Synthesis of sulfinamides via photocatalytic alkylation or arylation of sulfinylamine.

Sulfinamides are a versatile class of compounds that find applications in both organic synthesis and pharmaceuticals. Here we developed an efficient photocatalytic approach for the convenient preparation of sulfinamides. Commercially available potassium trifluoro(organo)borates and readily available sulfinyl amines are rationally used and converted to a series of alkyl or aryl sulfinamides in moderate to high yields. The reaction allows for the gram-scale preparation of sulfinamides. Moreover, sulfonimidamides, sulfonimidate esters and sulfonyl amides could be obtained in one pot.

The aptamer-based RNA-PROTAC.

RNA-binding proteins (RBPs) dysfunction has been implicated in a number of diseases, and RBPs have traditionally been considered to be undruggable targets. Here, targeted degradation of RBPs is achieved based on the aptamer-based RNA-PROTAC, which consists of a genetically encoded RNA scaffold and a synthetic heterobifunctional molecule. The target RBPs can bind to their RNA consensus binding element (RCBE) on the RNA scaffold, while the small molecule can recruit E3 ubiquitin ligase to the RNA scaffold in a non-covalent manner, thereby inducing proximity-dependent ubiquitination and subsequent proteasome-mediated degradation of the target protein. Different RBPs targets, including LIN28A and RBFOX1, have been successfully degraded by simply replacing the RCBE module on the RNA scaffold. In addition, the simultaneous degradation of multiple target proteins has been realized by inserting more functional RNA oligonucleotides into the RNA scaffold.

One-Pot Tandem Oxidative Bromination and Amination of Sulfenamide for the Synthesis of Sulfinamidines.

The sulfinamidines as aza analogues of sulfinamides received limited attention from both organic chemists and pharmaceutical chemists. Herein, we present a tandem oxidative/nucleophilic substitution approach for the synthesis of sulfinamidines in high yield (up to 98%). This cascade reaction method is enabled by N-bromosuccinimide (NBS) as an oxidant and diverse readily available amines as nucleophiles without any additives or catalysts. Notably, this method is highly time-economical, safe to operate, and easy to scale up and has excellent functional group compatibility.

Synthesis of Sulfilimines via Selective S-C Bond Formation in Water.

Sulfilimines are valuable compounds both in organic synthesis and in pharmaceuticals. Here we developed a mild and simplified method for preparation of sulfilimines via selective S-C bond formation rather than traditional S-N bond formation. The method is both attractive and useful for the following reasons: it uses a readily available alkylation reagent such alkyl bromide or alkyl iodide, it uses water as solvent, it is easy to perform, and it is convenient for late-stage diversification of drugs.

Synthesis of Chiral Sulfonimidoyl Chloride via Desymmetrizing Enantioselective Hydrolysis.

Direct construction of chiral S(VI) from prochiral S(II) is a formidable challenge due to the inevitable formation of stable chiral S(IV). Previous synthetic strategies rely on the conversion of chiral S(IV) or enantioselective desymmetrization of preformed symmetrical S(VI) substrates. Here, we report desymmetrizing enantioselective hydrolysis of in situ-generated symmetric aza-dichlorosulfonium from sulfenamides for the preparation of chiral sulfonimidoyl chlorides, which could be used as a general stable synthon for obtaining a series of chiral S(VI) derivatives.

Chiral Primary Amine Catalyzed Enantioselective Tandem Reactions Based on Heyns Rearrangement: Synthesis of α-Tertiary Amino Ketones.

Herein, we disclose a new catalytic asymmetric tandem reaction based on the Heyns rearrangement for the synthesis of chiral α-amino ketones with readily available substrates. The rearrangement is different from the Heyns rearrangement in that the α-amino ketones were obtained without the shift of the carbonyl group. The key to success is using chiral primary amine as a catalyst by mimicking glucosamine-6-phosphate synthase in catalyzing the efficient Heyns rearrangement in organisms.

Chiral Phosphoric Acid Catalyzed Enantioselective Desymmetrization of 1,4-Dihydropyridines by C(sp3 )-H Bromination.

Described herein is the enantioselective synthesis of Hantzsch-type 1,4-dihydropyridines (DHPs), which are frequently contained in pharmaceuticals. Readily available symmetrical 1,4-DHPs were used as substrates, and the methyl group at the 2- or 6-position of the 1,4-DHP was selectively monobrominated by desymmetrizing enantioselective bromination. The inert C-H bond was converted into a versatile C-Br bond, which guaranteed the modification of the chiral 1,4-DHP derivatives with high efficiency. Furthermore, axially chiral 4-aryl pyridines were accessible by central-to-axial chirality conversion.

