Natural Small Molecules in Gastrointestinal Tract and Associated Cancers: Molecular Insights and Targeted Therapies

Gastric cancer is one of the most common cancers of the gastrointestinal tract. Although surgery is the primary treatment, serious maladies that dissipate to other parts of the body may require chemotherapy. As there is no effective procedure to treat stomach cancer, natural small molecules are a current focus of research interest for the development of better therapeutics. Chemotherapy is usually used as a last resort for people with advanced stomach cancer. Anti-colon cancer chemotherapy has become increasingly effective due to drug resistance and sensitivity across a wide spectrum of drugs. Naturally-occurring substances have been widely acknowledged as an important project for discovering innovative medications, and many therapeutic pharmaceuticals are made from natural small molecules. Although the beneficial effects of natural products are as yet unknown, emerging data suggest that several natural small molecules could suppress the progression of stomach cancer. Therefore, the underlying mechanism of natural small molecules for pathways that are directly involved in the pathogenesis of cancerous diseases is reviewed in this article. Chemotherapy and molecularly-targeted drugs can provide hope to colon cancer patients. New discoveries could help in the fight against cancer, and future stomach cancer therapies will probably include molecularly formulated drugs.     

Synthesis and biological evaluation of anthranilamide-based non-peptide mimetics of ω-conotoxin GVIA

Non-peptide mimetics based on an anthranilamide ‘scaffold’ possessing fragments that mimic Lys2, Tyr13 and Arg17 in ω-conotoxin GVIA have been prepared. Compounds were assayed for binding to the voltage-gated calcium channels Ca_v2.2 (‘N-type’) and Ca_v2.1 (‘P/Q-type’) in rat brain. The primary synthetic target, 2-(6-amino-hexanoylamino)-5-(3-guanidino-propoxy)-N-[4-(4-hydroxyphenoxy)-phenyl]-benzamide (2a), exhibited low μM binding to Ca_v2.2 and was more than 30-fold selective for Ca_v2.2 over Ca_v2.1.     

New diorganotin(IV) derivatives of dipeptides: synthesis and characteristic spectral studies

Some new diorganotin(IV) derivatives of the formulae, R2SnL, where R=Me, n-Bu, Ph, and n-Oct, and L is the dianion of histidinylalanine (H2L-1) and histidinylleucine (H2L-2) have been synthesized by the reaction of R2SnCl2 and the preformed sodium salt of the respective dipeptides. The bonding and coordination behaviour in these derivatives are discussed on the basis of FT-IR, multinuclear 1H, 13C and 119Sn NMR and 119Sn M?ssbauer spectroscopic studies. These investigations suggest that dipeptides in R2SnL act as dianionic tridentate coordinating through the COO(-), NH2 and N(-)peptide groups. The 119Sn M?ssbauer studies, together with the NMR data, suggest a trigonal bipyramidal geometry around tin in R2SnL with the alkyl/aryl groups and Npeptide in the equatorial positions, while a carboxylic oxygen and the amino nitrogen atom occupy the axial positions.     

Ultrafast bimolecular electron transfer dynamics in micellar media

Ultrafast photoinduced bimolecular electron transfer (ET) dynamics between 7-aminocoumarin derivatives and N,N-dimethylaniline (DMAN) has been studied in neutral (TX100), cationic (DTAB) and anionic (SDS) micellar media. A very fast decay time constant (tau(fast)) shorter than approximately 10 ps has been observed for the coumarins in the presence of DMAN in all of the three micellar media. In this time scale, reactants in the micellar phase undergo ET interactions without involving diffusion or reorientation of the reactants and thus can be envisaged as equivalent to nondiffusive bimolecular ET reaction. The fastest ET rates estimated as the inverse of the shortest lifetime components of the fluorescence decay (k(et) congruent with tau(fast)(-1)) nicely follow the predicted Marcus inversion behavior with reaction exergonicity (-DeltaG degrees), irrespective of the nature of micelles considered. Onset of inversion in ET rates occur at approximately 0.61 eV lower exergonicity in SDS and TX100 micelles compared with that in DTAB micelle and are rationalized following two-dimensional ET (2DET) theory. These differences suggest the possibility of tuning Marcus inversion by proper selection of micelles. Interestingly, ET rates (k'(et)) obtained from the conventional Stern-Volmer analysis of the relatively longer time constants of the fluorescence decays also exhibit similar Marcus correlation with DeltaG degrees, showing clear inversion behavior. Fitting of Marcus correlation curves for k(et) and k'(et) indicate two largely different values for the electronic coupling parameters. In micellar media, as the interacting donor-acceptor molecules are on an average expected to be separated by an intervening surfactant chain and the reorientation rate of the reactants is quite slow, it is predicted that the ultrafast ET (k(et)) component arises because of the surfactant separated donor-acceptor pairs that are orientated perfectly to give the maximum electronic coupling. The slower ET (k'(et)) is predicted to arise because of those pairs where the donor-acceptor orientations are not very suitable but good enough to give a sizable electronic coupling.     

