Electrochemical Synthesis of Vinyl, Alkyl, and Allyl Sulfones from Sodium Sulfinates and Olefins.

An electrochemical synthesis of vinyl, alkyl, and allyl sulfones using sodium sulfinates and olefins was reported. This method uses direct current to pass through an undivided cell equipped with graphite carbon electrodes, and a series of diverse sulfone compounds can be synthesized at room temperature in high yields.

A Recyclable Electrochemical Reduction of Aldehydes and Ketones to Alcohols Using Water as the Hydrogen Source and Solvent.

There are several challenging problems such as the usage of combustible and hazardous hydrogen sources and severe environmental pollution in the conventional reduction of aldehydes/ketones to alcohols. We report here a practical, safe, and green electrochemical reduction, which solves these problems to a large extent. Through an undivided cell, Zn(+) and Sn(-) as the electrode, tetrabutylammonium chloride (TBAC) as the electrolyte, water as the solvent and hydrogen source, a wide range of aldehydes and ketones are converted into the corresponding alcohols in mild conditions. Furthermore, the electrolytes and water can be recycled, and reductive deuteration can be achieved by simply using D2O as the solvent. Finally, the reduction can be smoothly scaled up to a kilogram level.

Photoinduced Tandem Cyanomethylation/Cyclization of Unsaturated Compounds: Access to Cyanomethylated 7- or 5-Membered N-Heterocycles.

A cyanomethylation/cyclization of aryl acetylenes/ethylenes with bromoacetonitrile was finished in a photopromoted condition, which offers an efficient and mild protocol for the preparation of cyanomethylated 7- or 5-membered N-heterocycles with good yields. Meanwhile, trichloroacetonitrile was also compatible with this radical pathway. In addition, a variety of single-crystal X-ray diffraction measurements, scaled-up operations to 1 mmol, functional group transformations of final products, light on/off experiments, and even radial inhibition studies were smoothly performed in this tandem system.

Nitro-Spirocyclization of Biaryl Ynones with tert-Butyl Nitrite: Access to NO2-Substituted Spiro[5,5]trienones.

A metal/peroxide-free involved simple cascade 6-exo-trig spirocyclization of tert-butyl nitrite with biaryl ynones has been finished, which resulted in various NO2-modified spiro[5,5]trienones with good regioselectivity/yields. A variety of scaled-up experiments, reduction/epoxidation operations, and mechanistic studies were performed to verify the merits and spirocyclization process of this radical system. Finally, the structure of the spirocycles was confirmed by single-crystal X-ray diffraction.

Electrochemical Aerobic Oxidative Cleavage of (sp3)C-C(sp3)/H Bonds in Alkylarenes.

An electrochemistry-promoted oxidative cleavage of (sp3)C-C(sp3)/H bonds in alkylarenes was developed. Various aryl alkanes can be smoothly converted into ketones/aldehydes under aerobic conditions using a user-friendly undivided cell setup. The features of air as oxidant, scalability, and mild conditions make them attractive in synthetic organic chemistry.

Free Radical Promoted Trifluoromethylthiolation of Alkynes to Access SCF3-Containing Dibenzazepines or Dioxodibenzothiazepines.

Persulfate-promoted radical cascade trifluoromethylthiolation of aryl acetylenes with AgSCF3 provides a simple reaction system for the synthesis of SCF3-substituted dibenzazepines or dioxodibenzothiazepines with good Z/E selectivity. The single-crystal X-ray diffraction data confirms the structures of the final products. A series of scaled-up experiments, further transformations, and radical inhibition experiments were operated in the reaction system.

Advances in free-radical alkylation and arylation with organoboronic acids.

Organoboronic acids act as carbon-centered radical precursors that are widely utilized to construct diverse C-C bonds. This review summarizes the advances in this field. The content is divided into four parts according to the different categories of coupling partners with organoboronic acids. The reaction conditions as well as the mechanisms are demonstrated in each part.

Palladium-catalyzed C(sp3)-H nitrooxylation of masked alcohols.

A palladium-catalyzed ß-C(sp3)-H nitrooxylation of aliphatic alcohols with AgNO2 is reported. An 8-formylquinoline-derived oxime is installed as an exo-type directing group for sp3 C-H activation and selectfluor acts as the oxidant. The reaction tolerates a variety of functional groups and shows good selectivity for ß-C-H nitrooxylation of alcohols.