Preparation of Dihydronaphthofurans from α-Hydroxyl Ketones via a One-Pot Multicomponent Reaction Based on Heyns Rearrangement.

Polysubstituted 1,2-dihydronaphthofurans were efficiently obtained in high yields and good diastereoselectivities with readily available substrates. The reaction proceeds smoothly via a series of tandem reactions, including Heyns rearrangement, oxidation, Friedel-Crafts reaction, and cyclization. The high stereoselectivity of the reaction is ascribed to the activation of the imine via an intramolecular hydrogen bond. Air is directly used as the oxidation medium, which makes the reaction safe and easy to perform. Moreover, the reaction features multiple components, which ensures the diversity of products.

Catalytic asymmetric synthesis of N-substituted tetrahydroquinoxalines via regioselective Heyns rearrangement and stereoselective transfer hydrogenation in one pot.

N-Substituted tetrahydroquinoxalines (37 examples) were step-economically obtained in good yield (<97%) and ee (<99%) with readily available substrates. The reaction proceeds through an interesting regioselective Heyns rearrangement/enantioselective transfer hydrogenation in one pot. The substrate scope and the reaction mechanism were systematically investigated.

Regioselective, Diastereoselective, and Enantioselective One-Pot Tandem Reaction Based on an in Situ Formed Reductant: Preparation of 2,3-Disubstituted 1,5-Benzodiazepine.

The 1,5-benzodiazepines are important skeletons frequently contained in medicinal chemistry. Herein, we described an unexpected tandem cyclization/transfer hydrogenation reaction for obtaining chiral 2,3-disubstituted 1,5-benzodiazepines. The enolizable aryl aldehydes were chosen as substrates to react with symmetric and unsymmetric o-phenylenediamines. The unforeseen tandem reaction occurred among many possible latent side reactions under chiral phosphoric acid catalysis and affords the corresponding products in moderate yields and regioselectivities, good diastereoselectivities, and enantiomeric ratio (up to 99:1).

An organocatalytic asymmetric Friedel-Crafts reaction of 2-substituted indoles with aldehydes: enantioselective synthesis of α-hydroxyl ketones by low loading of chiral phosphoric acid.

Hydroxyl alkylation of indoles by Friedel-Crafts reaction with a carbonyl compound is a useful strategy. However, the reaction was restricted to ketones due to the easy formation of a bisindole byproduct. Therefore, hydroxyl alkylation of an aldehyde with indole is confronted with great challenges. Here, we report an efficient strategy for asymmetric hydroxyl alkylation of 2-substituted indoles with aldehydes under 0.1 mol% chiral phosphoric acid. A series of α-hydroxyl ketones were obtained in high yields (up to 99%) and good enantioselectivities (up to 97%).

Nrf2 knockout enhances intestinal tumorigenesis in Apc(min/+) mice due to attenuation of anti-oxidative stress pathway while potentiates inflammation.

Mutations in adenomatous polyposis coli (APC) gene are found in more than 80% of colorectal cancer (CRC) patients. The nuclear transcription factor Nrf2 plays a central role in the regulation of oxidative stress and inflammation. Previously, we have shown that chronic inflammation in Nrf2(-/-) (Nrf2 knockout; KO) mice resulted in higher expression of inflammatory markers and cytokines, coupled with higher inflammatory damage to the colonic crypt cells, as compared to the Nrf2(+/+) (wild type; WT) mice. Induction of mutation in the colon by administration of carcinogen, AOM prior to DSS-induced inflammation resulted in higher tumor incidence and numbers in Nrf2KO mice. These results indicate that Nrf2-dependent inhibition of inflammation appears to be critical in inhibiting mutation-initiated colorectal carcinogenesis. In this study, we aim to investigate if loss of Nrf2 would dose-dependently promote intestinal tumorigenesis in Apc(min/+) mice. To demonstrate the in vivo mechanisms, we constructed both Apc mutated and Nrf2 deficient strain Apc(min/+) mice with C57BL/6 Nrf2KO mice to obtain F1, Apc(min/+) ;Nrf2(+/-) and F2, Apc(min/+) ;Nrf2(-/-) mice. Nrf2KO decreased the protein expression of antioxidant enzyme NQO1 in Apc(min/+) . In contrast, Nrf2KO enhanced the expression of inflammatory markers such as COX-2, cPLA, LTB4 in Apc(min/+) . Finally, Nrf2KO resulted in higher level of PCNA and c-Myc expression in intestinal tissue, indicating the deficiency of Nrf2 promotes proliferation of intestinal crypt cells in Apc(min/+) . Taken together, our results suggest that Nrf2KO attenuates anti-oxidative stress pathway, induces inflammation, and increases proliferative potential in the intestinal crypts leading to enhanced intestinal carcinogenesis and adenomas in Apc(min/+) .

