Covering: up to 2020
Natural products have a long history in drug discovery, with their inherent biological activity often tailored by medicinal chemists to arrive at the final drug product. This ...process is illustrated by numerous examples, including the conversion of epothilone to ixabepilone, erythromycin to azithromycin, and lovastatin to simvastatin. However, natural products are also fruitful starting points for the creation of complex and diverse compounds, especially those that are markedly different from the parent natural product and accordingly do not retain the biological activity of the parent. The resulting products have physiochemical properties that differ considerably when compared to traditional screening collections, thus affording an opportunity to discover novel biological activity. The synthesis of new structural frameworks from natural products thus yields value-added compounds, as demonstrated in the last several years with multiple biological discoveries emerging from these collections. This Highlight details a handful of these studies, describing new compounds derived from natural products that have biological activity and cellular targets different from those evoked/engaged by the parent. Such re-engineering of natural products offers the potential for discovering compounds with interesting and unexpected biological activity.
Incorporating natural product-like features within small-molecule screening collections is of great interest. We highlight an emerging strategy that achieves this goal by using abundant natural products as starting points for compound construction.
The chemical diversification of natural products provides a robust and general method for the creation of stereochemically rich and structurally diverse small molecules. The resulting compounds have ...physicochemical traits different from those in most screening collections, and as such are an excellent source for biological discovery. Herein, we subject the diterpene natural product pleuromutilin to reaction sequences focused on creating ring system diversity in few synthetic steps. This effort resulted in a collection of compounds with previously unreported ring systems, providing a novel set of structurally diverse and highly complex compounds suitable for screening in a variety of different settings. Biological evaluation identified the novel compound ferroptocide, a small molecule that rapidly and robustly induces ferroptotic death of cancer cells. Target identification efforts and CRISPR knockout studies reveal that ferroptocide is an inhibitor of thioredoxin, a key component of the antioxidant system in the cell. Ferroptocide positively modulates the immune system in a murine model of breast cancer and will be a useful tool to study the utility of pro-ferroptotic agents for treatment of cancer.
The discovery of photoassisted diazonium activation toward gold(I) oxidation greatly extended the scope of gold redox catalysis by avoiding the use of a strong oxidant. Some practical issues that ...limit the application of this new type of chemistry are the relative low efficiency (long reaction time and low conversion) and the strict reaction condition control that is necessary (degassing and inert reaction environment). Herein, an alternative photofree condition has been developed through Lewis base induced diazonium activation. With this method, an unreactive AuI catalyst was used in combination with Na2CO3 and diazonium salts to produce a AuIII intermediate. The efficient activation of various substrates, including alkyne, alkene and allene was achieved, followed by rapid AuIII reductive elimination, which yielded the C−C coupling products with good to excellent yields. Relative to the previously reported photoactivation method, our approach offered greater efficiency and versatility through faster reaction rates and broader reaction scope. Challenging substrates such as electron rich/neutral allenes, which could not be activated under the photoinitiation conditions (<5 % yield), could be activated to subsequently yield the desired coupling products in good to excellent yield.
Winning with gold: An alternative photofree condition for gold oxidation has been developed through Lewis base induced diazonium activation. With this method, an unreactive AuI catalyst was used in combination with NaHCO3 and diazonium salts to produce a AuIII intermediate. The efficient activation of various substrates, including alkyne, alkene and allene was achieved, followed by rapid AuIII reductive elimination, which yielded the C−C coupling products with good to excellent yields. Challenging substrates such as electron rich/neutral allenes could also be activated to subsequently yield the desired coupling products in good to excellent yield.
Multidrug-resistant Gram-negative (GN) infections for which there are few available treatment options are increasingly common. The development of new antibiotics for these pathogens is challenging ...because of the inability of most small molecules to accumulate inside GN bacteria. Using recently developed predictive guidelines for compound accumulation in
, we have converted the antibiotic Ribocil C, which targets the flavin mononucleotide (FMN) riboswitch, from a compound lacking whole-cell activity against wild-type GN pathogens into a compound that accumulates to a high level in
, is effective against Gram-negative clinical isolates, and has efficacy in mouse models of GN infections. This compound allows for the first assessment of the translational potential of FMN riboswitch binders against wild-type Gram-negative bacteria.
