A Ring‐Distortion Strategy from Marine Natural Product Ilimaquinone Leads to Quorum Sensing Modulators

Abstract

We report herein a ring‐distortion strategy applied to marine natural substances ilimaquinone and 5‐epi‐ilimaquinone. A chemically diverse library of molecules was synthesised that included rearrangements of the sesquiterpene moiety and original reorganisations of the quinone ring. Chemoinformatic analyses evaluated the rise of structural diversity and the exploration of chemical space. Some focussed biological activities of this library were also investigated; quorum sensing activity of Vibrio harveyi was envisaged and some of the new compounds were shown to be good quorum sensing inhibitor candidates, whereas others were activators. Toxicities were also evaluated and some products showed micromolar activities against human umbilical vein endothelium, human hepatocellular carcinoma and human lung carcinoma (A549) cells.

Preparation of Structurally Diverse Compounds from the Natural Product Lycorine

“…To take advantage of the distinctive features of natural products while leveraging the power of synthetic organic chemistry, we have reported a strategy termed complexity-to-diversity (CtD), which uses ring system distortion and rearrangement reactions of natural products to rapidly generate collections of diverse compounds while maintaining desirable characteristics including a high fraction of sp 3 -hybridized carbons (Fsp3), ring fusion density, number of stereogenic centers, and rigidity of ring systems. Using this approach, compound collections have been reported from gibberellic acid, adrenosterone, quinine, abietic acid, sinomenine, pleuromutilin, yohimbine, hemeanthamine, ilimaquinone, and others . Structurally diverse, natural-product-like libraries have proven to be valuable tools in studying various biological processes. , For example, we recently reported the use of CtD compounds to assess the propensity of small molecules to accumulate in Gram-negative bacteria; for this purpose, compounds with a low number of rotatable bonds, a high ring-fusion density, and the presence of ionizable nitrogens were crucial, thus leading us to choose lycorine ( 1 ) as a starting point for further CtD synthetic efforts ( 2 – 14 , Scheme ).…”

“…6 To take advantage of the distinctive features of natural products while leveraging the power of synthetic organic chemistry, we have reported a strategy termed complexity-to-diversity (CtD), 7 which uses ring system distortion and rearrangement reactions of natural products to rapidly generate collections of diverse compounds while maintaining desirable characteristics including a high fraction of sp 3 -hybridized carbons (Fsp3), ring fusion density, number of stereogenic centers, and rigidity of ring systems. Using this approach, compound collections have been reported from gibberellic acid, 7a adrenosterone, 7a quinine, 7a abietic acid, 8 sinomenine, 9 pleuromutilin, 10 yohimbine, 11 hemeanthamine, 12 ilimaquinone, 13 and others. 14 Structurally diverse, natural-product-like libraries have proven to be valuable tools in studying various biological processes.…”

Addressing Antimicrobial Resistance through New Medicinal and Synthetic Chemistry Strategies

“…3 ). 59 The QS activity of compounds 13 and 14 ( Fig. 3 ) has been determined against an opportunistic pathogen bacterium of tropical marine organisms, Vibrio harveyi .…”

“…3 ) has been determined against an opportunistic pathogen bacterium of tropical marine organisms, Vibrio harveyi . 59…”

Limonin as a Starting Point for the Construction of Compounds with High Scaffold Diversity

“…TheC tD approach takes advantage of the structural complexity inherent within readily available natural products to generate unique complex compounds through ring distortion reactions (i.e., ring expansion, contraction, cleavage, fusion, and rearrangement). [32,33] This method has been applied to several natural products,i ncluding adrenosterone, [34] gibberellic acid, [34] quinine, [34] abietic acid, [35] sinomenine, [36] lycorine, [37] pleuromutilin, [38,39] yohimbine, [40] haemanthamine, [41] ilimaquinone [42] and steroids such as dutasteride and abiraterone acetate. [43] Theresulting collections of natural product-like compounds have been instrumental in developing predictive guidelines for small molecule accumulation in E. coli, [44] and led to Gp rotein-coupled receptor antagonists, [45] anew class of antiplasmodial agents, [46] and the discovery of an ovel and potent inducer of ferroptotic cell death.…”