Demethylzeylasteral Exhibits Strong Inhibition towards UDP-Glucuronosyltransferase (UGT) 1A6 and 2B7

Inhibition of UDP-glucuronosyltransferase (UGT) isoforms can result in severe clinical results, including clinical drug-drug interactions (DDI) and metabolic disorders of endogenous substances. The present study aims to investigate the inhibition of demethylzeylasteral (an important active component isolated from Tripterygium wilfordii Hook F.) towards three important UGT isoforms UGT1A6, UGT1A9 and UGT2B7. The results showed that 100 μM of demethylzeylasteral exhibited strong inhibition towards UGT1A6 and UGT2B7, with negligible influence towards UGT1A9. Furthermore, Dixon and Lineweaver-Burk plots showed the inhibition of UGT1A6 and UGT2B7 by demethylzeylasteral was best fit to competitive inhibition, and the inhibition kinetic parameters (Ki) were calculated to be 0.6 μM and 17.3 μM for UGT1A6 and UGT2B7, respectively. This kind of inhibitory effect need much attention when demethylzeylasteral and demethylzeyasteral-containing herbs (e.g., Tripterygium wilfordii Hook F.) were co-administered with the drugs mainly undergoing UGT1A6, UGT2B7-catalyzed metabolism. However, when extrapolating the in vivo clinical results using our present in vitro data, many complex factors might affect final results, including the contribution of UGT1A6 and UGT2B7 to the metabolism of compounds, and the herbal or patients' factors affecting the in vivo concentration of demethylzeylasteral.     

Strong inhibition of celastrol towards UDP-glucuronosyl transferase (UGT) 1A6 and 2B7 indicating potential risk of UGT-based herb-drug interaction

Celastrol, a quinone methide triterpene isolated from Tripterygium wilfordii Hook F., has various biochemical and pharmacological activities, and is now being developed as a promising anti-tumor agent. Inhibitory activity of compounds towards UDP-glucuronosyltransferase (UGT) is an important cause of clinical drug-drug interactions and herb-drug interactions. The aim of the present study is to investigate the inhibition of celastrol towards two important UDP-glucuronosyltransferase (UGT) isoforms UGT1A6 and UGT2B7. Recombinant UGT isoforms and non-specific substrate 4-methylumbelliferone (4-MU) were used. The results showed that celastrol strongly inhibited the UGT1A6 and 2B7-mediated 4-MU glucuronidation reaction, with 0.9 ± 0.1% and 1.8 ± 0.2% residual 4-MU glucuronidation activity at 100 μM of celastrol, respectively. Furthermore, inhibition kinetic study (Dixon plot and Lineweaver-Burk plot) demonstrated that celastrol noncompetitively inhibited the UGT1A1-mediated 4-MU glucuronidation, and competitively inhibited UGT2B7-catalyzed 4-MU glucuronidation. The inhibition kinetic parameters (Ki) were calculated to be 0.49 μM and 0.045 μM for UGT1A6 and UGT2B7, respectively. At the therapeutic concentration of celastrol for anti-tumor utilization, the possibility of celastrol-drug interaction and celastrol-containing herbs-drug interaction were strongly indicated. However, given the complicated nature of herbs, these results should be viewed with more caution.     

Ab initio SCF MO results for the carborane isomers 3,5-C2B6H8, 1, 7-C2B7H9, and 1,2-C2B7H9

We report the geometry-optimized total energies and bond distances for the closo-carborane isomers 3,5-C₂B₆H₈, 1,7-C₂B₇H₉, and 1,2-C₂B₇H₉ calculated by the ab initio SCF MO method using the STO -3G basis set. Relative energies are compared with those of the other carborane isomers in the 8- and 9- atom classes. These results complete the set of calculations at the same level of theory for all deltahedral carborane isomers except for those of the 11-atom class.     