Kinetics and mechanism for the aquation of bismalonatoethylenediaminecobaltate(III) ion in acid perchlorate media

Summary The title complex aquates in acid media, first to [Co(mal)-(H₂O)₂(en)]⁺ (1) (Step 1) and subsequently to [Co(H₂O)₄(en)]³⁺ (2) (Step 2). Complex species (1) has been separated and characterised in solution. While Step 1 involves only a second-order acid catalysed path, Step 2 involves both a first-order acid independent path and a second-order acid catalysed path. The rate constants and activation parameters evaluated for these reaction paths have been compared with those for similar carboxylato-cobalt(III) complexes. This, together with an observed isokinetic relation, indicates that the rate-determining step involves opening of the unprotonated (in the spontaneous acid independent path) or the protonated (for the acid catalysed path) chelate ring of the malonate ligand and insignificant solvation of the central metal ion.     

Fluorescent peptide-based sensors for the ratiometric detection of nanomolar concentration of heparin in aqueous solutions and in serum

New fluorescent peptide-based sensors (1–3) for monitoring heparin in serum sample were synthesized using short peptides (1∼3mer) as a receptor. The peptide-based sensors (2 and 3) showed a sensitive ratiometric response to heparin both in aqueous buffered solution (10 mM HEPES, pH 7.4) and in 2% human serum sample by increase of excimer emission of pyrene at 480 nm and concomitant decrease of monomer emission of pyrene at 376 nm, whereas the peptide-based sensor 1 showed a turn off response only by decrease of monomer emission at 376 nm. 2 and 3 exhibited excellent selectivity toward heparin among various anions and competitors of heparin including chondroitin 4-sulfate (ChS) and hyaluronic acid (HA). Peptide-based sensor 3 showed a more sensitive response to heparin than 2. The detection limit of 3 was determined as 36 pM (R² = 0.998) for heparin in aqueous solution and 204 pM (R² = 0.999) for heparin in aqueous solutions containing 2% human serum. The peptide-based sensors, 2 and 3 provided a practical and potential tool for the detection and quantification of heparin in real biological samples.     

Development and validation of an ultra high‐performance liquid chromatographic method for the determination of a diastereomeric impurity in (+)‐pinoresinol diglucoside chemical reference substance

(+)‐Pinoresinol 4,4′‐di‐O‐β‐D ‐glucopyranoside ((+)‐PDG) is one of the major lignans with various pharmacological activities which could be isolated from Duzhong and other plant species. In this study, a diastereomeric impurity, (?)‐pinoresinol 4,4′‐di‐O‐β‐D ‐glucopyranoside ((?)‐PDG), the main impurity was identified in (+)‐PDG chemical reference substance (CRS) and a reliable chromatographic method for rapid purity determination of (+)‐PDG CRS was firstly developed. The optimal chromatographic condition was found to be using ACN/1,4‐dioxane–water (2.5:6:91.5, v/v/v) as mobile phase on a Waters Acquity UPLC HSS T3 column (2.1 mm×100 mm, 1.8 μm) with column temperature of 37°C. The method was validated and applied to determine the chromatographic purity of five (+)‐PDG CRS samples. The content of (?)‐PDG in four commercial (+)‐PDG CRS was 8.47–20.30%, whereas no (?)‐PDG was detected in our in‐house prepared (+)‐PDG CRS in which purity was confirmed to be 99.80%. The above results confirmed that this method is fast and highly efficient for purity determination of the (+)‐PDG CRS.     

Synthesis and antispasmodic activity evaluation of bis-(papaverine) analogues

A new series of N-substituted bis-(tetrahydropapaverine) ring systems have been synthesised in expectation of better antispasmodic activity in comparison with papaverine. The synthesis of the targeted heterocycles is described along with a discussion of their structure activity relationship. The general synthetic methods of bis-(tetrahydropapaverine) analogues involve tetrahydropapaverine, various piperazines, diisocyanates and diisothiocyanates as starting materials. Pharmacological evaluation involves the in vitro antispasmodic activity on a freshly removed guinea pig ileum using a force displacement transducer amplifier connected to a physiograph. Among the analogues synthesized in the present study, N,N'-bis-[2-carbamoyl-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinyl]piperazine (22), was found to be the most potent muscle relaxant (IC(50): 0.31 microM).     

Polymer-supported nitroxyl radical catalyst for selective aerobic oxidation of primary alcohols to aldehydes

PS-TEMPO, a polymer-supported 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), was successfully applied as a recyclable, active and selective catalyst for the oxidation of primary aliphatic and benzylic alcohols to aldehydes by molecular oxygen in the presence of Co(NO3)2 and Mn(NO3)2 as co-catalysts.