Relevance of gene polymorphisms of NAT2 and NR1I2 to anti-tuberculosis drug-induced hepatotoxicity.

The recommended treatment regimen for tuberculosis is a combination of agents with antitubercular activity, during which hepatotoxicity is one of the most common side effects. In addition to the N-acetyltransferase 2 (NAT2) genotype, rs3814055 in nuclear receptor subfamily 1, group I, member 2 (NR1I2) has been demonstrated to be associated with anti-tuberculosis drug-induced hepatotoxicity (ATDH), but previous results have been inconsistent.A retrospective nested hospital-based case-control study was performed to investigate the association between genetic polymorphisms and the risk of ATDH. Fifteen genetic variants (13 SNPs and two null genotypes) in cytochrome P450 2E1, NR1I2, UDP-glucuronosyltransferase 1A1, NAT2, superoxide dismutase 1, superoxide dismutase 2, and glutathione S-transferases (GSTT1, GSTM1, GSTP1) were genotyped. Odds ratios with 95% confidence intervals were calculated with drug doses, body mass index comorbidity of diabetes mellitus, and baseline alanine transaminase value as covariates.Conditional logistic regression demonstrated that the NAT2 slow acetylation genotype and the T allele of rs3814055 in NR1I2 may contribute to susceptibility to ATDH.Stratified association analysis demonstrated that in NAT2 non-slow acetylators, the T allele of rs3814055 was a risk factor for ATDH, whereas the T allele did not increase the susceptibility to ATDH in slow acetylators.

Free Radical-Promoted Monochloroalkylarylation of Alkenes with Chloralkanes.

Free radical-initiated cascade cyclization of unactivated alkenes with chloralkanes, which undergoes selective activation of the α-C(sp3)-H bond of chloralkanes, provides a protocol for the synthesis of chlorinated heterocycles or polycyclic compounds. A series of radical inhibition experiments, radical capture operations, and radical clock tests were studied in this system.

Factors related to HIV testing frequency in MSM based on the 2011-2018 survey in Tianjin, China: a hint for risk reduction strategy.

BACKGROUND: In recent years, HIV testing has become one of the effective strategies to reduce the risk of the infection. Frequent quarterly HIV testing can be cost effective. Therefore, an in-depth study of factors related to the testing behavior of men who have sex with men (MSM) were analyzed to optimize intervention strategies. METHODS: From March 2011 to October 2018, the project was implemented in a Tianjin (China) bathhouse, and 5165 MSM were surveyed using snowball sampling. Factors related to HIV testing behavior were analyzed by ordinal logistic regression analysis after grouping according to testing frequency, and comprehensive analysis was performed. RESULTS: The multivariate logistic analysis showed that 6 variables including young MSM (OR = 0.67, 95% CI: 0.49-0.92, p = 0.01), low-educated MSM (OR = 0.60, 95% CI: 0.48-0.77, p < 0.0001), low HIV/AIDS knowledge (95% CI: 0.57-0.83, p < 0.0001), marital status (OR = 1.30, 95% CI: 1.07-1.57, p = 0.007), acceptance of condom promotion and distribution (OR = 14.52, 95% CI: 12.04-17.51, p < 0.0001), and frequency of condom use (p < 0.05) could link to HIV testing behaviors. CONCLUSIONS: In order to achieve the 95-95-95 goal, target publicity, HIV/AIDS education and promotion of HIV self-testing kits should be carried out to encourage frequent HIV testing among MSM who are young (especially students), married to women, poorly educated and who are reluctant to always use condoms.

Effect of availability of HIV self-testing on HIV testing frequency among men who have sex with men attending university in China (UniTest): protocol of a stepped-wedge randomized controlled trial.

