Synthetic Strategies toward Ortho-3-propanoate Substituted Aryl Phosphonates by Three-Component Coupling Reactions of Arynes, Phosphites, and Acrylates.

Mild, metal-free, and operationally simple three-component coupling reactions involving arynes, phosphites, and acrylates have been achieved. The reaction proceeded well with α- or ß-substituted acrylates. Additionally, various functional groups were tolerated under these reaction conditions, resulting in diverse ortho-3-propanoate-substituted aryl phosphonates. Moreover, the reaction can be used to synthesize a range of organophosphorus compounds present in natural products, materials, and biologically active compounds.

Identification of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffolds as potent Lck inhibitors as anti-cancer agents.

Lymphocyte-specific protein tyrosine kinase (Lck) plays vital roles in the T-cell receptor- mediated development, function, and differentiation of T-cells. Given its substantial involvement in T cell signaling, irregularities in the expression and functionality of Lck may lead to various diseases, including cancer. In this study, we found that compound 12a exerted significant inhibitory potency against Lck with an IC50 value of 10.6 nM. In addition, 12a demonstrated high efficacy in various colon cancer cell lines as indicated by GI50 values ranging from 0.24 to 1.26 µM. Notably, 12a inhibited the phosphorylation of Lck in Colo201 cells. Overall, the anti-proliferative effects of 12a on diverse cancer cell lines highlights its potential application for the treatment of various cancer types.

Discovery of Orally Bioavailable Phthalazinone Analogues as an ENPP1 Inhibitor for STING-Mediated Cancer Immunotherapy.

A lack of the T cell-inflamed tumor microenvironment limits the efficacy of immune checkpoint inhibitors (ICIs). Activation of stimulator of interferon genes (STING)-mediated innate immunity has emerged as a novel therapeutic approach in cancer therapy. 2',3'-Cyclic GMP-AMP (cGAMP) is a natural STING agonist; however, cGAMP is subjected to endogenous degradation by ecto-nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1). To improve the ICI response rate, we developed 29f, a novel ENPP1 inhibitor with phthalazin-1(2H)-one as the core scaffold. 29f inhibited the cGAMP hydrolysis by ENPP1 in vitro (IC50 = 68 nM) and enhanced the STING-mediated type I interferon response in both immune and tumor cells. 29f demonstrated excellent metabolic stability and bioavailability (F = 65%). Orally administered 29f promoted tumor growth inhibition in a CT26 syngeneic model and increased the anti-PD-L1 response. Furthermore, 29f-induced immunological memory prevented the tumor relapse against tumor rechallenge, suggesting the promising therapeutic potential of 29f.

Implications for Combination Therapy of Selective Monoamine Reuptake Inhibitors on Dopamine Transporters.

Monoamine transporters, including dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT, respectively), are important therapeutic targets due to their essential roles in the brain. To overcome the slow action of selective monoamine reuptake inhibitors, dual- or triple-acting inhibitors have been developed. Here, to examine whether combination treatments of selective reuptake inhibitors have synergistic effects, the pharmacological properties of DAT, NET, and SERT were investigated using the selective inhibitors of each transporter, which are vanoxerine, nisoxetine, and fluoxetine, respectively. Potencies were determined via fluorescence-based substrate uptake assays in the absence and presence of other inhibitors to test the multi-drug effects on individual transporters, resulting in antagonistic effects on DAT. In detail, fluoxetine resulted in a 1.6-fold increased IC50 value of vanoxerine for DAT, and nisoxetine produced a more drastic increase in the IC50 value by six folds. Furthermore, the effects of different inhibitors, specifically monovalent ions, were tested on DAT inhibition by vanoxerine. Interestingly, these ions also reduced vanoxerine potency in a similar manner. The homology models of DAT suggested a potential secondary inhibitor binding site that affects inhibition in an allosteric manner. These findings imply that the use of combination therapy with monoamine reuptake inhibitors should be approached cautiously, as antagonistic effects may occur.

Chiroptical Synaptic Heterojunction Phototransistors Based on Self-Assembled Nanohelix of π-Conjugated Molecules for Direct Noise-Reduced Detection of Circularly Polarized Light.