δ-tocopherol is more active than α - or γ -tocopherol in inhibiting lung tumorigenesis in vivo.

In contrast to strong epidemiologic, preclinical, and secondary clinical evidence for vitamin E (tocopherols) in reducing cancer risk, large-scale clinical cancer-prevention trials of α-tocopherol have been negative. This vexing contrast helped spur substantial preclinical efforts to better understand and improve the antineoplastic activity of tocopherol through, for example, the study of different tocopherol forms. We previously showed that the γ-tocopherol-rich mixture (γ-TmT) effectively inhibited colon and lung carcinogenesis and the growth of transplanted lung-cancer cells in mice. We designed this study to determine the relative activities of different forms of tocopherol in a xenograft model, comparing the anticancer activities of δ-tocopherol with those of α- and γ-tocopherols. We subcutaneously injected human lung cancer H1299 cells into NCr nu/nu mice, which then received α-, γ-, or δ-tocopherol or γ-TmT in the diet (each at 0.17% and 0.3%) for 49 days. δ-Tocopherol inhibited tumor growth most strongly. γ-Tocopherol and γ-TmT (at 0.3%) also inhibited growth significantly, but α-tocopherol did not. δ-Tocopherol also effectively decreased oxidative DNA damage and nitrotyrosine formation and enhanced apoptosis in tumor cells; again, γ-tocopherol also was active in these regards but less so, and α-tocopherol was not. Each supplemented diet increased serum levels of its tocopherol - up to 45 µmol/L for α-tocopherol, 9.7 µmol/L for γ-tocopherol, and 1.2 µmol/L for δ-tocopherol; dietary γ- or δ-tocopherol, however, decreased serum α-tocopherol levels, and dietary α-tocopherol decreased serum levels of γ-tocopherol. Each dietary tocopherol also increased its corresponding side-chain-degradation metabolites, with concentrations of δ-tocopherol metabolites greater than γ-tocopherol and far greater than α-tocopherol metabolites in serum and tumors. This study is the first in vivo assessment of δ-tocopherol in tumorigenesis and shows that δ-tocopherol is more active than α- or γ-tocopherol in inhibiting tumor growth, possibly through trapping reactive oxygen and nitrogen species and inducing apoptosis; δ-tocopherol metabolites could contribute significantly to these results.

Cancer prevention by tea: Evidence from laboratory studies.

The cancer preventive activities of tea (Camellia sinensis Theaceae) have been studied extensively. Inhibition of tumorigenesis by green tea extracts and tea polyphenols has been demonstrated in different animal models, including those for cancers of the skin, lung, oral cavity, esophagus, stomach, small intestine, colon, bladder, liver, pancreas, prostate, and mammary glands. Many studies in cell lines have demonstrated the modulation of signal transduction and metabolic pathways by (-)-epigallocatechin-3-gallate (EGCG), the most abundant and active polyphenol in green tea. These molecular events can result in cellular changes, such as enhancement of apoptosis, suppression of cell proliferation, and inhibition of angiogenesis. Nevertheless, the molecular mechanisms of inhibition of carcinogenesis in animals and humans remain to be further investigated. Future research directions in this area are discussed.

Rapid induction of colon carcinogenesis in CYP1A-humanized mice by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and dextran sodium sulfate.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant heterocyclic amine produced during the cooking of meats and fish, is suspected to be a human carcinogen. Metabolic activation of PhIP is primarily mediated by the enzyme cytochrome P450 (CYP) 1A2. Metabolism of PhIP by CYP1A2 differs considerably between humans and rodents, with more N(2)-hydroxylation (activation) and less 4'-hydroxylation (detoxication) in humans. Transgenic CYP1A-humanized mice (hCYP1A-mice), which have the human CYP1A1 and CYP1A2 genes but lack the murine orthologs Cyp1a1 and Cyp1a2, provide an excellent opportunity to develop a relevant model to study dietary-induced colon carcinogenesis. The treatment with 200 mg/kg PhIP by oral gavage, followed by 1.5% dextran sodium sulfate (DSS) in the drinking water for 7 days, was found to be an effective combination to induce colon carcinogenesis in hCYP1A-mice. Tumor multiplicity at week 6 was calculated to be 3.75 ± 0.70 and for week 10 was 3.90 ± 0.61 with 80-95% of the tumors being adenocarcinomas. No tumors were found in the similarly treated wild-type mice. Western blots revealed overexpression of ß-catenin, c-Myc, cyclin D1, inducible nitric oxide synthase and cyclooxygenase-2 in colon tumor samples. Strong nuclear localization of ß-catenin was observed in tumors. These results illustrate that PhIP and DSS combination produces rapid colon carcinogenesis in hCYP1A-mice and this is an effective model to mimic human colon carcinogenesis.

