Gemfibrozil-Platinum(IV) Precursors for New Enhanced-Starvation and Chemotherapy In Vitro and In Vivo.

A brand-new enhanced starvation is put forward to trigger sensitized chemotherapy: blocking tumor-relation blood vessel formation and accelerating nutrient degradation and efflux. Following this concept, two cisplatin-like gemfibrozil-derived Pt(IV) prodrugs, GP and GPG, are synthesized. GP and GPG had nanomolar IC50 against A2780 cells and higher selectivity against normal cells than cisplatin. Bioactivity results confirmed that GP and GPG highly accumulated in cells and induced DNA damage, G2-phase arrest, and p53 expression. Besides, they could increase ROS and MDA levels and reduce mitochondrial membrane potential and Bcl-2 expression to promote cell apoptosis. In vivo, GP showed superior antitumor activity in A2780 tumor-bearing mice with no observable tissue damage. Mechanistic studies suggested that highly selective chemotherapy could be due to the new enhanced starvation effect: blocking vasculature formation via inhibiting the CYP2C8/EETs pathway and VEGFR2, NF-κB, and COX-2 expression and cholesterol efflux and degradation acceleration via increasing ABCA1 and PPARα.

Timing umbilical therapy in treatment of neurogenic bladder after spinal cord injury based on midnight-noon and ebb-flow doctrine: a randomized controlled trial / 中国针灸

OBJECTIVES@#To observe the clinical efficacy of timing umbilical therapy for neurogenic bladder after spinal cord injury based on the midnight-noon and ebb-flow doctrine.@*METHODS@#Sixty patients with neurogenic bladder after spinal cord injury were randomly divided into a trial group and a control group, with 30 patients in each group. In the trial group, based on the midnight-noon and ebb-flow doctrine, umbilical therapy was given at the time zone, 15:00 to 17:00. In the control group, umbilical therapy was delivered at any time zones except the period 15:00 to 17:00. The herbal plaster was remained on the umbilicus for 4 h each time, once daily. One course of treatment was composed of 2 weeks and the treatment lasted 4 weeks. Before and after treatment, the urodynamic indexes (maximum urinary flow rate [Qmax], maximum detrusor pressure [Pdet-max], residual urine volume [RUV]), voiding diary (average daily number of voiding, average daily number of leakage, average daily voided volume), neurogenic bladder symptom score (NBSS), the score of urinary symptom distress scale (USDS) and the score of World Health Organization quality of life assessment-BREF (WHOQOL-BREF) were compared between the two groups; and the clinical efficacy of the two groups was assessed.@*RESULTS@#After treatment, Qmax, Pdet-max, the average daily voided volume and the scores of WHOQOL-BREF were increased (P<0.05); and RUV, the average daily number of voiding, the average daily number of leakage, NBSS and the scores of USDS were all reduced (P<0.05) in comparison with those before treatment in the two groups. When compared with those in the control group, Qmax, Pdet-max, the average daily voided volume and the score of WHOQOL-BREF were all higher (P<0.05); and RUV, the average daily number of voiding, the average daily number of leakage, NBSS and the score of USDS were lower (P<0.05) in the trial group. The total effective rate was 96.7% (29/30) in the trial group, higher than that (76.7%, 23/30) in the control group (P<0.05).@*CONCLUSIONS@#Timing umbilical therapy, based on the midnight-noon and ebb-flow doctrine, effectively relieves the symptoms of dysuria and improves the quality of life in patients with neurogenic bladder after spinal cord injury.

Enantioselective Synthesis of Fused Butyrolactones via Organocatalytic Formal [2 + 2 + 2] Annulation of γ-Butenolides, Methylene Indolinones, and Nitroolefins.

An organocatalyzed asymmetric synthesis of fused butyrolactones via formal [2 + 2 + 2] annulation between γ-butenolides, methylene indolinones, and nitroolefins in a one-pot process has been established. Products containing six contiguous stereocenters could be obtained in good yields (up to 95%) with excellent enantioselectivities (up to >99% ee) catalyzed by a l-tert-leucine-derived bifunctional thiourea catalyst.

