A DFT study on non-enzymatic degradations of anti-tuberculosis drug isoniazid.

CONTEXT: Isoniazid (INH) is one of the medications most used for tuberculosis (TB) treatment. However, long-term continuous therapy can cause hepatotoxicity and peripheral neuritis. The degradation of INH is an important aspect of the research in the field of drug stability as well as drug formulation for controlling release. It is thought that tautomerization, hydrolysis as well as nucleophilic substitutions can cause decrease in INH as non-enzymatic degradation. Therefore, it is crucial to understand the mechanisms and energies of the major reactions in order to provide reference for future drug formulation and application. This study is an effort to understand the kinetic and thermodynamic properties of the non-enzymatic degradation reactions. The chemical reaction phenomena are investigated using the density functional theory (DFT) method. This study shows that major degradation of INH can be done via tautomerization followed by hydrolysis. The general trends in nucleophilic degradation presented here are consistent with experimental pKa of nucleophiles. METHODS: All DFT calculations were performed using the Gaussian Software Packages (Gaussian 09 revision B.01 and GaussView 5.0.8). MOLEKEL 4.3 software was utilized to visualize the molecular graphics of all relevant species. The optimized molecular geometries were calculated using B3LYP/6-311 + G(d,p) level in the gas phase. The IEF-PCM/B3LYP/6-311 + G(d,p) level was selected for single-point and frequency calculations in aqueous media.

A new sesquiterpenoid juvenile hormone III from the stems of Cananga latifolia.

A new juvenile hormone III, canangalia I (1), along with six known juvenile hormone III analogues (2-7), was isolated from the methanolic extract of Cananga latifolia stems. All structures were elucidated using spectroscopic data and compared with data from previous literature. Canangalia I (1) was found to be cytotoxic against human cervical adenocarcinoma (HeLa) cells with an IC50 value of 35.00 ± 2.15 µg/ml after 72 h, but was not toxic to Vero cells.

A DFT calculation on nonenzymatic degradation of isoaspartic residue.

ßAsp is an isomer of Asp that can be formed by either deamidation of Asn or isomerization of Asp and known as biological clock. The presence of ßAsp affects the proteolytic stability of the protein. Formation of the isomerized Asp plays a diverse and crucial role in aging, cancer, autoimmune, neurodegenerative, and other diseases. A number of methods have been developed to detect ßAsp, and they are usually used in conjunction. Because of identical mass, differentiation of ßAsp and Asp residues is challenged. Degradation of ßAsp is still unclear and needed to be explored. The energetics and mechanism of five possible pathways for cleavages at ßAsp in peptide model have been investigated by DFT/B3LYP/6-311 + + G(d,p) level of the theory. The calculations show that peptide bond cleavage at α-chain (amino side) due to αOC → αCN ring closure is the most favorable reaction. The result is in agreement with experiment utilizing PSD/CRF method. The second most favorable pathway is due to αOC → ßC ring closure results in ß-chain cleavage. The cleavage products ßAsp and Asp fragments can be used to signify an abundance of ßAsp residue in nonenzymatic condition. Other three cyclizations initiated by either α- or ß-amino nitrogen result in various cleavages, isomerization to Asp, and reconversion to original ßAsp. These three cyclization pathways are obstructed because they require mostly high activation barriers and their intermediates are quite less thermodynamically stable. Thus, computational results also confirm that ßAsp → Asp is prohibited in case of nonenzymatic condition which means that protein L-isoaspartyl O-methyl transferase (PIMT) is needed for this modification.

Benzoyltyramine Alkaloids Atalantums A-G from the Peels of Atalantia monophylla and Their Cytotoxicity against Cholangiocarcinoma Cell Lines.

Seven new benzoyltyramines, atalantums A-G (1-7), and five known compounds were isolated from the peels of Atalantia monophylla. All compounds were examined for cytotoxicity against the cholangiocarcinoma cell lines KKU-M214, KKU-M213, and KKU-M156. Compound 5 exhibited the strongest cytotoxicity against KKU-M156 cells, with an IC50 value of 1.97 ± 0.73 µM, an approximately 4.7-fold higher activity than that of the ellipticine standard. Compound 1 displayed strong cytotoxicity against KKU-M214 cells, with an IC50 value of 3.06 ± 0.51 µM, nearly equal to that of the 5-fluorouracil standard. In the case of the KKU-M213 cell line, compounds 2, 4, and 11 exhibited stronger cytotoxicity than the ellipticine standard, with IC50 values of 2.36 ± 0.20, 5.63 ± 0.22, and 2.71 ± 0.23 µM, respectively. Compounds 1, 5, and 7 displayed cytotoxicity against KKU-M214 cells, with IC50 values of 3.06 ± 0.51, 8.44 ± 0.47, and 7.37 ± 1.29 µM, respectively.

Canangalias C-H, juvenile hormone III analogues from the roots of Cananga latifolia.

Chemical investigation of the roots of Cananga latifolia led to the isolation and purification of thirteen juvenile hormone III analogues. Six new analogues, canangalias C-H (1-6) and a new natural product, (2E,6E,10R)-10-acetoxy-11-hydroxy-3,7,11-trimethyldodeca-2,6-dienoic acid methyl ester (7), were isolated. In addition, six known juvenile hormone III analogues were isolated. Their structures were established by spectroscopic methods including 1D and 2D NMR, IR and mass spectrometry.

Cytotoxic coumarins from Toddalia asiatica.

Three new coumarins and 13 known compounds were isolated from the stem bark of Toddalia asiatica. Compounds 1, 3, 8, and 9 showed cytotoxicity against the NCI-H187 cell line with IC50 values ranging from 6 to 9 µg/mL. Compounds 4 and 9 exhibited cytotoxicity against the MCF-7 cell line with IC50 values of 3.17 and 9.79 µg/mL, respectively. Compound 9 also displayed cytotoxic activity against KB cells with an IC50 value of 8.63 µg/mL. In addition, compound 14 showed antimalarial activity against Plasmodium falciparum with an IC50 value of 3.66 µg/mL. Compounds 5, 9, and 16 exhibited antituberculosis activity against Mycobacterium tuberculosis with MIC values of 50, 50, and 25 µg/mL, respectively.