Inhibition of inflammation and carcinogenesis in the lung and colon by tocopherols.

Tocopherols, which exist in alpha, beta, gamma, and delta forms, are antioxidative nutrients also known as vitamin E. Although alpha-tocopherol (alpha-T) is the major form of vitamin E found in the blood and tissues, gamma- and delta-T have been suggested to have stronger anti-inflammatory activities. In the present study, using a tocopherol mixture that is rich in gamma-T (gamma-TmT, which contains 57%gamma-T), we demonstrated the inhibition of inflammation as well as of cancer formation and growth in the lung and colon in animal models. When given in the diet at 0.3%, gamma-TmT inhibited chemically induced lung tumorigenesis in the A/J mice as well as the growth of human lung cancer cell H1299 xenograft tumors. gamma-TmT also decreased the levels of 8-hydroxydeoxyguanosine, gamma-H2AX, and nitrotyrosine in tumors. More evident anti-inflammatory and cancer preventive activities of dietary gamma-TmT were demonstrated in mice treated with azoxymethane and dextran sulfate sodium. These results demonstrate the antioxidative, anti-inflammatory, and anticarcinogenic activities of tocopherols.

Pro-oxidative activities and dose-response relationship of (-)-epigallocatechin-3-gallate in the inhibition of lung cancer cell growth: a comparative study in vivo and in vitro.

(-)-Epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, has been shown to inhibit tumorigenesis and cancer cell growth in animal models. Nevertheless, the dose-response relationship of the inhibitory activity in vivo has not been systematically characterized. The present studies were conducted to address these issues, as well as the involvement of reactive oxygen species (ROS), in the inhibitory action of EGCG in vivo and in vitro. We characterized the inhibitory actions of EGCG against human lung cancer H1299 cells in culture and in xenograft tumors. The growth of tumors was dose dependently inhibited by EGCG at doses of 0.1, 0.3 and 0.5% in the diet. Tumor cell apoptosis and oxidative DNA damage, assessed by the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and phosphorylated histone 2A variant X (gamma-H2AX), were dose dependently increased by EGCG treatment. However, the levels of 8-OHdG and gamma-H2AX were not changed by the EGCG treatment in host organs. In culture, the growth of viable H1299 cells was dose dependently reduced by EGCG; the estimated concentration that causes 50% inhibition (IC(50)) (20 microM) was much higher than the IC(50) (0.15 microM) observed in vivo. The action of EGCG was mostly abolished by the presence of superoxide dismutase (SOD) and catalase, which decompose the ROS formed in the culture medium. Treatment with EGCG also caused the generation of intracellular ROS and mitochondrial ROS. Although EGCG is generally considered to be an antioxidant, the present study demonstrates the pro-oxidative activities of EGCG in vivo and in vitro in the described experimental system.

A gamma-tocopherol-rich mixture of tocopherols inhibits chemically induced lung tumorigenesis in A/J mice and xenograft tumor growth.

The present study investigated the effects of a preparation of a gamma-tocopherol-rich mixture of tocopherols (gamma-TmT) on chemically induced lung tumorigenesis in female A/J mice and the growth of H1299 human lung cancer cell xenograft tumors. In the A/J mouse model, the lung tumors were induced by either 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; intraperitoneal injections with 100 and 75 mg/kg on Week 1 and 2, respectively) or NNK plus benzo[a]pyrene (B[a]P) (8 weekly gavages of 2 mumole each from Week 1 to 8). The NNK plus B[a]P treatment induced 21 tumors per lung on Week 19; dietary 0.3% gamma-TmT treatment during the entire experimental period significantly lowered tumor multiplicity, tumor volume and tumor burden (by 30, 50 and 55%, respectively; P < 0.05). For three groups of mice treated with NNK alone, the gamma-TmT diet was given during the initiation stage (Week 0 to 3), post-initiation stage (Week 3 to 19) or the entire experimental period, and the tumor multiplicity was reduced by 17.8, 19.7 or 29.3%, respectively (P < 0.05). gamma-TmT treatment during the tumor initiation stage or throughout the entire period of the experiment also significantly reduced tumor burden (by 36 or 43%, respectively). In the xenograft tumor model of human lung cancer H1299 cells in NCr-nu/nu mice, 0.3% dietary gamma-TmT treatment significantly reduced tumor volume and tumor weight by 56 and 47%, respectively (P < 0.05). In both the carcinogenesis and tumor growth models, the inhibitory action of gamma-TmT was associated with enhanced apoptosis and lowered levels of 8-hydroxydeoxyguanine, gamma-H2AX and nitrotyrosine in the tumors of the gamma-TmT-treated mice. In cell culture, the growth of H1299 cells was inhibited by tocopherols with their effectiveness following the order of delta-T > gamma-TmT > gamma-T, whereas alpha-T was not effective. These results demonstrate the inhibitory effect of gamma-TmT against lung tumorigenesis and the growth of xenograft tumors of human lung cancer cells. The inhibitory activity may be due mainly to the actions of delta-T and gamma-T.

