Potential new antitumor agents from an innovative combination of demethylcantharidin, a modified traditional Chinese medicine, with a platinum moiety.

A combination of demethylcantharidin, a modified component of a traditional Chinese medicine (TCM), with a platinum moiety has produced a series of TCM-based platinum compounds [Pt(C(8)H(8)O(5))(NH(2)R)(2)] 1-5, which demonstrate selective cytotoxicity toward SK-Hep-1 (human liver) cell line, and circumvention of cross-resistance. The inclusion of demethylcantharidin rendered the compounds highly active as protein phosphatase (PP2A) inhibitors. The new TCM-Pt compounds may possess a novel dual mechanism of antitumor action: inhibition of PP2A and platination of DNA.

NTDB: Thermodynamic Database for Nucleic Acids.

A new thermodynamic database for normal and modified nucleic acids has been developed. This Thermodynamic Database for Nucleic Acids (NTDB) includes sequence, structure and thermodynamic information as well as experimental methods and conditions. In this release, there are 1851 sequences containing both normal and modified nucleic acids. A user-friendly web-based interface has been developed to allow data searching under different conditions. Useful thermodynamic tools for the study of nucleic acids have been collected and linked for easy usage. NTDB is available at http://ntdb.chem.cuhk.edu.hk.

Phenytoin and enteral feedings: does evidence support an interaction?

OBJECTIVE: To systematically review the reported interaction between oral dosage forms of phenytoin and enteral feeding formulations with respect to the evidence supporting or refuting its existence, proposed mechanism(s) underlying the interaction, and recommended interventions. DATA SOURCES: We conducted a MEDLINE search (1966-April 2000) for English-language articles on phenytoin-enteral feeding interactions; the search terms used were phenytoin, enteral feeding, and/or interaction, and/or in vitro. This search was supplemented by a bibliographic review of all relevant articles. STUDY SELECTION: Prospective, randomized, controlled studies; prospective, nonrandomized, controlled studies; prospective, nonrandomized, uncontrolled studies; retrospective studies; clinical experience reports; case reports; in vitro studies; and letters were evaluated for relevant information. DATA EXTRACTION: Data elements abstracted from these articles were study design, type (patients or healthy volunteers) and number of subjects involved, method of administration of phenytoin and enteral feeding, formulation of phenytoin, type of feeding (and whether it was continuous or interrupted), major findings, and proposed mechanisms of the interaction. DATA SYNTHESIS: Although four prospective, randomized, controlled trials in healthy human volunteers refute the existence of the interaction, there are numerous reports and studies showing dramatic decreases of serum phenytoin concentrations in patients when it is coadministered with enteral feeding formulations. Therefore, evidence supports the existence of this interaction in patients and in vitro studies, but not in healthy volunteers. Unfortunately, the exact mechanisms underlying this interaction remain unknown. Many methods have been devised to prevent and treat the interaction once it has occurred; however, a single, generally accepted, and practical intervention strategy is still lacking. CONCLUSIONS: The exact role of enteral feeding in this interaction is unclear due to the lack of prospective, randomized, controlled trials performed in patients. However, decreased serum phenytoin concentrations associated with enteral feeding may increase the risk of seizures. Clinicians should be aware of this potential drug-nutrient interaction and design a patient-specific care plan that includes consideration of the enteral feeding formulation and method of administration, as well as the phenytoin dosage form, schedule of administration, and monitoring.

Sequence-specific local structural variations in solution structures of d(CGXX'CG)2 and d(CAXX'TG)2 self-complementary deoxyribonucleic acids.

In this study, the solution structures of eight self-complementary deoxyribonucleic acid molecules, d(CGXX'CG)2 and d(CAXX'TG)2 (where X = C, G, T or A and X' is complementary to X), have been determined using NMR interproton distances, endocyclic sugar torsion angles, backbone torsion angles and hydrogen bond constraints. Based on the structural data obtained in solution, a novel sequence-specific local structure function, sigma LS, composed of the sum of the contributions from the helix twist omega, base roll rho, base-pair slide delta delta and propeller twist omega, is introduced to describe their sequence-specific local structures. Sigma LS is found to produce an acceptable correlation (r = 0.96) with the relative local stability (delta G0 10) of a base-pair-step. This result demonstrates that in addition to the inter-strand purine-purine clashes, the base morphology of nearest-neighbor base-pairs is also important in defining the local geometry of base-pairs. Thus, in analyzing the base-pair structural parameter blocks of trimers are used as the basic unit whereas for the base-pair-step structural parameters, the basic unit is composed of blocks of tetramers. The omega LS-delta G(zero) 10 correlation is the first experimental evidence demonstrating the relationship between the relative local stabilities and the sequence-specific local structures of DNA duplexes. It also forms the basis for using the trimer-tetramer model for the prediction of sequence-specific local structures of deoxyribonucleic acid molecules.

