Access to chiral dihydrophenanthridines via a palladium(0)-catalyzed Suzuki coupling and C-H arylation cascade reaction using new chiral-bridged biphenyl bifunctional ligands.

A class of chiral-bridged biphenyl phosphine-carboxylate bifunctional ligands CB-Phos has been developed and successfully applied to Pd(0)-catalyzed single enantioselective C-H arylation and a one pot cascade reaction involving Suzuki cross-coupling and C-H arylation. The catalytic system provides a new and convenient way for the synthesis of versatile chiral dihydrophenanthridines with rich structures and broad functional group tolerance. Good to excellent yields with high enantioselectivities were generally achieved. The reaction mechanism of the cascade reaction was also preliminarily discussed.

Chalcone-Based Synthesis of Tetrahydropyridazines via Cloke-Wilson-Type Rearrangement-Involved Tandem Reaction between Cyclopropyl Ketones and Hydrazines.

A facile and efficient approach for the synthesis of multisubstituted tetrahydropyridazines starting from cyclopropyl ketones and hydrazines has been developed. The transformation is chalcone-based and takes place via a Cloke-Wilson-type rearrangement-involved tandem reaction catalyzed by TfOH in HFIP.

Solvent-Free Buchwald-Hartwig Amination of Heteroaryl Chlorides by N-Heterocyclic Carbene-Palladium Complex (SIPr)Ph2Pd(cin)Cl at Room Temperature.

Using the robust N-heterocyclic carbene-palladium complex (SIPr)Ph2Pd(cin)Cl, a highly efficient and easy-to-operate method has been developed at room temperature for the solvent-free Buchwald-Hartwig amination of heteroaryl chlorides with various amines. The amount of catalyst can be as low as 0.05 wt %. The system was demonstrated on 47 substrates and successfully applied to the synthesis of commercial pharmaceuticals and candidate drugs with high yields. Furthermore, the protocol can be used to prepare aniline derivatives on a multigram scale without yield loss.

Saponins of Tomato Extract Improve Non-Alcoholic Fatty Liver Disease by Regulating Oxidative Stress and Lipid Homeostasis.

The present study investigated the impact of saponins of tomato extract (STE) on non-alcoholic fatty liver disease (NAFLD). The findings demonstrated that introducing STE in NAFLD mice revealed promising results in ameliorating symptoms of oxidative stress, lipid metabolism disorders, visceral fat deposition and fatty liver disease. Moreover, the mechanistic studies have demonstrated that STE delivers its effects by activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), thereby suppressing downstream protein expression associated with fatty acid synthesis. In such conditions, lipid metabolism can be improved. Simultaneously, STE enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) and entry into the nucleus and initiated the transcription of downstream antioxidant factors, thereby relieving oxidative stress induced by a high-fat diet and lowering oxidative damage to the liver. Such results imply that the administration of STE can be regarded as a viable treatment option for NAFLD, providing a mechanism that can regulate the AMPK and Nrf2 signaling pathways.

P(III)-Promoted Reductive Coupling of Aromatic and Aliphatic Nitro Compounds with Grignard Reagents.

A phosphine-promoted reductive coupling of nitro compounds with Grignard reagents is described. Polyfunctional and pharmaceutically relevant diarylamines were generated by this reaction in moderate to high yields. Aliphatic nitro compounds that are highly challenging substrates undergo a combination of α-arylation and reductive coupling to afford the α-arylated arylamines efficiently. A series of valuable biaryl compounds with polyfluorinated and heteroaryl rings are co-generated in 56-94% yields.

Discovery of a first-in-class Aurora A covalent inhibitor for the treatment of triple negative breast cancer.