Asymmetric Organocatalytic Access to Spiro-fused Heterocyclic Compounds: E1cB Elimination Mediates Formal [4 + 2] Annulation.

Based on the intramolecular E1cB elimination, a novel [4 + 2] cyclization was designed and successfully applied to the asymmetric synthesis of polycyclic compounds which contained both chromane and spirooxindole moieties. In the reaction, regardless of the competitive pathways resulting from multireactive sites of starting materials, products could be obtained in good yields (up to 84%) and with excellent enantioselectivities (most 98 to >99% ee) under the catalysis of a chiral bifunctional thiourea-tertiary amine (1-5 mol %).

Application of E1cB Elimination in Asymmetric Organocatalytic Cascade Reactions To Construct Polyheterocyclic Compounds.

By introducing a carbon functionality at 2-position of chromane, the formal asymmetric functionalization of the 3-position of 2-substituted chromane has been realized via a highly chemo-, regio-, and stereoselective organocatalytic cascade reaction in a sequential one-pot manner involving an E1cB mechanism governed ring-opening process. Critical to our success was the design of a chiral dipeptide-based bifunctional acid-base organocatalyst, which exhibited high catalytic activity at low catalyst loading (1-0.1 mol %), leading to biologically interesting polyheterocyclic compounds.

Asymmetric Organocatalyzed Reaction Sequence To Synthesize Chiral Bridged and Spiro-Bridged Benzofused Aminals via Divergent Pathways.

A highly efficient asymmetric organocatalysis-triggered reaction sequence is developed. 2-Hydroxy cinnamaldehydes and cyclic N-sulfonyl ketimines were both used as multisite substrates (more than two reactive sites) to access structurally diverse chiral bridged and spiro-bridged benzofused aminal derivatives, where an inseparable equilibrating mixture of isomers can be regioselectively converted into bridged benzofused aminals with different ring connectivities via divergent pathways. Several stereoselective transformations of the resulted bridged aminals are presented.

Organocatalytic Asymmetric Synthesis of Spiro-Bridged and Spiro-Fused Heterocyclic Compounds Containing Chromane, Indole, and Oxindole Moieties.

Following the reactivity inversion strategy, two different two-step sequences were designed and successfully applied to the asymmetric synthesis of spiro-bridged and spiro-fused heterocyclic compounds, which combined chromane, indole, and oxindole, three potential pharmacophores, in one molecule. The power of these two organocatalytic pathways is underscored by mild reaction conditions and high efficiency in the production of synthetically challenging, but biologically important heterocyclic products, which could be transformed into more biologically interesting heterocyclic structures.

Different hybridized oxygen atoms controlled chemoselective formation of oxocarbenium ions: synthesis of chiral heterocyclic compounds.

Based on the electronic properties of different hybridized oxygen atoms (sp3versus sp2) in the structure of O,O-acetals containing an enol ether moiety, the chemoselective formation of oxocarbenium ions was realized to furnish diversified chiral heterocyclic compounds with excellent stereoselectivities by reacting with different types of nucleophiles. Additionally, an unexpected intramolecular oxocarbenium ion transfer was also reported to form polycyclic products containing the O,O-acetal functional group.

From racemic precursors to fully stereocontrolled products: one-pot synthesis of chiral α-amino lactones and lactams.

Substituted racemic lactols or cyclic hemiaminals were directly used as nucleophiles in enamine-based asymmetric amination reactions to access enantioenriched α-amino lactones or lactams via a one-pot sequence. The desired products, which are very important building blocks in organic synthesis but difficult to be prepared in the optically enriched form, could be afforded with two stereogenic centers in high yields with excellent enantioselectivities. Moreover, starting from the racemic precursors and catalyzed by the enantiomeric pair of the catalyst, all possible stereoisomeric products were discretely provided only after simple column chromatography. Additionally, this protocol provides facile access to several novel bicyclic carbamates, and such drug-like heterocyclic compounds should be potentially useful in medicinal chemistry.