Spirocyclic cladosporicin A and cladosporiumins I and J from a Hydractinia-associated Cladosporium sphaerospermum SW67

Abstract

Here, we report the isolation and characterization of three new spirocyclic natural products named cladosporicin A (1), cladosporiumins I (2) and J (3) from the fungus Cladosporium sphaerospermum SW67. Cladosporicin A contains an unprecedented 2,7-diazaspiro[4.5]decane-1,4-dione skeleton conjugated with one 2,4-pyrrolidinedione moiety (tetramic acid). Cladosporiumins I and J are stereoisomers and are built of a tetramic acid core structure with a quaternary (C-3) center carrying a trans-hexylenic alcohol side chain and a six-membered lactone ring. The absolute structures of compounds 1–3 were elucidated by a combination of 1D and 2D NMR spectroscopy, modified Mosher s analysis, quantum chemical ECD calculations and computational NMR chemical shift calculations. Comparative genome sequence analysis led us to assign the putative new PKS-NRPS hybrid gene cluster (cls). Finally, we assessed bioactivities of compounds 1–3 in a series of pharmacological tests and found weak cytotoxicity against four human breast cancer cell lines (IC50 ∼ 70–90 μM).