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Ilamycins/rufomycins and cyclomarins are marine cycloheptapeptides containing unusual amino acids. Produced by Streptomyces sp., these compounds show potent activity against a range of mycobacteria, including multidrug-resistant strains of Mycobacterium tuberculosis. The cyclomarins are also very potent inhibitors of Plasmodium falciparum. Biosynthetically the cyclopeptides are obtained via a heptamodular nonribosomal peptide synthetase (NRPS) that directly incorporates some of the nonproteinogenic amino acids. A wide range of derivatives can be obtained by fermentation, while bioengineering also allows the mutasynthesis of derivatives, especially cyclomarins. Other derivatives are accessible by semisynthesis or total syntheses, reported for both natural product classes. The anti-tuberculosis (anti-TB) activity results from the binding of the peptides to the N-terminal domain (NTD) of the bacterial protease-associated unfoldase ClpC1, causing cell death by the uncontrolled proteolytic activity of this enzyme. Diadenosine triphosphate hydrolase (PfAp3Aase) was found to be the active target of the cyclomarins in Plasmodia. SAR studies with natural and synthetic derivatives on ilamycins/rufomycins and cyclomarins indicate which parts of the molecules can be simplified or otherwise modified without losing activity for either target. This review examines all aspects of the research conducted in the syntheses of these interesting cyclopeptides.

Antimicrobial resistance is a global health threat that requires the development of new treatment concepts. These should not only overcome existing resistance but be designed to slow down the emergence of new resistance mechanisms. Targeted protein degradation, whereby a drug redirects cellular proteolytic machinery towards degrading a specific target, is an emerging concept in drug discovery. We are extending this concept by developing proteolysis targeting chimeras active in bacteria (BacPROTACs) that bind to ClpC1, a component of the mycobacterial protein degradation machinery. The anti- Mycobacterium tuberculosis ( Mtb ) BacPROTACs are derived from cyclomarins which, when dimerized, generate compounds that recruit and degrade ClpC1. The resulting Homo-BacPROTACs reduce levels of endogenous ClpC1 in Mycobacterium smegmatis and display minimum inhibitory concentrations in the low micro- to nanomolar range in mycobacterial strains, including multiple drug-resistant Mtb isolates. The compounds also kill Mtb residing in macrophages. Thus, Homo-BacPROTACs that degrade ClpC1 represent a different strategy for targeting Mtb and overcoming drug resistance. Antimicrobial resistance is a global health threat and the development of alternative strategies to overcome it is of high interest. Here, the authors report proteolysis targeting chimeras active in bacteria (BacPROTACs) that bind to ClpC1, a component of the mycobacterial protein degradation machinery, and apply them for targeting a range of mycobacterial strains, including antibiotic-resistant ones.

The palladium‐catalyzed allylic alkylation of non‐stabilized ketone enolates was thought for a long time to be not as efficient as the analogous reactions of stabilized enolates, e. g. of malonates and β‐ketoesters. The field has experienced a rapid development during the last two decades, with a range of new, highly efficient protocols evolved. In this review, the early developments as well as current methods and applications of palladium‐catalyzed ketone enolate allylations will be discussed. The development of new methods for the asymmetric allylic alkylation of ketones, using either chiral ligands or chiral substrates, has been reviewed. Besides fundamental and mechanistic aspects, also applications of the new protocols as key steps in the synthesis of complex natural products have been discussed.

The formation of suberized and lignified barriers in the exodermis is suggested to be part of a suite of adaptations to flooded or waterlogged conditions, adjusting transport of solutes and gases in and out of roots. In this study, the composition of apoplasmic barriers in hypodermal cell walls and oxygen profiles in roots and the surrounding medium of four Amazon tree species that are subjected to long-term flooding at their habitat was analyzed. In hypodermal cell walls of the deciduous tree Crateva benthami, suberization is very weak and dominated by monoacids, 2-hydroxy acids, and ω-hydroxycarboxylic acids. This species does not show any morphological adaptations to flooding and overcomes the aquatic period in a dormant state. Hypodermal cells of Tabernaemontana juruana, a tree which is able to maintain its leaf system during the aquatic phase, are characterized by extensively suberized walls, incrusted mainly by the unsaturated C18 ω-hydroxycarboxylic acid and the α,ω-dicarboxylic acid analogon, known as typical suberin markers. Two other evergreen species, Laetia corymbulosa and Salix martiana, contained 3- to 4-fold less aliphatic suberin in the exodermis, but more than 85% of the aromatic moiety of suberin are composed of para-hydroxybenzoic acid, suggesting a function of suberin in pathogen defense. No major differences in the lignin content among the species were observed. Determination of oxygen distribution in the roots and rhizosphere of the four species revealed that radial loss of oxygen can be effectively restricted by the formation of suberized barriers but not by lignification of exodermal cell walls.