General Approach to Amides through Decarboxylative Radical Cross-Coupling of Carboxylic Acids and Isocyanides.

Herein, we report a silver-catalyzed protocol for decarboxylative cross-coupling between carboxylic acids and isocyanides, leading to linear amide products through a free-radical mechanism. The disclosed approach provides a general entry to a variety of decorated amides, accommodating a diverse array of radical precursors, including aryl, heteroaryl, alkynyl, alkenyl, and alkyl carboxylic acids. Notably, the protocol proved to be efficient for decarboxylative late-stage functionalization of several elaborate pharmaceuticals, demonstrating its potential applications.

Impact of the climatic changes in the Pliocene-Pleistocene transition on Irano-Turanian species. The radiation of genus Jurinea (Compositae).

The Irano-Turanian region is one of the world's richest floristic regions and the centre of diversity for numerous xerophytic plant lineages. However, we still have limited knowledge on the timing of evolution and biogeographic history of its flora, and potential drivers of diversification remain underexplored. To fill this knowledge gap, we focus on the Eurasian genus Jurinea (ca. 200 species), one of the largest plant radiations that diversified in the region. We applied a macroevolutionary integrative approach to explicitly test diversification hypotheses and investigate the relative roles of geography vs. ecology and niche conservatism vs. niche lability in speciation processes. To do so, we gathered a sample comprising 77% of total genus richness and obtained data about (1) its phylogenetic history, recovering 502 nuclear loci sequences; (2) growth forms; (3) ecological niche, compiling data of 21 variables for more than 2500 occurrences; and (4) paleoclimatic conditions, to estimate climatic stability. Our results revealed that climate was a key factor in the evolutionary dynamics of Jurinea. The main diversification and biogeographic events that occurred during past climate changes, which led to colder and drier conditions, are the following: (1) the origin of the genus (10.7 Ma); (2) long-distance dispersals from the Iranian Plateau to adjacent regions (∼7-4 Ma); and (3) the diversification shift during Pliocene-Pleistocene Transition (ca. 3 Ma), when net diversification rate almost doubled. Our results supported the pre-adaptation hypothesis, i.e., the evolutionary success of Jurinea was linked to the retention of the ancestral niche adapted to aridity. Interestingly, the paleoclimatic analyses revealed that in the Iranian Plateau long-term climatic stability favoured old-lineage persistence, resulting in current high species richness of semi-arid and cold adapted clades; whereas moderate climate oscillations stimulated allopatric diversification in the lineages distributed in the Circumboreal region. In contrast, growth form lability and high niche disparity among closely related species in the Central Asian clade suggest adaptive radiation to mountain habitats. In sum, the radiation of Jurinea is the result of both adaptive and non-adaptive processes influenced by climatic, orogenic and ecological factors.

Synthesis of pyrimidine-fused skeletons through copper-catalyzed consecutive Sonogashira coupling and aminocyclization.

A copper-catalyzed sequence involving a Sonogashira coupling reaction and 5-exo-dig aminocyclization between a terminal alkyne and a 2-(2-bromophenyl)pyrimidine analog based on six-membered rings is presented. This protocol provides a controlled and modular approach to access a variety of synthetically useful pyrimidine-fused skeletons with high efficiency, broad substrate scope, and excellent functional group compatibility. Under acidic conditions, the (Z)-configuration of products spontaneously converts into (E)-9-benzylidene-1,9-dihydro-11H-pyrazolo[4',3':4,5]pyrimido[2,1-a]isoindol-11-ones.

Construction of Phenanthridinone Skeletons through Palladium-Catalyzed Annulation.

Herein, a straightforward synthetic approach for the construction of phenanthridin-6(5H)-one skeletons is disclosed. The developed protocol relies on palladium catalysis, providing controlled access to a range of functionalized phenanthridin-6(5H)-ones in 59-88% yields. Furthermore, plausible reaction pathways are proposed based on mechanistic experiments.

