Nataxazole, a New Benzoxazole Derivative with Antitumor Activity Produced by Streptomyces sp. Tü 6176†

Abstract

The new benzoxazole derivative nataxazole was isolated from Streptomyces sp. (strain Tü 6176). Nataxazole is related in structure to the potent antitumor compounds UK-1 and AJI9561 and showed similar strong growth inhibitory activity against various human tumor cell lines.Keywords benzoxazole derivative, HPLC-diode array screening, antitumor activity, structure elucidation, Streptomyces Freshly isolated actinomycetes from soils collected in the environment of Natal, Rio Grande do Norte, Brasil, were grown in submerged culture in different media, and extracts prepared from mycelia and culture filtrates at various fermentation times were screened by HPLC-diode array analysis in combination with an in-house developed HPLC-UV-Vis database [2] to detect novel secondary metabolites. Strain Tü 6176 was found to be of special interest as it gave a mycelium extract that contained a dominant peak in the HPLC profile with a retention time of 14.8 minutes in standard reversed-phase gradient elution [2]. Its characteristic UV-visible spectrum (Fig. 1) differed from that of 867 reference compounds stored in the HPLC-UVVis database. Due to the collection site and its chemical structure (Fig. 2), the compound was named nataxazole (1).Strain Tü 6176 (RN-13.5) was isolated from a soil sample collected at Mata da Estrela, RN, Brazil. It was examined for a number of key properties known to be of value in streptomycete systematics. The presence of LLdiaminopimelic acid in the peptidoglycan [3] together with

Genome Mining of Streptomyces sp. Tü 6176: Characterization of the Nataxazole Biosynthesis Pathway

“…[1] The benzoxazole family of compounds includes othern atural products with cytotoxic activity,s uch as UK-1 [2] andA JI9561 [3] produced by Streptomyces spp. Tü 6176 is the producer of the cytotoxic benzoxazole nataxazole.…”

Intermolecular coupling of 2-iodoanilides with benzoxazoles: synthesis of N-(2-Benzoxazol-2-ylphenyl)benzamides via C–H activation

“…Currently we are exploring further mechanistic studies of this process and its application towards the synthesis of bis(benzoxazole)natural products such as Nataxazole. 14 …”

Exploring the biocombinatorial potential of benzoxazoles: generation of novel caboxamycin derivatives

“…NTK937 gene-deleted mutant strains ΔcbxA and ΔcbxA/ΔentC [13] were used respectively for heterologous expression of nataxazole cluster genes and for mutasynthesis; Streptomyces sp. Tü6176 [4], producer of nataxazole, source of natPK , natL1 and natL2 genes; S. albus J1074 [14] and S. albus B29 [15] were used as heterologous hosts for the expression of caboxamycin biosynthesis genes; E. coli DH10B (Invitrogen) and E. coli ET12567 (pUB307) [28] were used for subcloning and intergeneric conjugation, respectively.…”

“…NTK937 genome, a deep-sea sediment strain, revealed up to 35 putative gene clusters for the biosynthesis of secondary metabolites [1], including that for the biosynthesis of antibiotic caboxamycin. This compound belongs to the family of benzoxazoles [2], which includes compounds such as calcimycin [3], nataxazole [4], and A33853 [5], whose respective biosynthesis pathways have been characterized [6–9]. The benzoxazole scaffold is known to bear different pharmacological properties such as being cytotoxic and/or antibiotic [10], possessing anti-leishmanial properties [11], or inhibiting the replication of hepatitis C virus [12].…”