Acute kidney injury (AKI) is morphologically characterized by a synchronized plasma membrane rupture of cells in a specific section of a nephron, referred to as acute tubular necrosis (ATN). Whereas ...the involvement of necroptosis is well characterized, genetic evidence supporting the contribution of ferroptosis is lacking. Here, we demonstrate that the loss of ferroptosis suppressor protein 1 (Fsp1) or the targeted manipulation of the active center of the selenoprotein glutathione peroxidase 4 (Gpx4
) sensitize kidneys to tubular ferroptosis, resulting in a unique morphological pattern of tubular necrosis. Given the unmet medical need to clinically inhibit AKI, we generated a combined small molecule inhibitor (Nec-1f) that simultaneously targets receptor interacting protein kinase 1 (RIPK1) and ferroptosis in cell lines, in freshly isolated primary kidney tubules and in mouse models of cardiac transplantation and of AKI and improved survival in models of ischemia-reperfusion injury. Based on genetic and pharmacological evidence, we conclude that GPX4 dysfunction hypersensitizes mice to ATN during AKI. Additionally, we introduce Nec-1f, a solid inhibitor of RIPK1 and weak inhibitor of ferroptosis.
The first catalytic alkyne hydroboration of propargyl amine boranecarbonitriles is accomplished with triazole‐AuI complexes. While the typical L‐Au+ species decomposes within minutes upon addition of ...amine boranecarbonitriles, the triazole‐modified gold catalysts (TA‐Au) remained active, and allowed the synthesis of 1,2‐BN‐cyclopentenes in one step with good to excellent yields. With good substrate tolerability and mild reaction conditions (open‐flask), this new method provides an alternative route to reach the interesting cyclic amine borane with high efficiency.
Stable and active: The first catalytic alkyne hydroboration of propargyl amine boranecarbonitrile is accomplished. While the typical L‐Au+ species decomposed within minutes upon addition of amine boranecarbonitriles, the triazole‐modified gold catalysts (TA‐Au) remained active and allowed formation of 1,2‐BN‐cyclopentenes in excellent yields.
The combination of triazole/gold (TA‐Au) and Cu(OTf)2 is identified as the optimal catalytic system for promoting intramolecular hydroboration for the synthesis of a six‐membered cyclic amine–borane. ...Excellent yields (up to 95 %) and regioselectivities (5‐exo vs. 6‐endo) were achieved through catalyst control and sequential dilution. Good functional‐group tolerance was attained, thus allowing the preparation of highly functionalized cyclic amine–borane substrates, which could not be achieved using other methods. Deuterium‐labeling studies support the involvement of a hydride addition to a gold‐activated alkyne with subsequent C−B bond formation.
Golden combo: The combination of triazole/gold (TA‐Au) and copper salts is the optimum catalytic system for intramolecular hydroboration to synthesize six‐membered cyclic amine–boranes. Excellent yields and regioselectivities were achieved, and good functional‐group tolerance was attained. Deuterium‐labeling studies support the involvement of an initial hydride addition to a gold‐activated alkyne and subsequent C−B bond formation.
An intermolecular condensation of alkynols and terminal alkynes is reported. Using IPrAuNTf
, an efficient Au-catalyzed cyclization-alkynylation strategy furnishes (2-arylalkynyl) cyclic ethers in ...moderate to excellent yields (up to 94%). This strategy is extended to the synthesis of functionalized 2,3-dihydrooxepines via the sequential Au-catalyzed ring expansion of the cyclic ether substrates.
A highly efficient synthesis of substituted conjugated dienals was developed through a triazole–gold (TA–Au)-catalyzed propargyl vinyl ether rearrangement followed by an amine catalyzed ...allene–aldehyde tautomerization. Various substituted vinylogous aldehydes were prepared in one pot with good to excellent yields (up to 95%) under mild conditions with high atom economy.
Herein, we describe the synthesis of a novel bis-1,2,3-triazole ligand which contains an internal N-alkylated 2,2’-bipyrrolidine linker. By using simple starting materials, the ligand could be ...generated in good yield through several synthetic steps. To investigate the potential for the application of this ligand in transition metal catalysis, we generated a bis-Au(I) complex in nearly quantitative yield and examined its reactivity in the context of alkyne hydration. Both alkyl and aryl terminal alkynes could be efficiently converted to their corresponding ketones in nearly quantitative yields with only 1% catalyst loading under mild conditions.
PDF
