Synthesis of conjugated bisallenes by cooperative Cu/Pd-catalysed borylallenylation of 2-trifluoromethyl-1,3-enynes.

A cooperative Cu/Pd-catalysed borylallenylation of 2-trifluoromethyl-1,3-enynes with propargylic carbonates under mild reaction conditions was developed. This method provides facile and efficient access to conjugated bisallenes with a broad range of functional groups. Both aromatic and aliphatic 1,3-enynes can be utilized in this transformation to give the corresponding multi-substituted conjugated bisallenes.

Three-Component Borylallenylation of Alkynes: Access to Densely Boryl-Substituted Ene-allenes.

Ene-allenes serve as versatile building blocks in organic synthesis, and the development of their efficient preparation is valuable. Herein the synthesis of boryl-substituted ene-allenes utilizing a Cu/Pd-catalyzed borylallenylation of alkynes with propargylic carbonates and bis(pinacolato)diboron is reported. Densely (tetra-, penta-, and hexa-) substituted ene-allenes were synthesized in acceptable yield with high regio- and stereoselectivity. More important molecule structures can be obtained by subsequent modifications.

Diagnostic value of GLUT-1 in distinguishing malignant mesothelioma from reactive mesothelial cells: a meta-analysis.

Background: Previous studies have demonstrated the diagnostic value of glucose transporter 1 (GLUT-1) to distinguish malignant mesothelioma (MM) from reactive mesothelial cells (RMC), but the results are inconsistent. The purpose of this meta-analysis is to investigate the diagnostic accuracy of GLUT-1 in distinguishing MM from RMC.Methods: A systematical search was conducted until May 2019 in PubMed, Medline, Embase and the Cochrane Library. The revised tool for the quality assessment of diagnostic accuracy studies (QUADAS-2) was used to assess the quality of the eligible studies. The Stata15 and Review Manager5.3 software programmes were used to perform the meta-analysis.Results: A total of 24 studies, including 969 MM patients and 1080 RMC individuals were explored in the meta-analysis. The summary assessments revealed that the pooled sensitivity was 0.73 (95% CI, 0.62-0.81) and the pooled specificity was 0.95 (95% CI, 0.91-0.98). The area under the summary ROC curve (AUC) was 0.93 (95% CI: 0.91-0.95).Conclusions: GLUT-1 is highly accurate to distinguish MM from RMC.

Regioselective ß-Arylation of α-Angelica Lactone through Isomerization/Addition under Mild Conditions.

The conversion of biomass-based platform molecules into various high-value chemicals greatly promotes the utilization of renewable biomass resources. Herein, an example of Rh-catalyzed ß-arylation of levulinic-acid-derived α-angelica lactone was reported, providing the γ-lactone-structure products with high regioselectivity. Both arylboronic and alkenylboronic acids could be applied in this transformation. This reaction tolerated a variety of synthetically important functional groups. Moreover, the obtained γ-lactone products could be readily converted to high-value products such as 1,4-diols and γ-methoxy-carboxylates.

Rhodium(III)-Catalyzed Directed C-H Coupling with Methyl Trifluoroacrylate: Diverse Synthesis of Fluoroalkenes and Heterocycles.

An example of Rh-catalyzed C-H activation with methyl trifluoroacrylate for the synthesis of fluoroolefins and heterocycles (benzoindolizines) is reported. The types of products were determined by the directing group. The benzoindolizines and fluoroolefins were obtained by using pyridine and pyrazole as the directing group, correspondingly. These transformations present a number of advantages, such as oxidant-free reaction conditions and broad functional group tolerance. Moreover, this reaction greatly extends the application of fluoroolefins.

Copper-Catalyzed Alkynylboration of Alkenes with Diboron Reagents and Bromoalkynes.

An efficient method for the synthesis of homopropargylboronates by copper-catalyzed alkynylboration of alkenes with diboron reagents and bromoalkynes has been developed. The alkynylboration reaction features high selectivity and efficiency, mild reaction conditions, wide substrate scope, and functional-group compatibility, and is a highly attractive complement to existing methods for the synthesis of homopropargylboronates. Both the boryl and alkynyl groups are good potential functional groups for the subsequent manipulations that provide access to a variety of important molecule structures.

SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression.