Synthesis and biological activity of [MeTyr1,MeArg7,D-Leu8]-dynorphin A(1-9)-NHEt and [D-Cys2-Cys5,MeArg7,D-Leu8]-dynorphin A(1-9)-NH2

The opioid activities of [MeTyr1]-Dyn(1-7)-NH2, [MeTyr1,D-Leu8]-Dyn(1-8)-NH2, [MeTyr1,D-Leu8]-Dyn(1-9)-NH2, [MeTyr1,D-Leu8]-Dyn(1-10)-NH2, [MeTyr1,D-Leu8]-Dyn(1-11)-NH2, and [MeTyr1,D-Leu8,12]-Dyn(1-13)-NH2 were examined in the bioassays (guinea pig ileum, mouse vas deferens and rabbit vas deferens). Because [MeTyr1,D-Leu8]-Dyn(1-9)-NH2 showed the most potent opioid activity of the peptides tested, the biological activities of two kinds of Dyn(1-9) analogues, [MeTyr1,MeArg7,D-Leu8]-Dyn(1-9)-NHEt and [D-Cys2-Cys5,MeArg7,D-Leu8]-Dyn(1-9)-NH2 were determined and compared with those of [MeTyr1,MeArg7,D-Leu8]-Dyn(1-8)-NHEt and [D-Cys2-Cys5,MeArg7,D-Leu8]-Dyn(1-8)-NHEt in the three bioassays, in the receptor binding assays, and in the mouse tail pinch test after subcutaneous administration. The results suggest that the extension of the C-terminal in the peptide chain of [MeArg7,D-Leu8]-Dyn(1-8)-NH2 analogues by Arg is ineffective for increasing the kappa-opioid activities, kappa-receptor selectivity and/or analgesic effects of the peptides.     

State‐state transitions for CCl2(X1A1, A1B1, a3B1) radical and collisional quenching of CCl2(A1B1 and a3B1) by O2, N2, NO,N2O,NH3, and various aminated molecules

CCl₂ free radicals were produced by a pulsed dc discharge of CCl₄ in Ar. Ground electronic state CCl₂(X) radicals were electronically excited to the A¹B₁ (0,4,0) vibronic state with an Nd:YAG laser pumped dye laser at 541.52 nm. Experimental quenching data of excited CCl₂(A¹B₁ and a³B₁) by O₂, N₂, NO, N₂O, NH₃, NH(CH₃)₂, NH(C₂H₅)₂, and N(C₂H₅)₃ molecules were obtained by observing the time‐resolved total fluorescence signal of the excited CCl₂ radical in a cell, which showed a superposition of two exponential decay components under the presence of quencher. The quenching rate constants k_A of CCl₂(A) state and k_a of CCl₂(a) state were derived by analyzing the experimental data according to a proposed three‐level model to deal with the CCl₂(X¹A₁, A¹B₁, a³B₁) system. The formation cross sections of complexes of electronically excited CCl₂ radicals with O₂, N₂, NO, N₂O, NH₃, and aminated molecules were calculated by means of a collision‐complex model. © 2002 Wiley Periodicals, Inc. Int J Chem Kinet 34: 351–356, 2002     

Reversal of stability on metalation of pentagonal-bipyramidal (1-MB6H7(2-) 1-M-2-CB5H7(1-) and 1-M-2,4-C2B4H7) and Icosahedral (1-MB11H12(2-) 1-M-2-CB10H12(1-) and 1-M-2,4-C2B9H12) boranes (M = Al, Ga, In, and Tl): energetics of condensation and relationship to binuclear metallocenes