BACKGROUND: HIV testing plays a central role in the combat against HIV. We aimed to determine if the availability of HIV self-testing (HIVST) would increase the frequency of testing among men who have sex with men (MSM) attending university in China. METHODS: A stepped wedge randomized controlled trial will be conducted in 4 provinces in China: Chongqing, Guangdong, Shandong, and Tianjin. Eligibility assessment will include (1) male, aged 16 years or older, (2) university student (technical diploma and undergraduate students), (3) MSM (sexual behaviors including mutual masturbation, oral sex, and anal sex), (4) HIV negative, and (5) willing to provide informed consent. Participants will be randomly allocated to HIV self-testing intervention with free HIVST kits in every 30 days according to the intervention waiting lists with a computer-generated randomized sequence. All participants will complete a self-administrated online questionnaire onsite at baseline and 12-month follow-up and complete an online questionnaire at 4- and 8-month. The primary outcome is the effect of HIVST on HIV testing frequency. Secondary outcomes include the change in sexual behaviors and HIV incidence. DISCUSSION: No previous study had measured the effect of social media based HIVST intervention on the change in HIV testing behaviors, sexual behaviors and incident HIV infection among MSM attending university in China. Findings from this study will provide evidence for further interventional practice promotions and prevention strategies scale-up, including HIV testing, pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP), and sexual partner serosorting. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR1900020645. Registered 11 January 2019.

Identifying Regimens Containing TBI-166, a New Drug Candidate against Mycobacterium tuberculosis In Vitro and In Vivo.

TBI-166, derived from riminophenazine analogues, is under development in a phase I clinical trial in China. TBI-166 showed more potent anti-tuberculosis (anti-TB) activity than did clofazimine in in vitro and animal experiments. To identify potent regimens containing TBI-166 in TB chemotherapy, TBI-166 was assessed for pharmacological interactions in vitro and in vivo with several anti-TB drugs, including isoniazid (INH), rifampin (RFP), bedaquiline (BDQ), pretomanid (PMD), linezolid (LZD), and pyrazinamide (PZA). Using an in vitro checkerboard method, we found that TBI-166 did not show antagonism or synergy with the tested drugs. The interaction relationship between TBI-166 and each drug was indifferent. In in vivo experiments, aerosol infection models with BALB/c and C3HeB/FeJNju mice were established, testing drugs were administered either individually or combined in treatments containing TBI-166 and one, two, or three other drugs, and the bactericidal activities were determined after 4- and 8-week therapeutic treatments. In BALB/c mice, five TBI-166-containing regimens-TBI-166+BDQ, TBI-166+PZA, TBI-166+BDQ+LZD, TBI-166+BDQ+PMD, and TBI-166+BDQ+PMD+LZD-showed significantly more potent efficacy after 4 weeks of treatment compared to the control regimen, INH+RFP+PZA. At the end of an 8-week treatment, lung log CFU counts decreased to undetectable levels in mice treated with each of the five regimens. The rank order of the potency of the five regimens was as follows: TBI-166+BDQ+LZD > TBI-166+BDQ > TBI-166+PZA > TBI-166+BDQ+PMD+LZD > TBI-166+BDQ+PMD. In C3HeB/FeJNju mice, TBI-166+BDQ+LZD was also the most effective of the TBI-166-containing regimens. In conclusion, five potent chemotherapy regimens that included TBI-166 were identified. The TBI-166+BDQ+LZD regimen is recommended for further testing in a TBI-166 phase IIb clinical trial.

Atom-Transfer Radical Addition of Alcohols to Aliphatic Alkynes.

An intermolecular hydrogen bond-promoted atom-transfer radical addition of simple alcohols to aliphatic alkynes is demonstrated here. Through this strategy, a variety of allyl alcohols can be synthesized in high selectivity and yields. Furthermore, this work reveals the relationship between selectivity and the substrate.

Sesquiterpenoids from the roots of Inula helenium inhibit acute myelogenous leukemia progenitor cells.

One new eudesmane sesquiterpenoid, 11ß-hydroxy-13-chloro-eudesm-5-en-12, 8-olide (1), was isolated from the roots of Inula helenium together with nine eudesmanolides (2-10) and one germacranolide (11). Their structures were elucidated on the basis of detailed spectroscopic analyses. All isolates were evaluated for their antiproliferative activities against human leukemia stem-like cell line KG1a. Compound 10 exhibited the most potent effect with the IC50 value of 3.36 ±â€¯0.18 µM. A further investigation revealed that compound 10 could significantly induce apoptosis of KG1a cells. Additionally, compound 10 had an obvious effect on the levels of apoptosis-related proteins (Bcl-2, Bax, cytochrome c, caspase 9 and caspase 3), indicating that the antiproliferative effect of compound 10 on KG1a cells might be mediated through a mitochondria-dependent apoptotic pathway.