Blocking the oncoprotein murine double minute 2 (MDM2)-p53 protein-protein interaction has long been considered to offer a broad cancer therapeutic strategy, despite the potential risks of selecting tumors harboring p53 mutations that escape MDM2 control. In this study, we report a novel small-molecule inhibitor of the MDM2-p53 interaction, SAR405838 (MI-77301), that has been advanced into phase I clinical trials. SAR405838 binds to MDM2 with K(i) = 0.88 nmol/L and has high specificity over other proteins. A cocrystal structure of the SAR405838:MDM2 complex shows that, in addition to mimicking three key p53 amino acid residues, the inhibitor captures additional interactions not observed in the p53-MDM2 complex and induces refolding of the short, unstructured MDM2 N-terminal region to achieve its high affinity. SAR405838 effectively activates wild-type p53 in vitro and in xenograft tumor tissue of leukemia and solid tumors, leading to p53-dependent cell-cycle arrest and/or apoptosis. At well-tolerated dose schedules, SAR405838 achieves either durable tumor regression or complete tumor growth inhibition in mouse xenograft models of SJSA-1 osteosarcoma, RS4;11 acute leukemia, LNCaP prostate cancer, and HCT-116 colon cancer. Remarkably, a single oral dose of SAR405838 is sufficient to achieve complete tumor regression in the SJSA-1 model. Mechanistically, robust transcriptional upregulation of PUMA induced by SAR405838 results in strong apoptosis in tumor tissue, leading to complete tumor regression. Our findings provide a preclinical basis upon which to evaluate SAR405838 as a therapeutic agent in patients whose tumors retain wild-type p53.

A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice.

We previously reported the discovery of a class of spirooxindoles as potent and selective small-molecule inhibitors of the MDM2-p53 interaction (MDM2 inhibitors). We report herein our efforts to improve their pharmacokinetic properties and in vivo antitumor activity. Our efforts led to the identification of 9 (MI-888) as a potent MDM2 inhibitor (Ki = 0.44 nM) with a superior pharmacokinetic profile and enhanced in vivo efficacy. Compound 9 is capable of achieving rapid, complete, and durable tumor regression in two types of xenograft models of human cancer with oral administration and represents the most potent and efficacious MDM2 inhibitor reported to date.

Diastereomeric spirooxindoles as highly potent and efficacious MDM2 inhibitors.

Small-molecule inhibitors that block the MDM2-p53 protein-protein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment. We previously published a series of spirooxindole-containing compounds as a new class of MDM2 small-molecule inhibitors. We report herein a reversible ring-opening-cyclization reaction for some of these spirooxindoles, which affords four diastereomers from a single compound. Our biochemical binding data showed that the stereochemistry in this class of compounds has a major effect on their binding affinities to MDM2, with >100-fold difference between the most potent and the least potent stereoisomers. Our study has led to the identification of a set of highly potent MDM2 inhibitors with a stereochemistry that is different from that of our previously reported compounds. The most potent compound (MI-888) binds to MDM2 with a Ki value of 0.44 nM and achieves complete and long-lasting tumor regression in an animal model of human cancer.

Preclinical pharmacokinetics of MI-219, a novel human double minute 2 (HDM2) inhibitor and prediction of human pharmacokinetics.

PURPOSE: The two purposes of this study were evaluating preclinical pharmacokinetics of MI-219 and predicting clearance (CL) and volume of distribution at steady-state (Vdss) of MI-219 in humans. METHODS: Pharmacokinetic studies were conducted on mice, rats, dogs, and monkeys. Human CL of MI-219 was predicted using allometric scaling (SA), multi-exponential allometric scaling (ME), rule of exponents (RoE), single species scaling, two-term power equation (TTPE), physiologically based in vitro-in vivo extrapolation (IVIVE), and fu corrected intercept method (FCIM). In vitro assays were conducted to determine in vitro intrinsic CL, protein binding, and blood-plasma partition coefficients. To estimate half-life of MI-219, plasma concentration-time profile in humans was predicted using kallynochron and apolysichron time transformation (Dedrick plots) and normalization with MRT and Vdss (Wajima's method). In addition, simultaneous interspecies scaling of CL, Vdss and concentration-time profile were performed by using Nonlinear Mixed Effects Modeling (NONMEM). RESULTS: Preclinical studies showed that the elimination of MI-219 was mainly through metabolism. The validation using observed monkey CL and Vdss showed that MA, IVIVE and Oie-Tozer methods were accurately than the other methods. Human CL of MI-219 predicted by ME and IVIVE was between 0.237-0.342 L*h⁻¹*kg⁻¹. Human Vdss predicted by Oie-Tozer method and allometric scaling of unbound volume of distribution of tissues (VT/fuT) method was between 0.93-1.40 L*kg⁻¹. Superimposition of rat, monkey and dog data was observed in Dedrick plots and Wajima's transformations. CONCLUSIONS: The predicted human pharmacokinetics is useful for the design of first-in-human study.

Couple dynamics: PPARγ and its ligand partners.

