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The controlled liberation of molecules from a constructed framework is a subject of profound interest across various chemical fields. It allows for the masking of a molecule's properties and precise deployment upon a single controllable release event. While numerous methodologies have been developed for amines, alcohols, and thiols, approaches for utilising amides as payload‐release handles are still in their early stages of development, despite the prevalence of amides in therapeutic compounds and materials. Herein, is presented a comprehensive strategy for the controlled and selective release of a diverse range of amides with stable linkers. The versatility of this approach is demonstrated by its successful application in the targeted release of various amide‐containing drugs in their natural form via the use of commonly used trigger motifs, such as dipeptides or glycosides. As a proof of concept, the FDA‐approved antibiotic linezolid has been successfully converted into a prodrug form and released selectively only in the presence of the trigger event. Significantly, in its prodrug state, no activity against Mycobacterium tuberculosis was exhibited. Linezolid's full potential was achieved only upon controlled release, where an equipotent efficacy to the free linezolid control was demonstrated, thus emphasising the immense potential of this method. [ABSTRACT FROM AUTHOR]

Peptide stapling is a robust strategy for generating enzymatically stable, macrocyclic peptides. The incorporation of biologically relevant tags (such as cell‐penetrating motifs or fluorescent dyes) into peptides, while preserving their binding interactions and enhancing their stability, is highly sought after. Despite the unique opportunities offered by tryptophan's indole scaffold for targeted functionalisation, its utilisation in peptide stapling has been limited as compared to other amino acids. Herein, we present an approach for peptide stapling using the tryptophan‐mediated Petasis reaction. This method enables the synthesis of both stapled and labelled peptides and is applicable to both solution and solid‐phase synthesis. Importantly, the use of the Petasis reaction in combination with tryptophan facilitates the formation of stapled peptides in a straightforward, multicomponent fashion, while circumventing the formation of undesired by‐products. Furthermore, this approach allows for efficient and diverse late‐stage peptide modifications, thereby enabling rapid production of numerous conjugates for biological and medicinal applications. [ABSTRACT FROM AUTHOR]

Hemiasterlin is an antimitotic marine natural product with reported sub‐nanomolar potency against several cancer cell lines. Herein, we describe an expeditious total synthesis of hemiasterlin featuring a four‐component Ugi reaction (Ugi‐4CR) as the key step. The convergent synthetic strategy enabled rapid access to taltobulin (HTI‐286), a similarly potent synthetic analogue. This short synthetic sequence enabled investigation of both hemiasterlin and taltobulin as cytotoxic payloads in antibody–drug conjugates (ADCs). These novel ADCs displayed sub‐nanomolar cytotoxicity against HER2‐expressing cancer cells, while showing no activity against antigen‐negative cells. This study demonstrates an improved synthetic route to a highly valuable natural product, facilitating further investigation of hemiasterlin and its analogues as potential payloads in targeted therapeutics. [ABSTRACT FROM AUTHOR]

In recent years the pharmaceutical industry has benefited from the advances made in fragment‐based drug discovery (FBDD) with more than 30 fragment‐derived drugs currently marketed or progressing through clinical trials. The success of fragment‐based drug discovery is entirely dependent upon the composition of the fragment screening libraries used. Heterocycles are prevalent within marketed drugs due to the role they play in providing binding interactions; consequently, heterocyclic fragments are important components of FBDD libraries. Current screening libraries are dominated by flat, sp2‐rich compounds, primarily owing to their synthetic tractability, despite the superior physicochemical properties displayed by more three‐dimensional scaffolds. Herein, we report step‐efficient routes to a number of biologically relevant, fragment‐like heterocyclic spirocycles. The use of both electron‐deficient and electron‐rich 2‐atom donors was explored in complexity‐generating [3+2]‐cycloadditions to furnish products in 3 steps from commercially available starting materials. The resulting compounds were primed for further fragment elaboration through the inclusion of synthetic handles from the outset of the syntheses. [ABSTRACT FROM AUTHOR]

Abstract: N‐containing quaternary stereocenters represent important motifs in medicinal chemistry. However, due to their inherently sterically hindered nature, they remain underrepresented in small molecule screening collections. As such, the development of synthetic routes to generate small molecules that incorporate this particular feature are highly desirable. Herein, we describe the diversity‐oriented synthesis (DOS) of a diverse collection of structurally distinct small molecules featuring this three‐dimensional (3D) motif. The subsequent derivatisation and the stereoselective synthesis exemplified the versatility of this strategy for drug discovery and library enrichment. Chemoinformatic analysis revealed the enhanced sp3 character of the target library and demonstrated that it represents an attractive collection of biologically diverse small molecules with high scaffold diversity. [ABSTRACT FROM AUTHOR]