Discovery of aromatic amides with triazole-core as potent reversal agents against P-glycoprotein-mediated multidrug resistance.

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major impediment for clinical cancer therapy. 19 novel aromatic amides with triazole-core as MDR reversal agents were designed and synthesized via click chemistry to reverse MDR. Among them, compound 42 was identified as the most promising candidate with high potency (EC50 = 78.1 ±â€¯5.4 nM), low cytotoxity (SI > 1282) and persistent duration in reversing doxorubicin (DOX) resistance in K562/A02 cells. 42 also enhanced the potency of other P-gp associated cytotoxic agents with different structures. In further study, remarkably increased intracellular accumulation of Rh123 and DOX in K562/A02 cells was achieved by compound 42, while CYP3A4 activity had no change by compound 42. These results indicate that compound 42 as a relatively safe modulator of P-gp-mediated MDR has good potential for further development.

Design and synthesis of parthenolide-SAHA hybrids for intervention of drug-resistant acute myeloid leukemia.

A series of parthenolide-SAHA hybrids were synthesized and evaluated for their anti-AML activities against HL-60 and HL-60/ADR cell lines. The most active compound 26 exhibited high activity against HL-60/ADR cell line with IC50 value of 0.15 µM, which demonstrated 16.8-fold improvement compared to that of the parent compound PTL (IC50 = 2.52 µM). Moreover, it was six times more potent than the reference drug SAHA (IC50 = 0.90 µM) and fifty-one times more potent than ADR (IC50 = 7.72 µM). The preliminary molecular mechanism of 26 indicated that compound 26 could significantly induce apoptosis of HL-60/ADR cells. The effect of compound 26 was mainly through mitochondria pathway. Further investigation revealed that the protein level of HDAC1 and HDAC6 were reduced after the treatment of compound 26 with a dose-dependent manner. Compound 26 could significantly decrease ABCC1 expression, which increased the accumulation of intracellular drug for overcoming the drug resistance. On the base of these results, compound 26 might be considered as a promising candidate for further evaluation as a potential anti-AML drug.

Molecular Oxygen-Promoted General and Site-Specific Alkylation with Organoboronic Acid.

A general alkylating method using organoboronic acid under 1 atm of oxygen is developed. It allows a facile access to a wide range of functionalized molecules with privileged scaffolds in drugs and natural products such as oxindoles, quinolinones, chromones, naphthoquinones, coumarins, and quinolones. In contrast to previous alkylation approaches that generally requiring transition-metal catalysis and a stoichiometric chemical oxidant, the present strategy features metal-free, molecular oxygen as the terminal oxidant and site specificity.

Synthesis of Cucurbitacin B Derivatives as Potential Anti-Hepatocellular Carcinoma Agents.

Cucurbitacin B shows potent activity against tumor cells, but its high toxicity limits its application in the clinic. A series of cucurbitacin B derivatives was synthesized and evaluated for their anti-hepatocellular carcinoma (HCC) activities against the HepG-2 cell line. These compounds were also tested for their toxicity against the L-O2 normal cell line. The compound with the most potential, 10b, exhibited potent activity against the HepG-2 cell line with an IC50 value of 0.63 µM. Moreover, compound 10b showed the highest TI value (4.71), which is a 14.7-fold improvement compared to its parent compound cucurbitacin B. A preliminary molecular mechanism study of 10b indicated that 10b could inhibit P-STAT3 to induce the activation of mitochondrial apoptotic pathways. An in vivo acute toxicity study indicated that the compound 10b has preferable safety and tolerability compared with cucurbitacin B. These findings indicate that compound 10b might be considered as a lead compound for exploring effective anti-HCC drugs.

Free-Radical Bromotrifluoromethylation of Olefin via Single-Electron Oxidation of NaSO2CF3 by NaBrO3.

A free-radical bromotrifluoromethylation of olefin by using NaSO2CF3 and NaBrO3 has been achieved. Sodium bromate acts not only as a single-electron oxidant but also as a bromine source. A radical-clock experiment and electron-spin-resonance detection support a radical process.