High-performance chiroptical synaptic phototransistors are successfully demonstrated using heterojunctions composed of a self-assembled nanohelix of a π-conjugated molecule and a metal oxide semiconductor. To impart strong chiroptical activity to the device, a diketopyrrolopyrrole-based π-conjugated molecule decorated with chiral glutamic acid is newly synthesized; this molecule is capable of supramolecular self-assembly through noncovalent intermolecular interactions. In particular, nanohelix formed by intertwinded fibers with strong and stable chiroptical activity in a solid-film state are obtained through hydrogen-bonding-driven, gelation-assisted self-assembly. Phototransistors based on interfacial charge transfer at the heterojunction from the chiroptical nanohelix to the metal oxide semiconductor show excellent chiroptical detection with a high photocurrent dissymmetry factor of 1.97 and a high photoresponsivity of 218 A W-1 . The chiroptical phototransistor demonstrates photonic synapse-like, time-dependent photocurrent generation, along with persistent photoconductivity, which is attributed to the interfacial charge trapping. Through the advantage of synaptic functionality, a trained convolutional neural network successfully recognizes noise-reduced circularly polarized images of handwritten alphabetic characters with better than 89.7% accuracy.

Three-Component Coupling Reactions Involving Arynes, Phosphites, and Aldehydes toward 3-Mono-Substituted Benzoxaphosphole 1-Oxides.

A mild, efficient, and transition-metal-free three-component coupling reaction involving arynes, phosphites, and aldehydes was established to afford 3-mono-substituted benzoxaphosphole 1-oxides. A range of 3-mono-substituted benzoxaphosphole 1-oxides was obtained from both aryl- and aliphatic-substituted aldehydes in moderate to good yields. Moreover, the synthetic utility of the reaction was demonstrated by a Gram-scale reaction and the transformation of the products into various P-containing bicycles.

A Convergent Total Synthesis of (+)-Ineleganolide.

We report the total synthesis of the furanobutenolide-derived diterpenoid (+)-ineleganolide. The synthetic approach relies on a convergent strategy based on the coupling of two enantioenriched fragments, which are derived from (-)-linalool and (+)-norcarvone, respectively. A high-yielding, one-step Michael addition and aldol cascade furnishes a pentacyclic framework as a single diastereomer, thereby overcoming previous challenges in controlling stereochemistry. The endgame features an O2-facilitated C-H oxidation and a samarium diiodide-induced semipinacol rearrangement to furnish the highly rigid central seven-membered ring.

Synthetic Strategy for Aryl(alkynyl)phosphinates by a Three-Component Coupling Reaction Involving Arynes, Phosphites, and Alkynes.

An efficient and straightforward method for the synthesis of aryl(alkynyl)phosphinates was developed via a three-component coupling reaction involving arynes, phosphites, and alkynes. An array of aryl(alkynyl)phosphinates were produced from both aryl and aliphatic group-substituted acetylenes. This operationally simple reaction is tolerant to many functional groups, affording various aryl(alkynyl)phosphinates in moderate to good yields. The synthetic utility of alkynyl phosphinates afforded by this method was demonstrated by the elaboration of the products into various phosphorus-containing compounds.

Identification of novel pyrrolopyrimidine and pyrrolopyridine derivatives as potent ENPP1 inhibitors.

In an effort to discover novel scaffolds of non-nucleotide-derived Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors to stimulate the Stimulator of Interferon Genes (STING) pathway, we designed and synthesised pyrrolopyrimidine and pyrrolopyridine derivatives and performed structure-activity relationship (SAR) study. We found 18p possessed high potency (IC50 = 25.0 nM) against ENPP1, and activated STING pathway in a concentration dependent manner. Also, in response to STING pathway activation, cytokines such as IFN-ß and IP-10 were induced by 18p in a concentration dependent manner. Finally, we discovered that 18p causes inhibition of tumour growth in 4T1 syngeneic mouse model. This study provides new insight into the designing of novel ENPP1 inhibitors and warrants further development of small molecule immune modulators for cancer immunotherapy.

Discovery of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one derivatives as novel ENPP1 inhibitors.

Ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) negatively regulates the anti-cancer Stimulator of Interferon Genes (STING) pathway. We discovered that 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one derivatives possessed inhibitory activities on ENPP1. A structure-activity relationship (SAR) study led to the identification of 46 and 23 as potent ENPP1 inhibitors. Also, compounds 46 and 23 possessed high microsomal stabilities in human, rat, and mouse liver microsome. Additionally, CYPs (1A2, 2C9, 2C19, 2D6, and 3A4) were not inhibited by 46 and 23. Molecular dynamics simulations provided an insight of binding modes between ENPP1 and compounds (46 and 23).

Identification of highly selective type II kinase inhibitors with chiral peptidomimetic tails.