The J-coupling restrained molecular mechanics (JrMM) protocol--an efficient alternative for deriving DNA endocyclic torsion angle constraints. Part I: Correlation of endocyclic torsion angles and vicinal torsion angle phi 1'2'.

An efficient alternative which makes use of the reliable 3J1'2' value to derive the endocyclic torsion angle constraints is proposed in this study. Based on the information embedded in the two plots, (i) the vicinal proton-proton J-couplings, 3J1'2', 3J1'2", 3J2'3', 3J2"3' and 3J3'4' against the pseudorotation phase angle, and (ii) 3J1'2", 3J2'3', 3J2"3' and 3J3'4' against 3J1'2'; using the calculated J-couplings obtained for a range of sugar geometries of deoxyribose ring in nucleosides and nucleotides encountered along the pseudorotation itinerary [J. van Wijk, B.D. Huckriede, J.H. Ippel and C. Altona, Methods Enzymol. 211, 286-306 (1992)], it is suggested that the vicinal 3J1'2' possesses structural information other than the vicinal torsion angle phi 1'2'. This study is divided into two parts. In Part I, a correlation diagram between the endocyclic torsion angles nu(i) (i = 0,1,2,3,4) and the restrained vicinal torsion angle phi 1'2' is obtained through the use of the J-coupling restrained molecular mechanics (JrMM) protocol. The established phi 1'2'-nu(i) correlation shows nu(i) can be deduced from the reliable 3J1'2' value and it forms the basis for developing an alternative protocol to derive endocyclic torsion angle constraints. In Part II of this series, extensive testing demonstrating the validity of the JrMM protocol to derive nu(i) for defining the sugar geometry of solution DNA molecules is presented.

The J-coupling restrained molecular mechanics (JrMM) protocol--an efficient alternative for deriving DNA endocyclic torsion angle constraints. Part II: Experimental application of the JrMM protocol.

The J-coupling restrained molecular mechanics (JrMM) protocol, which correlates deoxyribose endocyclic torsion angles and vicinal proton-proton torsion angle phi 1'2' in Part I of this study, is demonstrated to be a viable alternative to efficiently derive the endocyclic torsion angle constraints for the determination of the solution structures of DNA molecules. Extensive testing demonstrating the validity of the JrMM-derived torsion angle constraints in the restrained molecular dynamics and energy minimization structural refinement processes is performed theoretically using an energy-minimized B-DNA model and experimentally using a DNA hexamer d(CGTACG)2. The results show that only a 0.2 A difference exists between the RMSD values of the refined structures using the ideal and the JrMM-derived endocyclic torsion angle constraints. The JrMM-derived torsion angles are also determined to be in good agreement with the torsion angles derived through the use of the vicinal J-derived torsion angles. These results show that through the use of reliably measured J1'2' values and computer simulation method, the endocyclic torsion angle constraints can be derived reliably and efficiently. Thus the JrMM method serves as an alternative strategy to generate endocyclic torsion angle constraints for the determination of the solution structures of DNA molecules.

Quantitative determination of glucose in blood plasma and in fruit juices by combined WATR-CPMG 1H NMR spectroscopy.

The quantitative analysis of pure glucose solution < or = 225 mM (< or = 40.8 mg/mL) in 90/10 H2O/D2O was successfully completed in dilute aqueous solution by the WATR-CPMG method whereby the T2 of the water resonance is manipulated by the WATR method followed by elimination of the water peak by the CPMG pulse sequence. The method was applied to the quantitative analysis of total glucose in blood plasma from human subjects undergoing the oral glucose tolerance test in the teaching hospital, and the results were compared to those obtained using a standard glucose oxidase method in a hospital chemical pathology laboratory. The accuracy of the results obtained using the WATR-CPMG method were generally within 5% of the glucose oxidase method. The coefficient of variation was determined to be better than 4% using plasma samples of diabetic subjects. Application to the quantitative analysis of orange and guava juice was also successfully demonstrated.