Ligand-regulated transcriptional activity is the most important property of nuclear receptors, including PPARγ. In this issue of Structure, Hughes et al. determined how the dynamic conformations of ligands and the receptor contribute to the degree of ligand-dependent activation of PPARγ, which provide further insights into design of PPARγ-based anti-diabetic drugs.

Studies on the structure-activity relationship of 1,3,3,4-tetra-substituted pyrrolidine embodied CCR5 receptor antagonists. Part 2: Discovery of highly potent anti-HIV agents.

Modification of 1,3,3,4-tetra-substituted pyrrolidine embodied CCR5 receptor antagonists revealed that introducing a fluoro group at the 3-position of the 3-phenyl group to reduce metabolism did not adversely affect the high potency against HIV infection, and that replacing the piperidine ring with a tropane ring could deliver the most potent anti-HIV agents. Stereochemistry of the substituted tropane ring is essential for maintaining the potent anti-HIV activity because only exo-isomers displayed subnanomolar whole cell activity.

Studies on the structure-activity relationship of 1,3,3,4-tetra-substituted pyrrolidine embodied CCR5 receptor antagonists. Part 1: Tuning the N-substituents.

A novel series of CCR5 antagonists has been identified, utilizing the lead, nifeviroc, which were further modified based on bioisosteric principles. Lead optimization was pursued by balancing potential toxicity and potency. Potent analogues with low toxic properties were successfully developed by formation of urea and amide bonds at the nitrogen at position 4- of the pyrrolidine ring.

Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction.

We report herein the design of potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. Compound 5 binds to MDM2 with a K(i) of 0.6 nM, activates p53 at concentrations as low as 40 nM, and potently and selectively inhibits cell growth in tumor cells with wild-type p53 over tumor cells with mutated/deleted p53. Compound 5 has a good oral bioavailability and effectively inhibits tumor growth in the SJSA-1 xenograft model.

Synthesis and biological evaluation of 1,3,3,4-tetrasubstituted pyrrolidine CCR5 receptor antagonists. Discovery of a potent and orally bioavailable anti-HIV agent.

A series of 1,3,3,4-tetrasubstituted pyrrolidine containing CCR5 receptor antagonists were designed, which were elaborated either by condensation of a lithium salt of 3-(N,N-dibenzyl)aminopropionic acid methyl ester with ethyl benzoformate or by Baylis-Hillman reaction of ethyl acrylate with ethyl benzoformate and subsequent 1,4-addition of benzylamine, in the key steps. These compounds bearing 4-(N,N-disubstituted)amino piperidine units showed low nanomolar potency against the CCR5 receptor, whereas molecules with a 4-phenylpiperidine moiety displayed poor activity. Asymmetric synthesis of the most potent compound 23 a gave rise to the (3R,4S)-enantiomer 30 and the (3S,4R)-enantiomer 31, which showed IC(50) values of 2.9 and 385.9 nM, respectively. These results indicated that (3R,4S)-configuration in the series of compounds is favored for their interaction with the CCR5 receptor. The possible binding mode of these antagonists with the CCR5 receptor was discussed using a computer-modeling method. Compound 30 displayed excellent replication inhibition of seven genetically diverse R5 HIV-1 strains in the PBMC model, in a concentration-dependent manner with EC(50) values ranging from 0.3 nM to 30 nM. This molecule showed oral bioavailabilities of 41.2 % and 21.6 % in rats and dogs, respectively. Thus, compound 30 is a promising candidate for the treatment of HIV-1 infection.

Total synthesis of clavepictines A and B and pictamine.

[Structure: see text] A short route for assembling clavepictines A and B and pictamine is described, which features elaboration of its trisubstituted piperidine moiety via condensation of a beta-keto sulfone with an l-alanine-derived bromide and subsequent alkylative cyclization and construction of its quinolizidine skeleton via a diastereoselective intramolecular conjugate addition. The possible stereochemical course for this conjugate addition is discussed.

A one-pot formal [4 + 2] cycloaddition approach to substituted piperidines, indolizidines, and quinolizidines. total synthesis of indolizidine (-)-209I.

[reaction: see text] Heating a mixture of substituted N-benzyl gamma-chloropropylamines, conjugated alkynoates or alkynones, sodium carbonate, and a catalytic amount of sodium iodide in i-PrOH at 70-83 degrees C delivers substituted piperidines in good yields. This transformation goes through a cascade Michael addition/alkylation process and represents a facile one-pot formal [4 + 2] cycloaddition approach to piperidine ring. Using secondary cyclic gamma-chloropropylamines as substrates, this process produces substituted indolizidines or quinolizidines. On the basis of this approach, indolizidine (-)-209I is elaborated in 11 steps from methyl 2-hexenoate.