I~VI (1~6) and a related spirodihydrobenzofuranalcohol, the previously described natural compound L-671,776 (7), were isolated from cultures of two different Stachybotrys species. These secondary metabolites showedantagonistic effects in the endothelin receptor binding assay and inhibited HIV-1 protease. Both biological activities are novel for L-671,776 (7). The pseudosymmetric spirodihydrobenzofuranlactam VI (6) is the most potent representative of this class of compoundsexhibiting IC50 values of 1.5^m in the ET-Areceptor binding assay and ll jjm in the HIV-1 protease inhibition assay.
The structures of six new homologues of 3-alkanoyl-5-hydroxymethyl tetronic acid (1~6) were determined by spectroscopic methods.Six new homologues of the 3-alkanoyl-5-hydroxymethyl tetronic acid (1~6) (Scheme 1) have been identified in extracts of the Actinomycete strain DSM7357 as inhibitors of HIV-1 protease. In the preceding paper1} we described the fermentation, isolation and biological properties of these secondary metabolites 1~6. The length and substitution pattern of the alkanoyl side chain of the tetronic acids (1~6) differ from a recently described naturally occurring tetronic acid2). Agglomerins A~D3) are tetronic acid derivatives with a different substitution of the butyrolactone ring, but exhibiting alkanoyl side chains of different length and branching. In this paper we will present the structure elucidation and physico-chemical properties of the tetronic acids 1~6.The FTIR spectrum of the tetronic acid 2, prepared as a potassium bromide pellet, is shown in Fig.
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