Copper-Catalyzed Consecutive Ullmann, Decarboxylation, Oxidation, and Dehydration Reaction for Synthesis of Pyrrolo or Pyrido[1,2-a]imidazo[1,2-c]quinazolines.

A protocol for a copper-catalyzed intermolecular cross-coupling cascade between 2-(2-bromoaryl)-1H-benzo[d]imidazole analogues and proline or pipecolic acid has been developed. The developed protocol allows access to a variety of synthetically useful N-fused pyrrolo or pyrido[1,2-a]imidazo[1,2-c]quinazoline scaffolds with high efficiency and good functional group compatibility. Proline or pipecolic acid plays a dual role in the reaction: as ligand and reactants. A mechanistically consecutive approach for the Ullmann coupling, decarboxylation, oxidation, and dehydration reaction process was presented.

Lysine-Specific Demethylase 1 Promises to Be a Novel Target in Cancer Drug Resistance: Therapeutic Implications.

Chemotherapy, targeted therapy, and immunotherapy are effective against most tumors, but drug resistance remains a barrier to successful treatment. Lysine-specific demethylase 1 (LSD1), a member of histone demethylation modifications, can regulate invasion, metastasis, apoptosis, and immune escape of tumor cells, which are associated with tumorigenesis and tumor progression. Recent studies suggest that LSD1 ablation regulates resensitivity of tumor cells to anticarcinogens containing immune checkpoint inhibitors (ICIs) via multiple upstream and downstream pathways. In this review, we describe the recent findings about LSD1 biology and its role in the development and progression of cancer drug resistance. Further, we summarize LSD1 inhibitors that have a reversal or resensitive effect on drug resistance and discuss the possibility of targeting LSD1 in combination with other agents to surmount resistance.

Histone deacetylases (HDACs) as the promising immunotherapeutic targets for hematologic cancer treatment.

Bone marrow transplantation is regarded as the most effective immunotherapy for hematologic cancer, but it generally faces difficulties in matching. Aberrant expression of histone deacetylases (HDACs) is closely related to the occurrence and development of hematological cancer. Recent studies suggested that HDACs might play a critical role in initiating anti-cancer immune response or enhancing anti-cancer immunotherapy. Besides, combining HDAC inhibition and immunotherapy could prevent immunotherapy resistance in some degree and reach an extended treatment window. This review summarized the relationship between HDACs and immune and described the current understanding of HDACs in immunotherapy for hematologic cancer.

Tandem Palladium/Copper-Catalyzed Decarboxylative Approach to Benzoimidazo- and Imidazophenanthridine Skeletons.

A protocol for a tandem Pd/Cu-catalyzed intermolecular cross-coupling cascade between o-bromobenzoic acids and 2-(2-bromoaryl)-1H-benzo[d]imidazoles or the corresponding imidazoles is presented. The protocol provides conceptually novel and controlled access to synthetically useful N-fused (benzo)imidazophenanthridine scaffolds with high efficiency, a broad substrate scope, and excellent functional group compatibility.

Silver-Catalyzed Controlled Intermolecular Cross-Coupling of Silyl Enol Ethers: Scalable Access to 1,4-Diketones.

A protocol for silver-catalyzed controlled intermolecular cross-coupling of silyl enolates is disclosed. The protocol displays good functional group tolerance and allows efficient preparation of a series of synthetically useful 1,4-diketones. Preliminary mechanistic investigations suggest that the reaction proceeds through a one-electron process involving free radical species in which PhBr acts as the oxidant.

Discovery of 1,3,4-oxadiazole derivatives containing a bisamide moiety as a novel class of potential cardioprotective agents.

