Enantioselective Cu-Catalyzed Nucleophilic Substitutions of Polyfluoroarenes: Synthesis of Chiral Polyfluoroaryl Diarylmethanes.

Optically pure diarylmethanes are frequently presented in pharmaceuticals and bioactive molecules. However, minor efforts have been devoted to chiral polyfluoroarene-containing diarylmethanes, and their synthesis is still challenging. Herein, we describe an enantioselective Cu/sulfoxide phosphine (SOP) catalyzed nucleophilic substitution reaction by using polyfluoroarenes as the polyfluoroaryl reagent. Under mild conditions, this protocol enables the efficient synthesis of chiral polyfluoroaryl diarylmethanes with fluorinated quaternary stereogenic center in good yields (up to 93%), high regioselectivties, and excellent enantioselectivities (up to 99% ee). Moreover, gram-scale experiments, product derivations, and late-stage diversifications were performed to demonstrate the utility of this method.

A Novel Method to Construct 2-Aminobenzofurans via [4 + 1] Cycloaddition Reaction of In Situ Generated Ortho-Quinone Methides with Isocyanides.

A new approach for the synthesis of 2-aminobenzofurans has been described via Sc(OTf)3 mediated formal cycloaddition of isocyanides with the in situ generated ortho-quinone methides (o-QMs) from o-hydroxybenzhydryl alcohol. Notably, as a class of readily available and highly active intermediates, o-QMs were first used in the construction of benzofurans. This [4 + 1] cycloaddition reaction provides a straightforward and efficient methodology for the construction of 2-aminobenzofurans scaffold in good yield (up to 93% yield) under mild conditions.

Enantioselective Cu-Catalyzed Nucleophilic Addition of Fluorinated Reagents: C-C Bond Formation for the Synthesis of Chiral Vicinal Difluorides.

Herein we described the first enantioselective Cu/sulfoxide phosphine (SOP) complex catalyzed nucleophilic addition of fluorinated enolates to gem-difluoroalkenes. The enantioenriched vicinal difluorides, containing a chiral tertiary fluoride and a fluoroalkene, were successfully afforded via C-C bond formation in good yields (up to 94% yield), high Z/E-selectivity (5:1 → 50:1 for Z-isomer), and excellent enantioselectivities (up to 98.5:1.5 er). Utility of this approach was demonstrated by modification of complex biologically active compounds.

Enantioselective Copper-Catalyzed Electrophilic Sulfenylation of Cyclic Imino Esters.

Herein we report an enantioselective sulfenylation of cyclic imino esters with the efficient and versatile sulfenylation reagent S-alkyl 4-methylbenzenesulfonothioates. By utilizing the Cu/tBu-Phosferrox catalytic system, we can assemble diverse S-alkyl groups into the cyclic imino esters under mild conditions in good yields and with excellent enantioselectivities. Remarkably, this method demonstrates a high tolerance of diverse functional groups and proves to be applicable in the late-stage functionalization of pharmaceuticals.

Associations of Prostate-Specific Antigen, Prostate Carcinoma Tissue Gleason Score, and Androgen Receptor Expression with Bone Metastasis in Patients with Prostate Carcinoma.

BACKGROUND Prostate carcinoma (PCa) is often not diagnosed until advanced disease with bone metastasis. Predictive factors for bone metastasis are required to improve patient outcomes. The study aimed to analyze the factors associated with bone metastases in newly diagnosed patients with PCa. MATERIAL AND METHODS This was a retrospective study of 80 patients newly diagnosed with PCa by pathological examination between January 2012 and December 2014. Bone metastases were diagnosed by positron emission computed tomography. Clinical data, serological laboratory results, and pathological examination results were collected. RESULTS Among the 80 patients, 45 (56%) had bone metastases. Age, serum alkaline phosphatase, prostate-specific antigen (PSA), erythrocyte sedimentation rate, PCa tissue Gleason score, androgen receptor (AR) expression, and Ki-67 expression were higher in patients with bone metastasis compared with those without (all P<0.05). Multivariate logistic regression showed that PSA (OR: 1.005; 95%CI: 1.001-1.010; P=0.016), Gleason score (OR: 4.095; 95%CI: 1.592-10.529; P=0.003), and AR expression (OR: 14.023; 95%CI: 3.531-55.6981; P=0.005) were independently associated with bone metastases. Cut-off values for PSA, Gleason score, and AR expression were 67.1 ng/ml (sensitivity: 55.6%; specificity: 97.1%), 7.5 (sensitivity: 75.6%; specificity: 82.9%), and 2.5 (sensitivity: 84.0%; specificity: 91.4%), respectively. CONCLUSIONS PSA, Gleason score, and AR expression in PCa tissues were independently associated with PCa bone metastases. These results could help identifying patients with PCa at high risk of bone metastases.