The exploitation of synthetic lethality by small-molecule targeting of pathways that maintain genomic stability is an attractive chemotherapeutic approach. The Ctf4/AND-1 protein hub, which links DNA replication, repair, and chromosome segregation, represents a novel target for the synthetic lethality approach. Herein, we report the design, optimization, and validation of double-click stapled peptides encoding the Ctf4-interacting peptide (CIP) of the replicative helicase subunit Sld5. By screening stapling positions in the Sld5 CIP, we identified an unorthodox i,i+6 stapled peptide with improved, submicromolar binding to Ctf4. The mode of interaction with Ctf4 was confirmed by a crystal structure of the stapled Sld5 peptide bound to Ctf4. The stapled Sld5 peptide was able to displace the Ctf4 partner DNA polymerase α from the replisome in yeast extracts. Our study provides proof-of-principle evidence for the development of small-molecule inhibitors of the human CTF4 orthologue AND-1. [ABSTRACT FROM AUTHOR]

There is a lack of current treatment options for ovarian clear cell carcinoma (CCC) and the cancer is often resistant to platinum-based chemotherapy. Hence there is an urgent need for novel therapeutics. The transcription factor hepatocyte nuclear factor 1β (HNF1β) is ubiquitously overexpressed in CCC and is seen as an attractive therapeutic target. This was validated through shRNA-mediated knockdown of the target protein, HNF1β, in five high- and low-HNF1β-expressing CCC lines. To inhibit the protein function, cell-permeable, non-helical constrained proteomimetics to target the HNF1β-importin α protein-protein interaction were designed, guided by X-ray crystallographic data and molecular dynamics simulations. In this way, we developed the first reported series of constrained peptide nuclear import inhibitors. Importantly, this general approach may be extended to other transcription factors. [ABSTRACT FROM AUTHOR]

There is a lack of current treatment options for ovarian clear cell carcinoma (CCC) and the cancer is often resistant to platinum-based chemotherapy. Hence there is an urgent need for novel therapeutics. The transcription factor hepatocyte nuclear factor 1β (HNF1β) is ubiquitously overexpressed in CCC and is seen as an attractive therapeutic target. This was validated through shRNA-mediated knockdown of the target protein, HNF1β, in five high- and low-HNF1β-expressing CCC lines. To inhibit the protein function, cell-permeable, non-helical constrained proteomimetics to target the HNF1β-importin α protein-protein interaction were designed, guided by X-ray crystallographic data and molecular dynamics simulations. In this way, we developed the first reported series of constrained peptide nuclear import inhibitors. Importantly, this general approach may be extended to other transcription factors. [ABSTRACT FROM AUTHOR]

Two divergent synthetic routes are reported offering access to four quinolone natural products from Pseudonocardia sp. CL38489. Key steps to the natural products involved a regioselective epoxidation, an intramolecular Buchwald-Hartwig amination and a final acid-catalysed 1,3-allylic-alcohol rearrangement to give two of the natural products in one step. This study completes the synthesis of all eight antibacterial quinolone natural products reported in the family. In addition, this modular strategy enables an improved synthesis towards two natural products previously reported. [ABSTRACT FROM AUTHOR]

Early phase drug discovery is a multi-parameter optimisation process. Finding drugable targets, discovering starting points for lead optimisation and creating novel structures with new biological properties within these constraints is challenging. As an example of a drug optimisation strategy, recent work on 5-HT1B antagonists will be described. This is put in the context of the drugability of the target, the desired physicochemical properties of the desired molecules and approaches to compound design to create high affinity, selective molecules that are optimised to have low Central Nervous System (CNS) penetration. [ABSTRACT FROM AUTHOR]

Fragment-based lead generation has proven to be an effective means of identifying high-quality lead compounds for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp2-rich aromatic compounds, which limits the structural (and hence biological) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially saturated bicyclic heteroaromatic scaffolds with enhanced sp3 character. Subsequent derivatization led to a fragment collection featuring regio- and stereo-controlled introduction of substituents on the saturated ring system, often with formation of new stereocenters. [ABSTRACT FROM AUTHOR]