Identification of highly selective type II kinase inhibitors is described. Two different chiral peptidomimetic scaffolds were introduced on the tail region of non-selective type II kinase inhibitor GNF-7 to enhance the selectivity. Kinome-wide selectivity profiling analysis showed that type II kinase inhibitor 7a potently inhibited Lck kinase with great selectivity (IC50 of 23.0 nM). It was found that 7a and its derivatives possessed high selectivity for Lck over even structurally conserved all Src family kinases. We also observed that 7a inhibited Lck activation in Jurkat T cells. Moreover, 7a was found to alleviate clinical symptoms in DSS-induced colitis mice. This study provides a novel insight into the design of selective type II kinase inhibitors by adopting chiral peptidomimetic moieties on the tail region.

Synthesis of Benzoxaphosphole 1-Oxide Heterocycles via a Three-Component Coupling Reaction Involving Arynes, Phosphites, and Ketones.

An efficient and transition-metal-free three-component reaction with benzynes formed in situ from 2-(trimethylsilyl)aryl triflate, phosphites, and ketones was developed for the synthesis of benzoxaphosphole 1-oxides. An array of benzoxaphosphole 1-oxides were prepared from both activated and non-activated ketones in moderate to good yields with a broad functional group tolerance. This reaction is useful for preparing organophosphorus compounds encountered in natural products and materials.

A Synthetic Strategy toward Eight-Membered Cyclic Amines by Cycloetherification and Claisen Rearrangement.

Eight-membered nitrogen-containing heterocycles were straightforwardly produced by a nickel-catalyzed cycloetherification and subsequent Claisen rearrangement of secondary and tertiary alcohols. In particular, a one-pot transformation was achieved with tertiary alcohols in moderate to good yields. This operationally simple reaction is tolerant of many functional groups and applicable to the synthesis of various medium-sized ring nitrogen-containing heterocycles.

Enantioselective Allenoate-Claisen Rearrangement Using Chiral Phosphate Catalysts.

Herein we report the first highly enantioselective allenoate-Claisen rearrangement using doubly axially chiral phosphate sodium salts as catalysts. This synthetic method provides access to ß-amino acid derivatives with vicinal stereocenters in up to 95% ee. We also investigated the mechanism of enantioinduction by transition state (TS) computations with DFT as well as statistical modeling of the relationship between selectivity and the molecular features of both the catalyst and substrate. The mutual interactions of charge-separated regions in both the zwitterionic intermediate generated by reaction of an amine to the allenoate and the Na+-salt of the chiral phosphate leads to an orientation of the TS in the catalytic pocket that maximizes favorable noncovalent interactions. Crucial arene-arene interactions at the periphery of the catalyst lead to a differentiation of the TS diastereomers. These interactions were interrogated using DFT calculations and validated through statistical modeling of parameters describing noncovalent interactions.

A mild and efficient approach to enantioenriched α-hydroxyethyl α,ß-unsaturated δ-lactams.

A straightforward approach toward enantioenriched α-substituted α,ß-unsaturated δ-lactams is described. Although a considerable number of approches toward α,ß-unsaturated δ-lactams have been reported, there are relatively few examples of enantioenriched α,δ-disubstituted α,ß-unsaturated δ-lactams formation. The δ-stereocenter was formed by addition of allylmagnesium bromide to an N-tert-butylsulfinyl imine. The α,ß-unsaturated δ-lactam was furnished by ring-closing metathesis. Although Baylis-Hillman chemistry failed on this cyclic compound, introduction of the hydroxyethyl group prior to ring-closing metathesis was successful. A Baylis-Hillman reaction was used to introduce the substituent at the α-position of the α,ß-unsaturated lactam.

Nickel-Catalyzed Intramolecular C-O Bond Formation: Synthesis of Cyclic Enol Ethers.

An efficient and exceptionally mild intramolecular nickel-catalyzed carbon-oxygen bond-forming reaction between vinyl halides and primary, secondary, and tertiary alcohols has been achieved. Zinc powder was found to be an essential additive for obtaining high catalyst turnover and yields. This operationally simple method allows direct access to cyclic vinyl ethers in high yields in a single step.

Discovery and optimization of adamantane carboxylic acid derivatives as potent diacylglycerol acyltransferase 1 inhibitors for the potential treatment of obesity and diabetes.

We have developed a series of adamantane carboxylic acid derivatives exhibiting potent diacylglycerol acyltransferase 1 (DGAT1) inhibitory activities. Optimization of the series led to the discovery of E-adamantane carboxylic acid compound 43c, which showed excellent in vitro activity with an IC50 value of 5 nM against human and mouse DGAT1, also good druggability as well as microsomal stability and safety profiles such as hERG, CYP and cytotoxicity. Compound 43c significantly reduced plasma triglyceride levels in vivo (in rodents and zebrafish) and also showed bodyweight gain reduction and glucose area under curve (AUC) lowering efficacy in diet-induced obesity (DIO) mice.

