Structure Revision of Penipacids A-E Reveals a Putative New Cryptic Natural Product, N -aminoanthranilic Acid, with Potential as a Transcriptional Regulator of Silent Secondary Metabolism.

Reconsideration of the spectroscopic data for penipacids A-E, first reported in 2013 as the acyclic amidines 1 - 5 from the South China deep sea sediment-derived fungus Penicillium paneum SD-44, prompted a total synthesis structure revision as the hydrazones 6 - 10 . This revision strongly supported the proposition that penipacids A-B ( 6 - 7 ) were artifact Schiff base adducts of the cryptic (undetected) natural product N -aminoanthranilic acid ( 11 ) with diacetone alcohol, induced by excessive exposure to acetone and methanol under acidic handling conditions. Likewise, the revised structures for penipacids C-D ( 8 - 9 ) and E ( 10 ) raise the possibility that they may also be artifact Schiff base adducts of 11 and the media constituents pyruvic acid and furfural, respectively. A review of the natural products literature revealed other Schiff base (hydrazone) natural products that might also be viewed as Schiff base adduct artifacts of 11 . Having raised the prospect that 11 is an undetected and reactive cryptic natural product, we went on to establish that 11 is not cytotoxic to a range of bacterial, fungal or mammalian (human) cell types. Instead, when added as a supplement to microbial cultivations, 11 can act as a chemical cue/transcriptional regulator, activating and/or enhancing the yield of biosynthetic gene clusters encoding for other natural product chemical defenses. This study demonstrates the value of challenging the structure and artifact status of natural products, as a window into the hidden world of cryptic and highly reactive natural products.