Synthetic macrocycles are an attractive area in drug discovery. However, their use has been hindered by a lack of versatile platforms for the generation of structurally (and thus shape) diverse macrocycle libraries. Herein, we describe a new concept in library synthesis, termed multidimensional diversity-oriented synthesis, and its application towards macrocycles. This enabled the step-efficient generation of a library of 45 novel, structurally diverse, and highly-functionalized macrocycles based around a broad range of scaffolds and incorporating a wide variety of biologically relevant structural motifs. The synthesis strategy exploited the diverse reactivity of aza-ylides and imines, and featured eight different macrocyclization methods, two of which were novel. Computational analyses reveal a broad coverage of molecular shape space by the library and provides insight into how the various diversity-generating steps of the synthesis strategy impact on molecular shape. [ABSTRACT FROM AUTHOR]

The synthesis of four quinolone natural products from the actinomycete Pseudonocardia sp. is reported. The key step involved a sp2-sp3 Suzuki-Miyaura reaction between a common boronic ester lateral chain and various functionalised quinolone cores. The quinolones slowed growth of E. coli and S. aureus by inducing extended lag phases. [ABSTRACT FROM AUTHOR]

Peptide stapling is a method for designing macro-cyclic alpha-helical inhibitors of protein–protein interactions. However, obtaining a cell-active inhibitor can require significant optimization. We report a novel stapling technique based on a double strain-promoted azide–alkyne reaction, and exploit its biocompatibility to accelerate the discovery of cell-active stapled peptides. As a proof of concept, MDM2-binding peptides were stapled in parallel, directly in cell culture medium in 96-well plates, and simultaneously evaluated in a p53 reporter assay. This in situ stapling/screening process gave an optimal candidate that showed improved proteolytic stability and nanomolar binding to MDM2 in subsequent biophysical assays. α-Helicity was confirmed by a crystal structure of the MDM2-peptide complex. This work introduces in situ stapling as a versatile biocompatible technique with many other potential high-throughput biological applications. [ABSTRACT FROM AUTHOR]

Small-molecule modulators of biological targets play a crucial role in biology and medicine. In this context, diversity-oriented synthesis (DOS) provides strategies toward generating small molecules with a broad range of unique scaffolds, and hence three-dimensionality, to target a broad area of biological space. In this study, an organocatalysis-derived DOS library of macrocycles was synthesized by exploiting the pluripotency of aldehydes. The orthogonal combination of multiple diversity-generating organocatalytic steps with alkene metathesis enabled the synthesis of 51 distinct macrocyclic structures bearing 48 unique scaffolds in only two to four steps without the need for protecting groups. Furthermore, merging organocatalysis and alkene metathesis in a one-pot protocol facilitated the synthesis of drug-like macrocycles with natural-product-like levels of shape diversity in a single step. [ABSTRACT FROM AUTHOR]

The 4 H-quinolizin-4-one scaffold is of significant pharmaceutical interest. This heterocyclic structure is predicted to have attractive physico-chemical properties and is present in a variety of biologically active molecules. Despite these interesting characteristics, 4 H-quinolizin-4-ones are largely under-represented in current small molecule screening libraries, and, therefore, this scaffold has been poorly investigated. Herein, a new strategy is reported for the syntheses of these rare and biologically interesting 4 H-quinolizin-4-ones. This modular route involves the regioselective N-alkylation of 6-halo-2-pyridones followed by a Stille cross-coupling, ring-closing metathesis, and palladium-catalyzed dehydrogenation reaction sequence. This method furnishes the target compounds in good yields and allows for access to unusual substitution patterns that are difficult to achieve by using other synthetic strategies. [ABSTRACT FROM AUTHOR]

Pectobacterium atrosepticum ( Pca) is a Gram-negative phytopathogen which causes disease by secreting plant cell wall degrading exoenzymes ( PCWDEs). Previous studies have shown that PCWDE production is regulated by (i) the intercellular quorum sensing ( QS) signal molecule, 3-oxo-hexanoyl- l-homoserine lactone ( OHHL), and (ii) the intracellular 'alarmone', (p)pp Gpp, which reports on nutrient limitation. Here we show that these two signals form an integrated coincidence circuit which ensures that metabolically costly PCWDE synthesis does not occur unless the population is simultaneously quorate and nutrient limited. A (p)pp Gpp null Δ relAΔ spoT mutant was defective in both OHHL and PCWDE production, and nutritional supplementation of wild type cultures (which suppresses (p)pp Gpp production) also suppressed OHHL and PCWDE production. There was a substantial overlap in the transcriptome of a (p)pp Gpp deficient relA mutant and of a QS defective expI ( OHHL synthase) mutant, especially with regards to virulence-associated genes. Random transposon mutagenesis revealed that disruption of rsmA was sufficient to restore PCWDE production in the (p)pp Gpp null strain. We found that the ratio of RsmA protein to its RNA antagonist, rsm B, was modulated independently by (p)pp Gpp and QS. While QS predominantly controlled virulence by modulating RsmA levels, (p)pp Gpp exerted regulation through the modulation of the RsmA antagonist, rsm B. [ABSTRACT FROM AUTHOR]

