Dietary Folate Deficiency Promotes Lactate Metabolic Disorders to Sensitize Lung Cancer Metastasis through MTOR-Signaling-Mediated Druggable Oncotargets.

Lactate metabolism plays a pivotal role in cancers but is often overlooked in lung cancer (LC). Folate deficiency has been linked to lung cancer development, but its impact on lactate metabolism and cancer malignancy is unclear. To investigate this, mice were fed either a folate-deficient (FD) or control diet and intrapleurally implanted with lung cancer cells pre-exposed to FD growth medium. Results showed that FD promoted lactate over-production and the formation of tumor oncospheroids (LCSs) with increased metastatic, migration, and invasion potential. Mice implanted with these cells and fed an FD diet developed hyperlactatemia in blood and lungs. This coincided with increased expression of hexokinase 2 (HK2), lactate dehydrogenase (LDH), and decreased expression of pyruvate dehydrogenase (PDH). Pre-treatment of the FD-LCS-implanted mice with the mTORC1 inhibitor, rapamycin, and the anti-metabolic drug metformin abolished FD/LCS-activated mTORC1 and its targets including HIF1α, HK2, LDH, and monocarboxylate transporters (MCT1 and MCT4), which coincided with the reduction in lactate disorders and prevention of LC metastasis. The findings suggest that dietary FD promotes lactate metabolic disorders that sensitize lung cancer metastasis through mTOR-signaling-mediated targets.

Suboptimal folic acid exposure rewires oncogenic metabolism and proteomics signatures to mediate human breast cancer malignancy.

Whether treatment with folic acid (FA) affects human breast cancer positively or negatively remains unclear. We subjected human Michigan Cancer Foundation-7 cells, a human breast cancer cell line, to suboptimal FA at low levels (10 nM; LF) and high levels (50 µM; HF) and investigated the molecular mechanisms underlying their effects through metabolic flux and systematic proteomics analyses. The data indicated that LF induced and HF aggravated 2-fold higher mitochondrial toxicity in terms of suppressed oxidative respiration, increased fermented glycolysis, and enhanced anchorage-independent oncospheroid formation. Quantitative proteomics and Gene Ontology enrichment analysis were used to profile LF- and HF-altered proteins involved in metabolism, apoptosis, and malignancy pathways. Through STRING analysis, we identified a connection network between LF- and HF-altered proteins with mammalian target of rapamycin (mTOR). Rapamycin-induced blockage of mTOR complex 1 (mTORC1) signaling, which regulates metabolism, differentially inhibited LF- and HF-modulated protein signatures of mitochondrial NADH dehydrogenase ubiquinone flavoprotein 2, mitochondrial glutathione peroxidase 4, kynureninase, and alpha-crystallin B chain as well as programmed cell death 5 in transcript levels; it subsequently diminished apoptosis and oncospheroid formation in LF/HF-exposed cells. Taken together, our data indicate that suboptimal FA treatment rewired oncogenic metabolism and mTORC1-mediated proteomics signatures to promote breast cancer development.

Enantioselective Total Syntheses of the Proposed and Revised Structures of Methoxystemofoline: A Stereochemical Revision.

This article describes the full details of our synthetic efforts toward the enantioselective total synthesis of the complex alkaloid methoxystemofoline. The enantioselective construction of the tetracyclic core features: (1) the Keck allylation at the N-α bridgehead carbon to forge the tetrasubstituted stereocenter; (2) an olefin cross-metathesis reaction for the side-chain elongation that is amenable for the synthesis of congeners and analogues; and (3) a regioselective aldol addition reaction with methyl pyruvate that ensured the subsequent regioselective cyclization reaction to construct the fourth ring. Overman's method was employed to install the 5-(alkoxyalky1idene)-3-methyl-tetronate moiety. In the last step, a nonstereoselective reaction resulted in the formation of both the proposed structure of methoxystemofoline and its E-stereoisomer, the natural product (revised structure), in a 1:1 ratio. We suggest to rename the natural product as isomethoxystemofoline, and report for the first time the complete 1H NMR data for this natural product.