Myocardial injury is a nonnegligible problem in cardiovascular diseases and cancer therapy. The functional feature of N-containing heterocycles in the cardiovascular field has attracted much attention in recent years. Herein, we discovered a lead compound 12a containing 1,3,4-oxadiazole by extensive screening of anticancer derivatives containing nitrogen-heterocycle, which exhibited potential protective activity against oxidative stress in cardiomyocytes. Follow-up structure-activity relationship (SAR) studies also highlighted the role of substitution sites and bisamide moiety in enhancing the protective activity against oxidative stress. Specifically, compound 12d exhibited low cytotoxicity under high concentration and potent myocardial protection against oxidative stress in H9c2 cells. Preliminary mechanistic studies showed compound 12d could decrease the expression of cardiac hypertrophy and oxidative stress-related proteins/genes and reduce mitochondria-mediated cell apoptosis, thereby enhancing the cell vitality of injured cardiomyocytes. In this study, 1,3,4-oxadiazole may represent a novel pharmacophore that possesses potential myocardial protection and provides more choices for future optimization of cardiovascular drugs, especially for the treatment of onco-cardiology.

Silver-Promoted (4 + 1) Annulation of Isocyanoacetates with Alkylpyridinium Salts: Divergent Regioselective Synthesis of 1,2-Disubstituted Indolizines.

An unprecedented silver-promoted regioselective (4 + 1) annulation of isocyanoacetates with pyridinium salts is reported. The established protocol provides controlled, facile, and modular access to a range of synthetically useful N-fused heterocyclic scaffolds containing indolizines, pyrrolo[1,2-a]quinolines, pyrrolo[2,1-a]isoquinolines, and 1H-imidazo[4,5-a]indolizin-2(3H)-ones. A mechanistic pathway involving nucleophilic addition/protonation/elimination/cycloisomerization is proposed.

Modular synthesis of 3-substituted isocoumarins via silver-catalyzed aerobic oxidation/6-endo heterocyclization of ortho-alkynylbenzaldehydes.

A method involving silver-catalyzed aerobic oxidation/6-endo heterocyclization of ortho-alkynylbenzaldehydes to yield 3-substituted isocoumarins is described. The developed protocol allows convenient access to a range of synthetically useful 3-substituted isocoumarins and related fused heterocyclolactones in good to high yields, using silver tetrafluoroborate as the catalyst, and atmospheric oxygen as the terminal oxidant and the source of endocyclic oxygen. Mechanistic studies suggest the involvement of a free-radical pathway.

Stereoselective synthesis of unnatural α-amino acid derivatives through photoredox catalysis.

A protocol for stereoselective C-radical addition to a chiral glyoxylate-derived N-sulfinyl imine was developed through visible light-promoted photoredox catalysis, providing a convenient method for the synthesis of unnatural α-amino acids. The developed protocol allows the use of ubiquitous carboxylic acids as radical precursors without prior derivatization. The protocol utilizes near-stoichiometric amounts of the imine and the acid radical precursor in combination with a catalytic amount of an organic acridinium-based photocatalyst. Alternative mechanisms for the developed transformation are discussed and corroborated by experimental and computational studies.

Molecular mechanisms of mutualistic and antagonistic interactions in a plant-pollinator association.

Many insects metamorphose from antagonistic larvae into mutualistic adult pollinators, with reciprocal adaptation leading to specialized insect-plant associations. It remains unknown how such interactions are established at molecular level. Here we assemble high-quality genomes of a fig species, Ficus pumila var. pumila, and its specific pollinating wasp, Wiebesia pumilae. We combine multi-omics with validation experiments to reveal molecular mechanisms underlying this specialized interaction. In the plant, we identify the specific compound attracting pollinators and validate the function of several key genes regulating its biosynthesis. In the pollinator, we find a highly reduced number of odorant-binding protein genes and an odorant-binding protein mainly binding the attractant. During antagonistic interaction, we find similar chemical profiles and turnovers throughout the development of galled ovules and seeds, and a significant contraction of detoxification-related gene families in the pollinator. Our study identifies some key genes bridging coevolved mutualists, establishing expectations for more diffuse insect-pollinator systems.

Synthesis of Sulfonylated Heterocycles via Copper-Catalyzed Heteroaromatization/Sulfonyl Transfer of Propargylic Alcohols.

