Correction: Lin et al. Potent Anticancer Effects of Epidithiodiketopiperazine NT1721 in Cutaneous T Cell Lymphoma. 2021, , 3367.

There is an omission in the Institutional Review Board Statement and Conflict of Interest statements of the paper [...

Constructing Saturated Guanidinum Heterocycles by Cycloaddition of -Amidinyliminium Ions with Indoles.

We report that structurally complex guanidinium heterocycles can be prepared in one step by regio- and stereoselective [4 + 2]-cycloadditions of amidinyliminium ions with indoles or benzothiophene. In contrast to reactions of these heterodienes with alkenes, density functional theory (DFT) calculations show that these cycloadditions take place in a concerted asynchronous fashion. The [4 + 2]-cycloaddition of -amidinyliminium ions (1,3-diaza-1,3-dienes) with indoles and benzothiophene are distinctive, as related [4 + 2]-cycloadditions of acyliminium ions (1-oxa-3-aza-1,3-dienes) are apparently unknown.

Potent Anticancer Effects of Epidithiodiketopiperazine NT1721 in Cutaneous T Cell Lymphoma.

Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of debilitating, incurable malignancies. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes, accounting for ~65% of CTCL cases. Patients with advanced disease have a poor prognosis and low median survival rates of four years.

Strategic Use of Visible-Light Photoredox Catalysis in Natural Product Synthesis.

Recent progress in the development of photocatalytic reactions promoted by visible light is leading to a renaissance in the use of photochemistry in the construction of structurally elaborate organic molecules. Because of the rich functionality found in natural products, studies in natural product total synthesis provide useful insights into functional group compatibility of these new photocatalytic methods as well as their impact on synthetic strategy. In this review, we examine total syntheses published through the end of 2020 that employ a visible-light photoredox catalytic step.

Lewis Acid Activation of Fragment-Coupling Reactions of Tertiary Carbon Radicals Promoted by Visible-Light Irradiation of EDA Complexes.

The addition of tertiary carbon radicals generated from -(acyloxy)phthalimide esters to cyclic α,β-unsaturated ketones and lactones is markedly enhanced by the addition of substoichiometric amounts of a Ln(OTf). The reaction is accomplished by irradiation with visible light in the absence of a photosensitizer and is suggested to proceed by excitation of a ternary electron donor-acceptor complex between the NHPI ester, Hantzsch ester, and a Ln(OTf).

General Access to Concave-Substituted -Dioxabicyclo[3.3.0]octanones: Enantioselective Total Syntheses of Macfarlandin C and Dendrillolide A.

The evolution of a strategy to access the family of rearranged spongian diterpenoids harboring a concave-substituted -2,8-dioxabicyclo[3.3.0]octan-3-one fragment is described.

Enantioselective Total Synthesis of Macfarlandin C, a Spongian Diterpenoid Harboring a Concave-Substituted cis-Dioxabicyclo[3.3.0]octanone Fragment.

The enantioselective total synthesis of the rearranged spongian diterpenoid (-)-macfarlandin C is reported. This is the first synthesis of a rearranged spongian diterpenoid in which the bulky hydrocarbon fragment is joined via a quaternary carbon to the highly hindered concave face of the cis-2,8-dioxabicyclo[3.3.

Attenuation of hedgehog/GLI signaling by NT1721 extends survival in pancreatic cancer.

Background: Pancreatic cancer is one of the most lethal malignancies due to frequent late diagnosis, aggressive tumor growth and metastasis formation. Continuously raising incidence rates of pancreatic cancer and a lack of significant improvement in survival rates over the past 30 years highlight the need for new therapeutic agents. Thus, new therapeutic agents and strategies are urgently needed to improve the outcome for patients with pancreatic cancer.

Facile Preparation of Spirolactones by an Alkoxycarbonyl Radical Cyclization-Cross-Coupling Cascade.

An alkoxycarbonyl radical cyclization-cross-coupling cascade has been developed that allows functionalized γ-butyrolactones to be prepared in one step from simple tertiary alcohol-derived homoallylic oxalate precursors. The reaction succeeds with aryl and vinyl electrophiles and is compatible with heterocyclic fragments in both coupling partners. This chemistry allows for the rapid construction of spirolactones, which are of interest in drug discovery endeavors.

Canvass: A Crowd-Sourced, Natural-Product Screening Library for Exploring Biological Space.

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays.

Forging C(sp)-C(sp) Bonds with Carbon-Centered Radicals in the Synthesis of Complex Molecules.

Radical fragment coupling reactions that unite intricate subunits have become an important class of transformations within the arena of complex molecule synthesis. This Perspective highlights some of the early contributions in this area, as well as more modern applications of radical fragment couplings in the preparation of natural products. Additionally, emphasis is placed on contemporary advances that allow for radical generation under mild conditions as a driving force for the implementation of radical fragment couplings in total synthesis.

Total Synthesis of (-)-Chromodorolide B By a Computationally-Guided Radical Addition/Cyclization/Fragmentation Cascade.

The first total synthesis of a chromodorolide marine diterpenoid is described. The core of the diterpenoid is constructed by a bimolecular radical addition/cyclization/fragmentation cascade that unites two complex fragments and forms two C-C bonds and four contiguous stereogenic centers of (-)-chromodorolide B in a single step. This coupling step is initiated by visible-light photocatalytic fragmentation of a redox-active ester, which can be accomplished in the presence of an iridium or a less-precious electron-rich dicyanobenzene photocatalyst, and employs equimolar amounts of the two addends.