Aurora kinases, which belong to the serine/threonine protein family, play critical roles in the regulation of the cell cycle and mitotic spindle assembly. They are frequently highly expressed in various types of tumors, and the use of selective Aurora kinase inhibitors has become a potential treatment option for cancer therapy. Despite the development of some reversible Aurora kinase inhibitors, none has been approved for clinical use yet. In this study, we report the discovery of the first-in-class irreversible Aurora A covalent inhibitors that target a cysteine residue at the substrate binding site. These inhibitors were characterized in enzymatic and cellular assays, and 11c exhibited selective inhibition to normal and cancer cells, as well as to Aurora A and B kinases. The covalent binding of 11c to Aurora A was confirmed by SPR, MS, and enzyme kinetic analysis, and Cys290-mediated covalent inhibition was supported through a bottom-up analysis of inhibitor-modified targets. Moreover, Western blotting assays were conducted on cells and tissues, and cellular thermal shift assays (CETSA) were further performed on cells to demonstrate the selectivity to Aurora A kinase. 11c displayed comparable therapeutic efficacy in an MDA-MB-231 xenograft mouse model relative to the positive control ENMD-2076, while requiring only half the dose of ENMD-2076. These results confirmed that 11c may be a promising drug candidate for the treatment of triple negative breast cancer (TNBC). Our work may provide a new perspective on the design of covalent inhibitors of Aurora kinase.

Discovery of novel benzamide derivatives bearing benzamidophenyl and phenylacetamidophenyl scaffolds as potential antitumor agents via targeting PARP-1.

Poly(ADP-ribose) polymerase-1 (PARP-1) plays a crucial role in DNA damage repair and has been identified as a promising therapeutic target in cancer therapy. As a continuation of our efforts on the development of novel PARP-1 inhibitors with potent anticancer activity, a series of benzamide derivatives containing the benzamidophenyl and phenylacetamidophenyl scaffolds were designed and synthesized based on the structure optimization of our previously reported compound IX. All target compounds were screened for their in vitro antiproliferative activities against human colorectal cancer cells (HCT116, DLD-1 and SW480) and human normal colonic epithelial cells (NCM460). Among them, compound 13f exhibited the most potent anticancer activity against HCT116 cells and DLD-1 cells with IC50 = 0.30 µM and 2.83 µM, respectively. Moreover, 13f displayed significant selectivity in inhibiting HCT116 cancer cells over the normal NCM460 cells. Furthermore, 13f exhibited excellent PARP-1 inhibitory effect with IC50 = 0.25 nM. Besides, 13f was found to effectively inhibit colony formation and migration of HCT116 cells. Studies on the mechanisms revealed that 13f could arrest cell cycle at G2/M phase, accumulate DNA double-strand breaks, reduce mitochondrial membrane potential and ultimately induce apoptosis in HCT116 cells. In addition, molecular docking study indicated that 13f could combine firmly with the catalytic pocket of PARP-1 through multiple hydrogen bond interactions. Collectively, these findings demonstrated that 13f could serve as a promising anticancer candidate and deserves further investigation.

Identification of novel Pyrrolo[2,3-d]Pyrimidine-based KRAS G12C inhibitors with anticancer effects.

Oncogene KRAS plays predominant roles in human cancers by regulating cell proliferation, differentiation, and migration. Recent progress revealed that directly target KRAS G12C with allosteric inhibitors that covalently bind to the switch Ⅱ pocket is feasible. Herein, series of pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized through systematic structural optimization, leading to the discovery of compound 2-((S)-1-acryloyl-4-(2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-methyl-6-(8-methylnaphthalen-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (50) with high KRAS/SOS1 inhibitory potency (IC50 = 0.21 µM) and strong anti-proliferation activities on cancer cells harboring KRAS p.G12C. Compound 50 also exhibited satisfactory selectivity, moderate pharmacokinetic characters, and good anticancer effects in vivo. Meaningfully, the identification of these compounds highlights the necessity of an appropriate conformational constraint for acquiring the applicable binding pose in the cryptic pocket of KRAS, and the results support efforts toward design of KRAS inhibitors with novel skeleton and binding mechanism could be beneficial for targeting the acquired drug resistance.

Discovery of a potent EGFR and ALK dual mutation inhibitor containing N-(3-((4-((2-(cyclopropylsulfinyl)phenyl)amino)pyrimidin-2-yl)amino) phenyl)acrylamide scaffold.