Beneficial effect of Burdock complex on asymptomatic Helicobacter pylori-infected subjects: A randomized, double-blind placebo-controlled clinical trial.

BACKGROUND: Burdock complex (BC) constitutes of burdock (Arctium lappa), angelica (Angelica sinensis), gromwell (Lithospermum erythrorhizon), and sesame (Sesamum indicum) oil, which are commonly used in traditional Chinese medicine (TCM) for treating various disorders. This study intended to examine the anti-H. pylori activity of BC on AGS cell model as well as in asymptomatic H. pylori-infected subjects. MATERIALS AND METHODS: AGS cell incubated with H. pylori and treated with BC to evaluate the minimum inhibition concentration (MIC), cell viability (MTT) anti-adhesion activity, and inflammatory markers. In case of clinical trial, H. pylori-positive subjects (urea breath test [UBT] >10%, n = 36) were enrolled and requested to intake BC (n = 19) or placebo (n = 17) for 8 weeks. Antioxidant capacity, total phenol, UBT, inflammatory markers were analyzed at the initial, 4th, 8th, and 10th weeks. Moreover, the endoscopic examination was carried out on baseline and 10th week. RESULTS: In vitro studies showed that BC treatment significantly inhibited (P < .05) the inflammatory markers and adhesion of H. pylori to AGS cell. However, H. pylori-infected subject ingested with BC for 8 weeks significantly decreased (P < .05) the UBT value, inflammatory markers with improved antioxidant activity, and phenolic levels as compared to placebo. Also, consumption of BC considerably healed the ulcer wound. CONCLUSION: Overall, the BC could attenuate H. pylori infection by inhibiting H. pylori adhesion and subsequent inflammatory response on the gastric epithelial cell (AGS) as well as clinically ameliorated UBT, antioxidant capacity, and alleviated inflammation to display its anti-H. pylori activity.

Enantioselective total synthesis of (+)-methoxystemofoline and (+)-isomethoxystemofoline.

The first enantioselective total synthesis of (+)-methoxystemofoline (2) and (+)-isomethoxystemofoline (3) has been reported. The synthesis employed the halide-assisted bromotropanonation method that we developed recently to construct the core structure, and Overman's strategy for the implementation of the butenolide moiety. Through this work, the structure of methoxystemofoline was revised as with an E-alkene, and its absolute configuration was established.

Versatile construction of functionalized tropane ring systems based on lactam activation: enantioselective synthesis of (+)-pervilleine B.

The halo-assisted intramolecular addition of silyl enol ethers with in situ activated lactams yielded (hydroxylated) 1-halo-8-azabicyclo[3,2,1]octane and 1-halo-9-azabicyclo[3,3,1]nonane ring systems, which provided an easy enantioselective access to 6ß-silyloxytropane-3-one, 3α,6ß-dihydroxytropane, and pervilleine B. The absolute configuration of the natural (-)-pervilleine B was determined to be 1R,3R,5S,6R.

The first synthesis of Krempene B.

The synthesis of Krempene B, which can be isolated from the marine soft coral Cladiella krempfi, is achieved in 23.9% overall yield from commercially available 3ß-acetoxy-5-pregnen-20-one by 11 steps. Key transformations include the dienone-phenol rearrangement of steroids and Wittig reaction.

Concise asymmetric total synthesis of 9-epi-sessilifoliamide J.

A 10-step asymmetric synthesis of 9-epi-sessilifoliamide J (20), together with sessilifoliamide J (6), has been accomplished from the key chiral building block 11 via a threo-selective vinylogous Mannich reaction and a Ley oxidation-SmI(2)-mediated coupling lactonization. The absolute configuration of the natural sessilifoliamide J was established.

(S)-1,5-Dibenzyl-3-tert-butyl-imidazol-idin-4-one.

