Synthesis of Natural Rubrolides B, I, K, L, M, O and Analogues

Abstract

The chlorinated natural products, rubrolides B, I, K, L, M and O and analogues were synthesized in only five steps employing a robust and divergent synthetic strategy. The synthesis is performed without using protecting groups starting from a key intermediate, which can be synthesized from commercially available tetronic acid in only two steps. Selective halogenation and vinylogous aldol condensation enable the efficient synthesis of highly halogenated natural occurring rubrolides as well as synthetic analogues to build up a compound library for antiviral and antibiofilm testing. All synthesized compounds were then tested for their activity against the two influenza A virus strains pH1N1 and H3N2 as well as for their antibiofilm activity. Naturally occurring as well as synthetic analogues showed promising antiviral and antibiofilm activities.

Molecular Insight into Gene Response of Diorcinol- and Rubrolide-Treated Biofilms of the Emerging Pathogen Stenotrophomonas maltophilia

“…The same study also demonstrated for the first time that diorcinols can cause a 54% reduction of S. maltophilia K279a (here referred to as K279a) biofilms; therefore, diorcinols seem to be promising antibiofilm substances. Additionally, we also previously demonstrated that rubrolides had a significant antibiofilm activity against K279a ( 37 ).…”

“… S. maltophilia is highly resistant against most antibiotics, and, as consequence, biofilms of clinical isolates are very difficult to treat. Recently, we showed that diorcinols and rubrolides strongly reduced biofilm formation of S. maltophilia K279a ( 36 , 37 ). Intrigued by this initial and encouraging observation, we asked if we could identify individual genes and pathways involved in biofilm inhibition and what the impact was on the overall biofilm architecture and gene expression profiles of S. maltophilia biofilms.…”

“…Several studies demonstrated an antibacterial activity against Gram-positive, but not against Gram-negative, bacteria ( 50 , 51 ). Furthermore, rubrolides seem to have antiviral activity ( 37 , 49 , 52 ), and, similar to the diorcinols, some rubrolides have antitumor activity ( 46 , 47 , 49 , 53 ). Interestingly, synthetic rubrolide analogues, but especially lactams derived from rubrolides, revealed antibiofilm activity against Gram-positive and Gram-negative bacteria ( 54 – 56 ).…”

Synthesis of β-Arylbutenolides Mediated by BF3·OMe2

“…This methodology is faster and with lower cost than other methodologies described in the literature to provide direct access to -(hydroxyaryl)butenolides which have biological properties 7,22 and are synthons for the synthesis of more complex compounds. 4,23,24…”

“…The -arylbutenolide moiety is present in several natural and synthetic products that have important biological properties such as congestive heart failure, 1 antiviral and antimicrobial properties, [2][3][4] inhibitor of tumor necrosis factor (TNF-), 5 inhibitor of BACE, 6 and antitumor activity 7 (Figure 1).…”