Debromomarinone

Terpenoids are arguably the largest and most diverse family of natural products, featuring prominently in e.g. signalling, self-defence, UV-protection and electron transfer. Prenyltransferases are essential players in terpenoid and hybrid isoprenoid biosynthesis that install isoprene units on target molecules and thereby often modulate their bioactivity. In our search for new prenyltransferase biocatalysts we focused on the marine-derived Streptomyces sp. CNQ-509, a particularly rich source of meroterpenoid chemistry. Sequencing and analysis of the genome of Streptomyces sp. CNQ-509 revealed seven putative phenol/phenazine-specific ABBA prenyltransferases, and one putative indole-specific ABBA prenyltransferase. To elucidate the substrate specificity of the ABBA prenyltransferases and to learn about their role in secondary metabolism, CnqP1 -CnqP8 were produced in Escherichia coli and incubated with various aromatic and isoprenoid substrates. Five of the eight prenyltransferases displayed enzymatic activity. The efficient conversion of dihydroxynaphthalene derivatives by CnqP3 (encoded by AA958_24325) and the co-location of AA958_24325 with genes characteristic for the biosynthesis of THN (tetrahydroxynaphthalene)-derived natural products indicates that the enzyme is involved in the formation of debromomarinone or other naphthoquinone-derived meroterpenoids. Moreover, CnqP3 showed high flexibility towards a range of aromatic and isoprenoid substrates and thus represents an interesting new tool for biocatalytic applications.

A concise and divergent strategy for the synthesis of the naphterpin and marinone meroterpenoid families has been developed. The approach features a succession of pericyclic reactions-an aromatic Claisen rearrangement, a retro-6π-electrocyclization, and two Diels-Alder reactions-which facilitated the first total synthesis of naphterpin itself in five steps from 2,5-dimethoxyphenol, alongside similar syntheses of 7-demethylnaphterpin and debromomarinone. Late-stage oxidation and bromination reactions were also investigated, leading to the first total syntheses of naphterpins B and C and isomarinone.

A member of the marine streptomycete clade MAR4, Streptomyces sp. CNQ-509, has genetic potential for the biosynthesis of hybrid isoprenoids and produces several meroterpenoids such as naphterpin, nitropyrrolin and marinophenazine. Our research on the strain CNQ-509 led to the isolation of two new naphterpin derivatives (1 and 2) comprised of naphthoquinone and geranyl moieties along with the known terpenoid, debromomarinone. The two-dimensional structure of these compounds was determined through spectral data analysis using data from NMR, MS and UV spectroscopy. Furthermore, the full structures of 1 and 2 including absolute configurations were unequivocally established by a combination of NMR experiments and chemical modifications.