Microtubules continue to be one of the most successful anticancer drug targets and a favorite hit for many naturally occurring molecules. While two of the most successful representative agents in clinical use, the taxanes and the vinca alkaloids, come from terrestrial sources, the sea has also proven to be a rich source of new tubulin-binding molecules. We describe herein the first isolation, structural elucidation and total synthesis of two totally new polyketides isolated from the Madagascan sponge Lithoplocamia lithistoides . Both PM050489 and PM060184 show antimitotic properties in human tumor cells lines at subnanomolar concentrations and display a distinct inhibition mechanism on microtubules. The development of an efficient synthetic procedure has solved the supply problem and, following pharmaceutical development, has allowed PM060184 to start clinical studies as a promising new drug for cancer treatment.

Pipecolidepsin A is a head-to-side-chain cyclodepsipeptide isolated from the marine sponge Homophymia lamellosa. This compound shows relevant cytotoxic activity in three human tumour cell lines and has unique structural features, with an abundance of non-proteinogenic residues, including several intriguing amino acids. Although the moieties present in the structure show high synthetic difficulty, the cornerstone is constituted by the unprecedented and highly hindered g-branched b-hydroxy-a-amino acid D-allo-(2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid (AHDMHA) residue, placed at the branching ester position and surrounded by the four demanding residues L-(2S,3S,4R)-3,4-dimethylglutamine, (2R,3R,4S)-4,7-diamino-2,3-dihydroxy-7-oxoheptanoic acid, D-allo-Thr and L-pipecolic acid. Here we describe the first total synthesis of a D-allo-AHDMHA-containing peptide, pipecolidepsin A, thus allowing chemical structure validation of the natural product and providing a robust synthetic strategy to access other members of the relevant head-to-side-chain family in a straightforward manner.

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

The marine environment is a rich source of metabolites with potential therapeutic properties and applications for humans. Here we describe the first isolation, solid-phase total synthesis, and full structural assignment of a new class of cyclodepsipeptides from the Madagascan sponge Ecionemia acervus that shows in vitro cytotoxic activities at submicromolar concentrations. Seven structures belonging to a new family of compounds, given the general name stellatolides, were characterized. The sequence and stereochemistry of all the amino acids in these molecules were established by a combination of spectroscopic analysis, chemical degradation, and derivatization studies. Furthermore, the complete structure of stellatolide A was confirmed by an efficient solid-phase method for the first total synthesis and the full structural assignment of this molecule, including the asymmetric synthesis of the unique β-hydroxy acid moiety (Z)-3-hydroxy-6,8-dimethylnon-4-enoic acid.

On treatment with tributyltin hydride, the vinyl bromide 11 and the vinyl iodide 26 cyclize to give mixtures of the (E)-and (Z)-4-(alkoxycarbonylmethylene)tetrahydropyrans 12/13 and 27/28 in which the (E)-isomers 12 and 27 are the major components accounting for 80% of the products. Addition of triphenyltin hydride to the alkyne 34 similarly initiates cyclization giving a mixture of products 35-37, the composition of the mixture depending upon the concentration of the tin hydride. These results are consistent with faster cyclization of the (Z)-vinyl radical with kinetic formation of five-membered ring containing products which are either trapped by hydrogen transfer from the tin hydride or which rearrange to form a 4-methylenetetrahydropyran. This chemistry was applied to prepare the cis-2,6-disubstituted 4-(methoxycarbonylmethylene)tetrahydropyran 50 which may be useful for the introduction of the C(10)-C(16) fragment into the bryostatins. Cyclization of the p-methoxybenzyl protected vinyl iodide 58 is less stereoselective, perhaps because of intramolecular hydrogen transfer from the p-methoxybenzyl group.The bryostatins, e.g. bryostatin 7 1, comprise an important group of macrolides which are isolated from invertebrate filter feeders including Bugula neritina and which display potent antitumour activity. 1 The total synthesis of the bryostatins is of considerable interest at present because of the potential of these compounds as chemotherapeutic reagents with a need for a better understanding of their structure-activity relationships. To date one total synthesis of a bryostatin has been described 2 together with several reports of approaches to the synthesis of various fragments. 3-5