A series of EGFR and ALK dual inhibitors containing sulfoxide and cyclopropyl groups were designed and synthesized. The lead compound 8a showed a significant activity against EGFR and ALK in both the enzymatic and cellular assays. The study of anti-tumor mechanism indicated that 8a could effectively block the phosphorylation of EGFR and ALK proteins, so as to effectively inhibiting the proliferation and inducing apoptosis of H1975 tumor cells, blocking the cell cycle and reducing the mitochondrial membrane potential inhibited the migration of H1975 cells. In vivo studies, compounds 8a and 8d can significantly subside the tumor tissue of nude mice without obvious toxicity.

Design, synthesis, biological evaluation and molecular docking study of novel urea-based benzamide derivatives as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors.

Poly(ADP-ribose) polymerase-1 (PARP-1) is one of the key members of DNA repair enzymes that is responsible for the repair of DNA single-strand breaks. Inhibition of PARP-1 has been demonstrated to be a promising strategy to selectively kill tumor cells by targeting DNA repair pathway. Herein, a series of novel urea-based benzamide derivatives were designed and synthesized based on the structure-based drug design strategy. The anticancer activities against five human cancer cell lines including HCT116, MDA-MB-231, HeLa, A579 and A375 were evaluated and the preliminary structure-activity relationships were summarized. Among them, compounds 23f and 27f exhibited potent antiproliferative effects against HCT116 cells with IC50 values of 7.87 µM and 8.93 µM, respectively. Moreover, both compounds displayed excellent PARP-1 inhibitory activities with IC50 values of 5.17 nM and 6.06 nM, respectively. Mechanistic investigations showed that 23f and 27f could effectively inhibit colony formation and cell migration of HCT116 cells. Furthermore, 23f and 27f could cause cell cycle arrest at G2/M phase, and induce apoptosis by upregulating the expression of Bax and cleaved Caspase-3 and downregulating the expression of Caspase-3 and Bcl-2 in HCT116 cells. In addition, molecular docking studies provided the rational binding modes of these compounds in complex with PARP-1. Collectively, these results suggested that 23f and 27f could serve as promising drug candidates for further investigation.

Target Profiling of an Iridium(III)-Based Immunogenic Cell Death Inducer Unveils the Engagement of Unfolded Protein Response Regulator BiP.

Clinical chemotherapeutic drugs have occasionally been observed to induce antitumor immune responses beyond the direct cytotoxicity. Such effects are coined as immunogenic cell death (ICD), representing a "second hit" from the host immune system to tumor cells. Although chemo-immunotherapy is highly promising, ICD inducers remain sparse with vague drug-target mechanisms. Here, we report an endoplasmic reticulum stress-inducing cyclometalated Ir(III)-bisNHC complex (1a) as a new ICD inducer, and based on this compound, a clickable photoaffinity probe was designed for target identification, which unveiled the engagement of the master regulator protein BiP (binding immunoglobulin protein)/GRP78 of the unfolded protein response pathway. This has been confirmed by a series of cellular and biochemical studies including fluorescence microscopy, cellular thermal shift assay, enzymatic assays, and so forth, showing the capability of 1a for BiP destabilization. Notably, besides 1a, the previously reported ICD inducers including KP1339, mitoxantrone, and oxaliplatin were also found to engage BiP interaction, suggesting the important role of BiP in eliciting anticancer immunity. We believe that the ICD-related target information in this work will help to understand the mode of action of ICD that is beneficial to designing new ICD agents with high specificity and improved efficacy.

Construction of α,ß-Diamino Diacid Derivatives with Adjacent Acyclic Tetrasubstituted Stereocenters.

A convenient strategy for the diastereoselective synthesis of α,ß-diamino diacid derivatives bearing congested vicinal acyclic tetrasubstituted stereocenters via catalytic Mannich-type reactions of azlactones and 2-aminoacrylates was established. A diverse set of α,ß-diamino diacid derivatives were synthesized in good to excellent yields and diastereoselectivities. Good enantioselectivity (up to 98:2 er) was achieved by employing the catalyst (DHQD)2PHAL in the subsequent asymmetric study.

