Natalenamides A–C, Cyclic Tripeptides from the Termite-Associated Actinomadura sp. RB99

Abstract

In recent years, investigations into the biochemistry of insect-associated bacteria have increased. When combined with analytical dereplication processes, these studies provide a powerful strategy to identify structurally and/or biologically novel compounds. Non-ribosomally synthesized cyclic peptides have a broad bioactivity spectrum with high medicinal potential. Here, we report the discovery of three new cyclic tripeptides: natalenamides A⁻C (compounds <b>1</b>⁻<b>3</b>). These compounds were identified from the culture broth of the fungus-growing termite-associated <i>Actinomadura</i> sp. RB99 using a liquid chromatography (LC)/ultraviolet (UV)/mass spectrometry (MS)-based dereplication method. Chemical structures of the new compounds (<b>1</b>⁻<b>3</b>) were established by analysis of comprehensive spectroscopic methods, including one-dimensional (¹H and ¹³C) and two-dimensional (¹H-¹H-COSY, HSQC, HMBC) nuclear magnetic resonance spectroscopy (NMR), together with high-resolution electrospray ionization mass spectrometry (HR-ESIMS) data. The absolute configurations of the new compounds were elucidated using Marfey's analysis. Through several bioactivity tests for the tripeptides, we found that compound <b>3</b> exhibited significant inhibitory effects on 3-isobutyl-1-methylxanthine (IBMX)-induced melanin production. The effect of compound <b>3</b> was similar to that of kojic acid, a compound extensively used as a cosmetic material with a skin-whitening effect.