Stereochemical evaluation of bis(phosphine) copper catalysts for the asymmetric alkylation of 3-bromooxindoles with α-arylated malonate esters.

An improved method for the asymetric alkylation of 3-bromooxindoles with α-arylated malonate esters is described. The asymmetric alkylation demonstrated was achieved up to 70% ee utilizing a copper(II) bis(phosphine) complex.

Catalytic enantioselective construction of quaternary stereocenters: assembly of key building blocks for the synthesis of biologically active molecules.

The ever-present demand for drugs with better efficacy and fewer side effects continually motivates scientists to explore the vast chemical space. Traditionally, medicinal chemists have focused much attention on achiral or so-called "flat" molecules. More recently, attention has shifted toward molecules with stereogenic centers since their three-dimensional structures represent a much larger fraction of the chemical space and have a number of superior properties compared with flat aromatic compounds. Quaternary stereocenters, in particular, add greatly to the three-dimensionality and novelty of the molecule. Nevertheless, synthetic challenges in building quaternary stereocenters have largely prevented their implementation in drug discovery. The lack of effective and broadly general methods for enantioselective formation of quaternary stereocenters in simple molecular scaffolds has prompted us to investigate new chemistry and develop innovative tools and solutions. In this Account, we describe three approaches to constructing quaternary stereocenters: nucleophilic substitution of 3-halooxindoles, conjugate addition of boronic acids to cyclic enones, and allylic alkylation of enolates. In the first approach, malonic ester nucleophiles attack electrophilic 3-halooxindoles, mediated by a copper(II)-bisoxazoline catalyst. A variety of oxindoles containing a benzylic quaternary stereocenter can be accessed through this method. However, it is only applicable to the specialized 3,3-disubstituted oxindole system. To access benzylic quaternary stereocenters in a more general context, we turned our attention to the enantioselective conjugate addition of carbon nucleophiles to α,ß-unsaturated carbonyl acceptors. We discovered that in the presence of catalytic palladium-pyridinooxazoline complex, arylboronic acids add smoothly to ß-substituted cyclic enones to furnish ketones with a ß-benzylic quaternary stereocenter in high yields and enantioselectivities. The reaction is compatible with a wide range of arylboronic acids, ß-substituents, and ring sizes. Aside from benzylic quaternary stereocenters, a more challenging motif is a quaternary stereocenter not adjacent to an aromatic group. Such centers represent more general structures in chemical space but are more difficult to form by asymmetric catalysis. To address this greater challenge, and motivated by the greater reward, we entered the field of palladium-catalyzed asymmetric allylic alkylation of prochiral enolate nucleophiles about a decade ago. On the basis of Tsuji's work, which solved the issue of positional selectivity for unsymmetrical ketones, we discovered that the phosphinooxazoline ligand effectively rendered this reaction enantioselective. Extensive investigations since then have revealed that the reaction exhibits broad scope and accepts a range of substrate classes, each with its unique advantage in synthetic applications. A diverse array of carbonyl compounds bearing α-quaternary stereocenters are obtained in excellent yields and enantioselectivities, and more possibilities have yet to be explored. As an alternative to palladium catalysis, we also studied iridium-catalyzed asymmetric allylic alkylations that generate vicinal quaternary and tertiary stereocenters in a single transformation. Overall, these methods provide access to small molecule building blocks with a single quaternary stereocenter, can be applied to various molecular scaffolds, and tolerate a wide range of functional groups. We envision that the chemistry reported in this Account will be increasingly useful in drug discovery and design.

Evolution of a unified, stereodivergent approach to the synthesis of communesin F and perophoramidine.

Expedient synthetic approaches to the highly functionalized polycyclic alkaloids communesin F and perophoramidine are described using a unified approach featuring a key decarboxylative allylic alkylation to access a crucial and highly congested 3,3-disubstituted oxindole. Described are two distinct, stereoselective alkylations that produce structures in divergent diastereomeric series possessing the critical vicinal all-carbon quaternary centers needed for each synthesis. Synthetic studies toward these challenging core structures have revealed a number of unanticipated modes of reactivity inherent to these complex alkaloid scaffolds. Additionally, several novel and interesting intermediates en route to the target natural products, such as an intriguing propellane hexacyclic oxindole encountered in the communesin F sequence, are disclosed. Indeed, such unanticipated structures may prove to be convenient strategic intermediates in future syntheses.