Methyl-selenium compounds inhibit prostate carcinogenesis in the transgenic adenocarcinoma of mouse prostate model with survival benefit.

Chemoprevention of prostate cancer by second-generation selenium compounds in reference to selenomethionine holds strong promise to deal with the disease at the root. Here we used the transgenic adenocarcinoma mouse prostate (TRAMP) model to establish the efficacy of methylseleninic acid (MSeA) and methylselenocysteine (MSeC) against prostate carcinogenesis and to characterize potential mechanisms. Eight-week-old male TRAMP mice (C57B/6 background) were given a daily oral dose of water, MSeA, or MSeC at 3 mg Se/kg body weight and were euthanized at either 18 or 26 weeks of age. By 18 weeks of age, the genitourinary tract and dorsolateral prostate weights for the MSeA- and MSeC-treated groups were lower than for the control (P < 0.01). At 26 weeks, 4 of 10 control mice had genitourinary weight >2 g, and only 1 of 10 in each of the Se groups did. The efficacy was accompanied by delayed lesion progression, increased apoptosis, and decreased proliferation without appreciable changes of T-antigen expression in the dorsolateral prostate of Se-treated mice and decreased serum insulin-like growth factor I when compared with control mice. In another experiment, giving MSeA to TRAMP mice from 10 or 16 weeks of age increased their survival to 50 weeks of age, and delayed the death due to synaptophysin-positive neuroendocrine carcinomas and synaptophysin-negative prostate lesions and seminal vesicle hypertrophy. Wild-type mice receiving MSeA from 10 weeks did not exhibit decreased body weight or genitourinary weight or increased serum alanine aminotransferase compared with the control mice. Therefore, these selenium compounds may effectively inhibit this model of prostate cancer carcinogenesis.

Benzene-induced hematopoietic toxicity transmitted by AhR in wild-type mouse and nullified by repopulation with AhR-deficient bone marrow cells: time after benzene treatment and recovery.

Previously, we found an aryl hydrocarbon receptor (AhR)-transmitted benzene-induced hematotoxicity; that is, AhR-knockout (KO) mice did not show any hematotoxicity after benzene exposure [Yoon, B.I., Hirabayashi, Y., Kawasaki, Y., Kodama, Y., Kaneko, T., Kanno, J., Kim, D.Y., Fujii-Kuriyama, Y., Inoue, T., 2002. Aryl hydrocarbon receptor mediates benzene-induced hematotoxicity. Toxicol. Sci. 70, 150-156]. Furthermore, our preliminary study showed a significant attenuation of benzene-induced hematopoietic toxicity by AhR expression, when the bone marrow (BM) of mice was repopulated with AhR-KO BM cells [Hirabayashi, Y., Yoon, B.I., Li, G., Fujii-Kuriyama, Y., Kaneko, T., Kanno, J., Inoue, T., 2005a. Benzene-induced hematopoietic toxicity transmitted by AhR in the wild-type mouse was negated by repopulation of AhR deficient bone marrow cells. Organohalogen Comp. 67, 2280-2283]. In this study, benzene-induced hematotoxicity and its nullification by AhR-KO BM cells were further precisely reevaluated including the duration of the effect after benzene treatment and recovery after the cessation of exposure. Exposure routes, namely, intraperitoneal (i.p.) injection used in our previous study and intragastric (i.g.) administration used in this study, were also compared in terms of their toxicologic outcomes. From the results of this study, mice that had been lethally irradiated and repopulated with BM cells from AhR-KO mice essentially did not show any benzene-induced hematotoxicity. The AhR-KO BM cells nullified benzene-induced toxicities in notably different hematopoietic endpoints between the i.p. treatment and the i.g. treatment; however, the number of granulo-macrophage colony-forming unit in vitro (CFU-GM) was a common target parameter, the benzene-induced toxicity of which was nullified by the AhR-KO BM cells.