1,6-Addition of Tertiary Carbon Radicals Generated From Alcohols or Carboxylic Acids by Visible-Light Photoredox Catalysis.

The addition of tertiary carbon radicals generated by an Ir-catalyzed visible-light photocatalyst to electron-deficient 1,3-dienes proceeds in good yields to append a δ-substituted β,γ-unsaturated carbonyl fragment to a tertiary alcohol or carboxylic acid precursor and construct a new quaternary carbon center.

Short Enantioselective Total Syntheses of Cheloviolenes A and B and Dendrillolide C via Convergent Fragment Coupling Using a Tertiary Carbon Radical.

The development of a convergent fragment coupling strategy for the enantioselective total syntheses of a group of rearranged spongian diterpenoids that harbor the cis-2,8-dioxabicyclo[3.3.0]octan-3-one unit is described.

Versatile Construction of 6-Substituted cis-2,8-Dioxabicyclo[3.3.0]octan-3-ones: Short Enantioselective Total Syntheses of Cheloviolenes A and B and Dendrillolide C.

A short enantioselective synthesis of 6-substituted cis-2,8-dioxabicyclo[3.3.0]octan-3-ones is described.

NT1721, a novel epidithiodiketopiperazine, exhibits potent in vitro and in vivo efficacy against acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive malignancy characterized by heterogeneous genetic and epigenetic changes in hematopoietic progenitors that lead to abnormal self-renewal and proliferation. Despite high initial remission rates, prognosis remains poor for most AML patients, especially for those harboring internal tandem duplication (ITD) mutations in the fms-related tyrosine kinase-3 (FLT3). Here, we report that a novel epidithiodiketopiperazine, NT1721, potently decreased the cell viability of FLT3-ITD+ AML cell lines, displaying IC50 values in the low nanomolar range, while leaving normal CD34+ bone marrow cells largely unaffected.

Palladium(II)-Catalyzed Enantioselective Reactions Using COP Catalysts.

Allylic amides, amines, and esters are key synthetic building blocks. Their enantioselective syntheses under mild conditions is a continuing pursuit of organic synthesis methods development. One opportunity for the synthesis of these building blocks is by functionalization of prochiral double bonds using palladium(II) catalysis.

Analogues of Marine Guanidine Alkaloids Are in Vitro Effective against Trypanosoma cruzi and Selectively Eliminate Leishmania (L.) infantum Intracellular Amastigotes.

Synthetic analogues of marine sponge guanidine alkaloids showed in vitro antiparasitic activity against Leishmania (L.) infantum and Trypanosoma cruzi. Guanidines 10 and 11 presented the highest selectivity index when tested against Leishmania.

Fragment Coupling with Tertiary Radicals Generated by Visible-Light Photocatalysis.

Convergent synthesis strategies in which a target molecule is prepared by a branched approach wherein two or more complex fragments are combined at a late stage are almost always preferred over a linear approach in which the overall yield of the target molecule is eroded by the efficiency of each successive step in the sequence. As a result, bimolecular reactions that are able to combine complex fragments in good yield and, where important, with high stereocontrol are essential for implementing convergent synthetic strategies. Although intramolecular reactions of carbon radicals have long been exploited to assemble polycyclic ring systems, bimolecular coupling reactions of structurally complex carbon radicals have rarely been employed to combine elaborate fragments in the synthesis of structurally intricate molecules.

Short Enantioselective Total Syntheses of trans-Clerodane Diterpenoids: Convergent Fragment Coupling Using a trans-Decalin Tertiary Radical Generated from a Tertiary Alcohol Precursor.

The evolution of a convergent fragment-coupling strategy for the enantioselective total synthesis of trans-clerodane diterpenoids is described. The key bond construction is accomplished by 1,6-addition of a trans-decalin tertiary radical with 4-vinylfuran-2-one. The tertiary radical is optimally generated from the hemioxalate salt of the corresponding tertiary alcohol upon activation by visible light and an Ir(III) photoredox catalyst.

Generation of the Methoxycarbonyl Radical by Visible-Light Photoredox Catalysis and Its Conjugate Addition with Electron-Deficient Olefins.

Visible-light photoredox-catalyzed fragmentation of methyl N-phthalimidoyl oxalate allows the direct construction of a 1,4-dicarbonyl structural motif by a conjugate addition of the methoxycarbonyl radical to reactive Michael acceptors. The regioselectivity of the addition of this alkoxyacyl radical species to electron-deficient olefins is heavily influenced by the electronic nature of the acceptor, behavior similar to that exhibited by nucleophilic alkyl radicals.

Diastereoselective Coupling of Chiral Acetonide Trisubstituted Radicals with Alkenes.

The stereochemical outcome of reactions of chiral nucleophilic trisubstituted acetonide radicals with electron-deficient alkenes is dictated by a delicate balance between destabilizing non-bonding interactions and stabilizing hydrogen-bonding between substituents on the α and β carbons.

H3K9me3 Inhibition Improves Memory, Promotes Spine Formation, and Increases BDNF Levels in the Aged Hippocampus.

Unlabelled: An increasing number of studies show that an altered epigenetic landscape may cause impairments in regulation of learning and memory-related genes within the aged hippocampus, eventually resulting in cognitive deficits in the aged brain. One such epigenetic repressive mark is trimethylation of H3K9 (H3K9me3), which is typically implicated in gene silencing. Here, we identify, for the first time, an essential role for H3K9me3 and its histone methyl transferase (SUV39H1) in mediating hippocampal memory functions.