Synthesis and Structural Revision of Cyslabdan

Abstract

Cyslabdan was isolated from the culture broth of Streptomyces sp. K04-0144 as a new potentiator of imipenem activity against methicillin-resistant Staphylococcus aureus. We accomplished the synthesis of cyslabdan according to a previously reported structure. However, we subsequently found that this structure was incorrect; our analysis of natural cyslabdan showed that it possessed R stereochemistry at the C8 position, not S, as had previously been reported. Thus, we completed the protecting-group-free synthesis of the correct structure of cyslabdan, which is described herein.

Enzymatic Carbon–Sulfur Bond Formation in Natural Product Biosynthesis

“…Cyslabdan is a diterpene natural product bearing a N -acetylcysteine residue isolated from Streptomyces cyslabdanicus K04-0144. − While cyslabdan alone does not display significant antibacterial activity, it potentiates the activity of carbapenem antibiotics against methicillin-resistant Staphylococcus aureus by >1000-fold. − Genome mining for the biosynthetic gene cluster identified four genes cld A–D, which when expressed in a heterologous host lead to the production of cyslabdan A . Additionally, a new compound bearing an epoxide was detected.…”

Diterpenoids from Streptomyces: Structures, Biosyntheses and Bioactivities

“…His main research interests are the combinatorial biosynthesis of new bioactive natural products from microorganisms and construction of chassis to improve the yield of these compounds using synthetic biology tools. stereochemistry that was previously reported by Ōmura et al [25] Two congeners, cyslabdans B (3) and C (4), were later obtained from the same strain, Streptomyces sp. K04-0144, [9b] which was later named S. cyslabdanicus K04-0144.…”

“…K04‐0144 [9a,24] (Figure 3). By the total synthesis of 2 , Nagamitsu and colleagues revised the stereochemistry at C8 position to be R , rather than the S stereochemistry that was previously reported by Ōmura et al [25] . Two congeners, cyslabdans B ( 3 ) and C ( 4 ), were later obtained from the same strain, Streptomyces sp.…”

“…[11b] The mode of action for 18-20 cytotoxicity seems to be the inhibition of matrix metalloproteinases, thereby influencing cell proliferation, cancer migration, and invasion. [11b] Microeunicellol A (25) showed cytotoxic activity against cancer cell lines MCF-7 (IC 50 of 5.3 μM) and MDA-MB-231 (IC 50 of 8.6 μM). However, 26 exhibited no cytotoxic activity with an IC 50 > 100 μM.…”

β-Lactams from the Ocean

“…Remarkably, this interpretation has not received subsequent verification, possibly as a result of the separation between laboratories having access to the marine-derived structure, and laboratories with the ability to carry out a rigorous mechanistic study using enzymes from notable bacterial pathogens. Synthetic access to cyslabdan structures is, however, established [ 94 ]. Lipoxazolidinones are a class of marine-derived Gram-positive antibiotics [ 95 , 96 ].…”