Stereoselective Synthesis of Trisubstituted Alkenes by Nickel-Catalyzed Benzylation and Alkene Isomerization.

Catalytic strategies that provide stereoselective access to highly substituted alkenes from abundant monosubstituted substrates are exceedingly sought-after but rare. Here, we show that a N-heterocyclic carbene-NiI catalytic species mediates efficient union of electronically polarized terminal olefins with benzyl chlorides, in the presence of trimethylsilyl triflate and trimethylamine additives, to generate trisubstituted boron- and arene-containing trans alkenes in excellent regio- and stereoselectivities. Control experiments provide evidence for a mechanism involving branched-selective Heck-type benzylation that overrides substrate control, followed by trans-selective 1,3-hydrogen shift. The method represents a significant addition to the toolbox of reactions for the concise synthesis of unsaturated biologically active compounds.

Synthesis of Phenolic Coumestans via a Sequential Dehydrogenation/Oxa-Michael Addition Reaction of 2',4'-Dihydroxyl-3-arylcoumarins.

A facile and practical approach for the synthesis of natural coumestans and derivatives starting from 2',4'-dihydroxyl-3-arylcoumarins has been developed. The process involved a seqential intramolecular dehydrogenation/oxa-Micheal reaction efficiently promoted by 1,8-diazabicyclo[5.4.0]undec-7-ene at 40 °C under metal- and ligand-free conditions with good functional group compatibility.

Effects of Behavioral Economics-Based Messaging on Appointment Scheduling Through Patient Portals and Appointment Completion: Observational Study.

BACKGROUND: Behavioral economics-based techniques have been an increasingly utilized method in health care to influence behavior change by modifying language in patient communication (through choice architecture and the framing of words). Patient portals are a key tool for facilitating patient engagement in their health, and interventions deployed via patient portals have been effective in improving utilization of preventive health services. OBJECTIVE: We examined the impacts of behavioral economics-based nudge health maintenance reminders on appointment scheduling through a patient portal and appointment completion for 2 preventive services: Medicare wellness visits and Pap smear. METHODS: We conducted a retrospective observational study using electronic health record data from an integrated health care system in Northern California. Nudge health maintenance reminders with behavioral economics-based language were implemented for all sites in November 2017 for Medicare wellness visits and for selected sites in February 2018 for Pap smears. We analyzed 125,369 health maintenance reminders for Medicare wellness visits, and 585,358 health maintenance reminders for Pap smear sent between January 2017 and February 2020. The primary outcomes were rate of appointments scheduled through the patient portal and appointment completion rate. We compared the outcomes between those who received the new, behavioral economics-based health maintenance reminders (the nudge group) and those who received the original, standard health maintenance reminders (the control group). We used segmented regression with interrupted time series to assess the immediate and gradual effect of the nudge for Medicare wellness visits, and we used logistic regression to assess the association of nudge health maintenance reminders, adjusting for the propensity to receive a nudge health maintenance reminder, for Pap smear. RESULTS: The rates of appointments scheduled through the patient portal were higher for nudge health maintenance reminder recipients than those for control health maintenance reminder recipients (Medicare wellness visits-nudge: 12,537/96,839, 13.0%; control: 2,769/28,530, 9.7%, P<.001; Pap smear-nudge: 8,239/287,149, 2.9%; control: 1,868/120,047, 1.6%; P<.001). Rates of appointment completion were higher for nudge health maintenance reminders for Pap smear (nudge: 67,399/287,149, 23.5% control: 20,393/120,047, 17.0%; P<.001) but were comparable for Medicare wellness visits (nudge: 49,835/96,839, 51.5% control: 14,781/28,530, 51.8%; P=.30). There was a marginally gradual effect of nudge on number of appointments scheduled through the patient portal for the overall Medicare wellness visits sample (at a monthly rate of 0.26%, P=.09), and a significant gradual effect among scheduled appointments (at a monthly rate of 0.46%, P=.04). For Pap smear, nudge health maintenance reminders were positively associated with number of appointments scheduled through the patient portal (overall sample: propensity adjusted odds ratio [OR] 1.62; 95% CI 1.50-1.74; among scheduled appointments: propensity adjusted OR 1.61, 95% CI 1.47-1.76) and with appointment completion (propensity adjusted OR 1.07; 1.04-1.10). CONCLUSIONS: Nudges, a behavioral economics-based approach to providing health maintenance reminders, increased the number of appointments scheduled through the patient portal for Medicare wellness visits and Pap smear. Our study demonstrates that a simple approach-framing and modifying language in an electronic message-can have a significant and long-term impact on patient engagement and access to care.