The title compound, C(21)H(26)N(2)O, was obtained as an unexpected by-product when attempting to prepare (S)-2-benzyl-N-tert-butyl-1,2,3,4-tetra-hydro-isoquinoline-3-carboxamide from (S)-2-benzyl-amino-N-tert-butyl-3-phenyl-propanamide and dimethoxy-methane. The mol-ecules are linked by weak C-H⋯O hydrogen bonds, generating linear chains parallel to the b axis. C-H⋯π inter-actions provide further stability for the crystal structure. The planes of the two phenyl rings make a dihedral angle of 84.1 (1)°. The absolute configuration was known from the starting material.

(1S,3S,4S)-tert-Butyl N-[1-benzyl-3-hydr-oxy-5-phenyl-4-(picolinamido)pent-yl]carbamate.

The title compound, C(29)H(35)N(3)O(4), was obtained by the reaction of (2S,4S,5S)-tert-butyl N-(4-amino-1-benzyl-3-hydr-oxy-5-phenyl-pent-yl)carbamate and picolinic acid using oxalyl chloride as a chlorinating reagent to activate the carboxyl group. In the crystal structure there are two mol-ecules in the asymmetric unit, which are aligned edge-to-face. In one mol-ecule, the pyridyl ring forms a dihedral angle of 22.0 (1)° with the phenyl ring of the terminal benzyl group and 14.3 (1)° with the other phenyl ring; in the other mol-ecule, the corresponding angles are 12.1 (1) and 10.6 (1)°, respectively. The packing is stabilized by inter-molecular hydrogen bonds and C-H⋯π inter-actions.

A divergent asymmetric approach to aza-spiropyran derivative and (1S,8aR)-1-hydroxyindolizidine.

BACKGROUND: Spiroketals and the corresponding aza-spiroketals are the structural features found in a number of bioactive natural products, and in compounds possessing photochromic properties for use in the area of photochemical erasable memory, self-development photography, actinometry, displays, filters, lenses of variable optical density, and photomechanical biomaterials etc. And (1R,8aS)-1-hydroxyindolizidine (3) has been postulated to be a biosynthetic precursor of hydroxylated indolizidines such as (+)-lentiginosine 1, (-)-2-epilentiginosine 2 and (-)-swainsonine, which are potentially useful antimetastasis drugs for the treatment of cancer. In continuation of a project aimed at the development of enantiomeric malimide-based synthetic methodology, we now report a divergent, concise and highly diastereoselective approach for the asymmetric syntheses of an aza-spiropyran derivative 7 and (1S,8aR)-1-hydroxyindolizidine (ent-3). RESULTS: The synthesis of aza-spiropyran 7 started from the Grignard addition of malimide 4. Treatment of the THP-protected 4-hydroxybutyl magnesium bromide with malimide 4 at -20 degrees C afforded N,O-acetal 5a as an epimeric mixture in a combined yield of 89%. Subjection of the diastereomeric mixture of N,O-acetal 5a to acidic conditions for 0.5 h resulted in the formation of the desired functionalized aza-spiropyran 7 as a single diastereomer in quantitative yield. The stereochemistry of the aza-spiropyran 7 was determined by NOESY experiment. For the synthesis of ent-3, aza-spiropyran 7, or more conveniently, N,O-acetal 5a, was converted to lactam 6a under standard reductive dehydroxylation conditions in 78% or 77% yield. Reduction of lactam 6a with borane-dimethylsulfide provided pyrrolidine 8 in 95% yield. Compound 8 was then converted to 1-hydroxyindolizidine ent-3 via a four-step procedure, namely, N-debenzylation/O-mesylation/Boc-cleavage/cyclization, and O-debenzylation. Alternatively, amino alcohol 8 was mesylated and the resultant mesylate 12 was subjected to hydrogenolytic conditions, which gave (1S,8aR)-1-hydroxyindolizidine (ent-3) in 60% overall yield from 8. CONCLUSION: By the reaction of functionalized Grignard reagent with protected (S)-malimide, either aza-spiropyran or (1S,8aR)-1-hydroxyindolizidine skeleton could be constructed in a concise and selective manner. The results presented herein constitute an important extension of our malimide-based synthetic methodology.