[Predictive factors for bone metastases of prostate cancer].

OBJECTIVE: To investigate the correlation between a diverse of clinical factors and bone metastases of prostate cancer. METHODS: The clinical data of 80 patients with prostate cancer were collected and analyzed. The correlations of age, alkaline phosphotase (ALP), prostate specific antigen (PSA), erythrocyte sedimentation rate (ESR), Gleason score, and expressions of androgen receptor (AR) and Ki-67 with bone metastases were analyzed by one-way ANOVA and Logistic regression analysis. The cutoff value, sensitivity and specificity of the independent correlation factors were calculated. RESULTS: Forty-five of the 80 patients (56%) were found to have bone metastasis, who had significantly older age and higher levels of ALP, PSA, ESR, Gleason score, and expressions of AR and Ki-67 than those without bone metastasis (P<0.05). Logistic regression analysis identified PSA, Gleason score and AR expression as independent factors correlated with bone metastasis with OR (95% CI) of 1.005 (1.001, 1.009) (P=0.008), 5.356 (1.431, 20.039) (P=0.013), and 18.594 (2.460, 140.524) (P=0.005), respectively. The cutoff values of PSA, Gleason Score and AR were 67.1 ng/ml, 7.5, and 2.5, respectively; their sensitivities were 55.6%, 75.6%, and 84.0% for predicting bone metastasis with specificities of 97.1%, 82.9%, and 91.4%, respectively. CONCLUSION: Of the factors analyzed, PSA, Gleason score and AR expression, but not age, ALP, PSA, ESR, or Ki-67 expression, are the predictive factors of bone metastasis of prostate cancer.

Comparison of long-term impact of immunosuppressants at therapeutic doses on hepatic function and histological changes in unilateral nephrectomized rats.

Cyclosporine, tacrolimus and sirolimus are commonly used in renal transplant recipients to prevent rejection. Various adverse effects of these agents on the multiple organ system have been reported clinically. However, animal studies are necessary to determine and compare these effects on individual organ given the presence of multiple confounding factors and multi-pharmacy in clinical settings. In a physiologically and clinically relevant rat model of unilateral nephrectomy, the long-term impacts of commonly used immunosuppressants at doses equivalent to the therapeutic levels used for post-renal transplant patients on hepatic function and histological changes of the liver were examined. Cyclosporine induced significant hepatocellular injury, impairment of synthetic function of the liver, hyperbilirubinemia and cholestasis, and dyslipidemia accompanied by profound histological changes of hepatic structures on both light and electron microscopic examinations. On the other hand, neither tacrolimus nor sirolimus developed any hepatotoxic effects except for more remarkable dyslipidemia was observed in animals treated with sirolimus. Our study indicates that long-term administration of commonly used immunosuppressants has various impacts on biochemical parameters as well as histological alterations of the liver even at therapeutic levels. These data may therefore provide useful information for judicious selection of immunosuppressive agents based on different clinical settings.

Long-term impact of immunosuppressants at therapeutic doses on male reproductive system in unilateral nephrectomized rats: a comparative study.

Cyclosporine, tacrolimus, and sirolimus are commonly used in renal transplant recipients to prevent rejection. However, information for comparative effects of these agents on the male productive system is extremely limited and controversial. In a physiologically and clinically relevant rat model of unilateral nephrectomy, we demonstrated that long-term oral administration of both cyclosporine and sirolimus at doses equivalent to the therapeutic levels used for postrenal transplant patients significantly affects testicular development and the hypothalamic-pituitary-gonadal axis accompanied by profound histological changes of testicular structures on both light and electron microscopic examinations. Spermatogenesis was also severely impaired as indicated by low total sperm counts along with reduction of sperm motility and increase in sperm abnormality after treatment with these agents, which may lead to male infertility. On the other hand, treatment with therapeutic dose of tacrolimus only induced mild reduction of sperm count without histological evidence of testicular injury. The current study clearly demonstrates that commonly used immunosuppressants have various impacts on male reproductive system even at therapeutic levels. Our data provide useful information for the assessment of male infertility in renal transplant recipients who wish to father children. Clinical trials to address these issues should be urged.

Approximately diagonalizing matrices over C(Y).

Let X be a compact metric space which is locally absolutely retract and let ϕ: C(X) → C(Y,M(n)) be a unital homomorphism, where Y is a compact metric space with dim Y ≤ 2. It is proved that there exists a sequence of n continuous maps α(i,m): Y → X (i = 1,2,…,n) and a sequence of sets of mutually orthogonal rank-one projections {p(1,m),p(2,m),…,p(n,m)} C(Y,M(n)) such that [see formula]. This is closely related to the Kadison diagonal matrix question. It is also shown that this approximate diagonalization could not hold in general when dim Y ≥ 3.