Eight-Membered Ring-Containing Jadomycins: Implications for Non-enzymatic Natural Products Biosynthesis

Abstract

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Streptomyces venezuelae ISP5230 Maintains Excretion of Jadomycin upon Disruption of the MFS Transporter JadL Located within the Natural Product Biosynthetic Gene Cluster

“…The E-ring present in the jadomycin angucyclic framework arises from a rare spontaneous biosynthetic step involving the incorporation of an amino acid. This chemistry enables a strategy for facile derivatization of the jadomycins using culture media containing a single amino (Jakeman et al, 2005, 2009b; Robertson et al, 2015). Recently, as a result of genome analysis a number of natural products have been discovered from S. venezuelae ISP5230, including gaburedin (Sidda et al, 2014), venezuelin (Goto et al, 2010), forxymithine (Kodani et al, 2015), (+)-isodauc-8-en-11-ol (Rabe et al, 2015), and venemycin (Thanapipatsiri et al, 2016).…”

Characterization of l-Digitoxosyl-phenanthroviridin from Streptomyces venezuelae ISP5230

“…Although production of a jadomycin analogue with the appropriate m/z for L-lysine incorporation was confirmed by LC-MS/MS analysis of the crude growth media, 19 attempts to isolate the product using standard methodologies successfully employed for other jadomycins or by chemical derivatization were unsuccessful due to compound instability. 15,20 During investigations of crude fermentation extracts, we identified an intriguing unknown amber-colored compound by TLC that proved to be sufficiently stable for isolation and characterization. Herein, we report the isolation, characterization, and cytotoxic evaluation of the new phenanthroviridin analogue L-digitoxosyl-phenanthroviridin (1).…”

Isolation and Synthetic Diversification of Jadomycin 4-Amino-l-phenylalanine

“…It was found that it was beneficial to derivatize the crude jadomycin extract, as has been previously described, 6,11 to reduce breakdown of the derivatives during the purification process. Reaction progress was monitored by thin layer chromatography (TLC), observing the disappearance of 1 (R f = 0.25, 5:5:1 CH 3 CN/EtOAc/H 2 O) with the formation of a new band at a higher R f (see SI).…”

“…HMBC correlations were observed from H3a to a signal at approximately 55 ppm, which was assigned as C1. The chemical shift for H1 (3.34 ppm) is different from those of recently isolated eight-membered-ring structures (∼4.5 ppm) 11 and past oxazolone-ring-containing jadomycins (∼5.0 ppm), 5 and the origin of this difference remains unclear. Rotating frame Overhauser effect spectroscopy (ROESY) NMR was also conducted to confirm through-space interactions.…”

“…5,6 This methodology has been utilized to afford upward of 25 novel jadomycins (Scheme 1). 5 Some of these amino acids have introduced specific chemical handles into the jadomycin structure that can be used to selectively alter the natural product, as was shown with the jadomycin triazoles 6 and jadomycin Oct. 11 The introduction of new amino acids and subsequent derivatization will lead to novel structural diversity and potentially improved bioactivity. 12 It is known that within S. venezuelae ISP5230 4-aminophenylalanine is an intermediate in the chloramphenicol biosynthetic pathway.…”