An unprecedented copper-catalyzed heteroaromatization/sulfonyl transfer of propargylic alcohols with isocyanide has been developed. 3-Sulfonyl benzofurans and indoles were produced under Cu(I) catalysis in good to high yields. The developed catalytic methodology provides controlled, modular, and facile access to sulfonyl benzoheterocycle scaffolds.

A chromosome-scale genome assembly of a diploid alfalfa, the progenitor of autotetraploid alfalfa.

Alfalfa (Medicago sativa L.) is one of the most important and widely cultivated forage crops. It is commonly used as a vegetable and medicinal herb because of its excellent nutritional quality and significant economic value. Based on Illumina, Nanopore and Hi-C data, we assembled a chromosome-scale assembly of Medicago sativa spp. caerulea (voucher PI464715), the direct diploid progenitor of autotetraploid alfalfa. The assembled genome comprises 793.2 Mb of genomic sequence and 47,202 annotated protein-coding genes. The contig N50 length is 3.86 Mb. This genome is almost twofold larger and contains more annotated protein-coding genes than that of its close relative, Medicago truncatula (420 Mb and 44,623 genes). The more expanded gene families compared with those in M. truncatula and the expansion of repetitive elements rather than whole-genome duplication (i.e., the two species share the ancestral Papilionoideae whole-genome duplication event) may have contributed to the large genome size of M. sativa spp. caerulea. Comparative and evolutionary analyses revealed that M. sativa spp. caerulea diverged from M. truncatula ~5.2 million years ago, and the chromosomal fissions and fusions detected between the two genomes occurred during the divergence of the two species. In addition, we identified 489 resistance (R) genes and 82 and 85 candidate genes involved in the lignin and cellulose biosynthesis pathways, respectively. The near-complete and accurate diploid alfalfa reference genome obtained herein serves as an important complement to the recently assembled autotetraploid alfalfa genome and will provide valuable genomic resources for investigating the genomic architecture of autotetraploid alfalfa as well as for improving breeding strategies in alfalfa.

Switchable Copper-Catalyzed Approach to Benzodithiole, Benzothiaselenole, and Dibenzodithiocine Skeletons.

A copper-catalyzed reaction between 2-bromo-benzothioamides and S8 or Se involving sulfur rearrangement is reported, enabling access to benzodithioles 2 and benzothiaselenoles 6 in the presence of Cs2CO3. In the absence of S8 or Se, the reaction affords dibenzodithiocines 7 via two consecutive C(sp2)-S Ullmann couplings.

CuBr-Catalyzed α-Arylation and Aerobic Oxidative Dehydrogenative C-N Coupling for the Synthesis of Spiro[cyclohexane-1,12'-isoindolo[1,2-b]quinazolin]-10'-one Derivatives.

A copper-catalyzed approach was disclosed for C(sp3)-C(sp2) bond formation via an α-arylation of carbonyl, and the subsequent oxidative dehydrogenation coupling occurred to form a C(sp3)-N bond, wherein O2 served as a green oxidant. This protocol provided a domino method for the synthesis of spiro[cyclohexane-1,12'-isoindolo[1,2-b]quinazolin]-10'-ones containing a nitrogen-substituted quaternary carbon center.

Silver-Assisted [3 + 2] Annulation of Nitrones with Isocyanides: Synthesis of 2,3,4-Trisubstituted 1,2,4-Oxadiazolidin-5-ones.

A silver-assisted method for [3 + 2] annulation of nitrones with isocyanides has been developed. The developed protocol allows access to a variety of 2,3,4-trisubstituted 1,2,4-oxadiazolidin-5-one derivatives as single diastereomers in good to excellent yields using silver oxide as the catalyst and molecular oxygen as the terminal oxidant. A plausible mechanism involving a nucleophilic addition/cyclization/protodeargentation/oxidation pathway is proposed on the basis of experimental results.