Characterization, Antioxidant and Antitumor Activities of Oligosaccharides Isolated from Evodia lepta (Spreng) Merr. by Different Extraction Methods.

Evodia lepta (E. lepta) is a traditional Chinese herbal medicine with various biological activities. One of the active components of this widely used medicinal plant is believed to be an oligosaccharide. The extraction yields, structural characteristics, antioxidant, and antitumor activities of four oligosaccharide extracts obtained by hot water extraction (HEO), ultrasound-assisted extraction (UEO), enzyme-assisted (EEO), and microwave-assisted extraction (MEO) were investigated. Matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS), X-ray diffraction (XRD), and Scanning electron microscopy (SEM) results indicated that the extraction methods had a difference on the molecular mass distribution, structure, and morphology of the EOs. In addition, HEO and MEO showed strong antioxidant activities, which might be related to their uronic acid and protein contents. More interestingly, MEO was more active toward MDA-MB-231 cells compared to other cells, and cell growth inhibition was proposed to occur through apoptosis. Overall, microwave-assisted extraction is a promising technique for the extraction of high quality EO.

Dibrominated addition and substitution of alkenes catalyzed by Mn2(CO)10.

A practical method for the dibromination of alkenes without using molecular bromine is consistently appealing in organic synthesis. Herein, we report Mn-catalyzed dibrominated addition and substitution of alkenes only with N-bromosuccinimide, producing a variety of synthetically valuable dibrominated compounds in moderate to high yields.

Demethylative Alkylation of Methionine Residue by Employing the Sulfonium as the Key Intermediate.

Methionine (Met) offers a valuable handle to achieve peptide chemical modification owing to its unique thioether functional group. In contrast with cysteine, the site-selective functionalization of the hydrophobic and redox-sensitive thioether motif on peptides is still challenging, and strategies for diversification on the Met residue are rarely disclosed. Herein we report a transition-metal-free and redox-neutral approach for Met diversification with substrate diversity, which could be applied to synthesize cyclic peptides.

Aromatic C-H Methylation and Other Functionalizations via the Rh(III)-Catalyzed Migratory Insertion of Bis(phenylsulfonyl)carbene and Subsequent Transformations.

The Rh(III)-catalyzed migratory insertion of bis(phenylsulfonyl)carbene into aromatic C-H bonds has been developed. A variety of bis(phenylsulfonyl)methyl derivatives were prepared with good yields under mild conditions. The methylated products were readily obtained after reductive desulfonylation. Furthermore, the diverse transformations of bis(phenylsulfonyl)methyl to trideuteriomethyl, aldehyde, and other functional groups were demonstrated.

Synthesis and evaluation of novel 2,4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibition agents.

Anaplastic lymphoma kinase (ALK) targeted therapies have demonstrated remarkable efficacy in ALK-positive lung adenocarcinomas. Here we synthesized and evaluated sixteen new 2,4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibitors. The optimal compound 9e exhibited excellent antiproliferative activity against non-small cell lung cancer NCI-H2228 cells, which is better than that of Brigatinib and similar to Ceritinib. Mechanism study revealed that the optimal compound 9e decreased the mitochondrial membrane potential and arrested NCI-H2228 cells in the G0/G1 phase, finally resulting in cellular apoptosis. It is interesting that 9e could effectively inhibit the migration of NCI-H2228 cells and may be a promising leading compound for chemotherapy of metastatic cancer.