The introduction of effective antibacterial therapies for infectious diseases in the mid-20th century completely revolutionized clinical practices and helped to facilitate the development of modern medicine. Many potentially life-threatening conditions became easily curable, greatly reducing the incidence of death or disability resulting from bacterial infections. This overwhelming historical success makes it very difficult to imagine life without effective antibacterials; however, the inexorable rise of antibiotic resistance has made this a very real and disturbing possibility for some infections. The ruthless selection for resistant bacteria, coupled with insufficient investment in antibacterial research, has led to a steady decline in the efficacy of existing therapies and a paucity of novel structural classes with which to replace them, or complement their use. This situation has resulted in a very pressing need for the discovery of novel antibiotics and treatment strategies, the development of which is likely to be a key challenge to 21st century medicinal chemistry. [ABSTRACT FROM AUTHOR]

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The Hiyama cross-coupling reaction is a powerful method for carbon-carbon bond formation. To date, the substrate scope of this reaction has predominantly been limited to sp2-sp2 coupling reactions. Herein, the palladium-catalysed Hiyama type cross-coupling of vinyldisiloxanes with benzylic and allylic bromides, chlorides, tosylates and mesylates is reported. A wide variety of functional groups were tolerated, and the synthetic utility of the methodology was exemplified through the efficient total synthesis of the cytotoxic natural product bussealin A. In addition, the antiproliferative ability of bussealin A was evaluated in two cancer-cell lines. [ABSTRACT FROM AUTHOR]

In Gram-negative bacteria, quorum sensing control of gene expression is mediated by transcription factors of the LuxR family, whose DNA-binding affinity is modulated by diffusible N-acyl homoserine lactone (AHL) signalling molecules. In Serratia sp. ATCC 39006 and the plant pathogen Erwinia carotovora ssp. carotovora ( Ecc), the biosynthesis of the β-lactam antibiotic 1-carbapen-2-em-3-carboxylic acid (Car) is under quorum sensing control. This study has revealed that, uniquely, the LuxR family transcriptional activator CarR from Serratia 39006 has no detectable affinity for cognate AHL molecules. Furthermore, CarR was shown to be naturally competent to bind to its target promoter with high affinity, activate transcription and resist cellular proteolysis, and was unaffected by AHL signals. Experiments with chimeric proteins suggest that the C-terminal DNA-binding domain of CarR may be responsible for conferring AHL independence. In contrast, we show that the homologous CarR protein binds to its 3O-C6-HSL ligand with high affinity, and that the highly conserved Trp-44 residue is critical for this interaction. Unlike TraR from Agrobacterium tumefaciens, CarR is not directly protected from cellular proteolysis by AHL binding, but via AHL-induced DNA binding. At physiological protein concentrations, AHL binding induces CarR to bind to its target promoter with higher affinity and activate transcription. [ABSTRACT FROM AUTHOR]

Summary Many Gram-negative bacteria use quorum sensing (QS) to regulate expression of multiple genes, by utilizing small diffusible signalling molecules called N-acyl homoserine lactones (acyl-HSLs). Serratia sp. ATCC 39006 produces the red pigment prodigiosin under QS control, in response to the short-chain signal C4-HSL. In this study, we have demonstrated that an acyl-HSL-deficient mutant can be used as a visual biosensor to detect short-chain acyl-HSLs. We have quantified the acyl-HSL sensitivity spectrum of the Serratia 39006 prodigiosin QS system, and have demonstrated a strong specificity for the natural ligand C4-HSL. Mutations in the pigX and pigZ genes in Serratia 39006 resulted in an overproduction of prodigiosin, caused by increased transcription of the prodigiosin biosynthetic operon. A new biosensor (SP19) with enhanced prodigiosin production was created by addition of pigX and pigZ mutations to the existing biosensor. We have demonstrated that SP19 is superior to biosensor strains CV026 and Agrobacterium NTL4 (pZLR4) for the detection of short-chain acyl-HSLs present in spent culture supernatants. Researchers working with QS bacteria that produce short-chain acyl-HSLs can use strain SP19 as a simple visual acyl-HSL biosensor with no requirement for expensive detection equipment. [ABSTRACT FROM AUTHOR]

Review: 54 refs. [ABSTRACT FROM AUTHOR]