The usual assumption of the extra stability of icosahedral boranes (2) over pentagonal-bipyramidal boranes (1) is reversed by substitution of a vertex by a group 13 metal. This preference is a result of the geometrical requirements for optimum overlap between the five-membered face of the ligand and the metal fragment. Isodesmic equations calculated at the B3LYP/LANL2DZ level indicate that the extra stability of 1-M-2,4-C(2)B(4)H(7) varies from 14.44 kcal/mol (M = Al) to 15.30 kcal/mol (M = Tl). Similarly, M(2,4-C(2)B(4)H(6))(2)(1-) is more stable than M(2,4-C(2)B(9)H(11))(2)(1-) by 9.26 kcal/mol (M = Al) and by 6.75 kcal/mol (M = Tl). The preference for (MC(2)B(4)H(6))(2) over (MC(2)B(9)H(11))(2) at the same level is 30.54 kcal/mol (M = Al), 33.16 kcal/ mol (M = Ga) and 37.77 kcal/mol (M = In). The metal-metal bonding here is comparable to those in CpZn-ZnCp and H(2)M-MH(2) (M= Al, Ga, and In).     

A novel reaction of (2a7-trinito-9H-fluoren-9-ylidene)-propanedinitrile with N-arylisoindolines

N-Arylisoindolines 1a-c reacted with (2,4, 7-trinitro-9H-fluoren-9-ylidene)propanedinitrile ( A ) in pyridine with admission of air via a net α-H-atom abstraction and formation of [3-(2-aryl-3-arylimino-2,3-dihydro- 1H-isoindol-1-ylidene)-2-aryl-2,3-dihydro-1H-isoindol-1-ylidene]propanedinitriles 2a-c , N-[2-aryl-3-(2-aryl-3-arylimino-2,3-dihydro-1H-isoindolyl-1-idene)-2,3-dihydro-1H-isoindol-1-ylidene]arenamines 3a, b , N, N'-[2-aryl-1H-isoindole-1,3(2H)-diylidene]bisarenamines 4a, b and N-arylphthalimides 5a-c in moderate yields. 2,4,7-Trinitro-9-fluorenone as well as one reduction product each of the latter and of A, namely compounds 6 and 7 , respectively, are also found. The structure of 2b has been unambiguously confirmed by an X-ray crystal structure analysis. A rationale for the conversions observed is presented. These involve dehydrogenation and oxidative couplings of 1a-c as well as transfer of N-aryl fragment from 1a-c to intermediate products.     

Synthesis and structure of a new heptaborate oxoanion isomer: B7O9(OH)5(2-)

The nonmetal borate [H3N(CH2)7NH3][B7O9(OH)5].H2O (1) was prepared via a neat reaction of 1,7-diaminoheptane with excess boric acid under mild nonhydrothermal conditions. Single-crystal X-ray characterization of 1 revealed a new isomer of the heptaborate anion, B7O9(OH)5(2-). The heptaborate anion in 1 is comprised of four fused (BO)3 rings sharing three four-coordinate boron atoms and a single three-coordinate oxygen atom. This anion is a structural isomer of another recently described heptaborate anion, consisting of a chain of three (BO)3 rings. Compound 1 crystallized in the triclinic space group P1 with a=9.3266(17) A, b=10.1222(19) A, c=10.847(2) A, alpha=89.422(2) degrees, beta=82.349(2) degrees, gamma=75.158(2) degrees, V=980.7(3) A3, and Z=2.     

Thermal transformations of B10H12(NH3)2, B10H12(C5H5N)2, and B10H12(C9H7N)2

Conclusions For B₁₀H₁₂L₂, where L=NH₃, C₅H₅N, or C₉H₇N, features of thermal transformations in the range 25–850°C and the composition of the pyrolysis products are determined. The latter are x-ray amorphous phases, containing nitride, carbide, boron carbide, boron, and carbon.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 11, pp. 2481–2484, November, 1988.     

Titanium(II)-mediated cyclizations of (silyloxy)enynes: a total synthesis of (-)-7-demethylpiericidin A1

A concise total synthesis of 7-demethylpiericidin A1 has been completed. The synthesis features a titanium(II)-mediated cyclization of a (silyloxy)enyne as the key step and proceeds in nine steps from tiglic aldehyde.     

2'-hydroxypyridoxol, a biosynthetic precursor of vitamins B(6) and B(1) in yeast

In separate experiments cultures of the yeast Saccharomyces cerevisiae ATTC 7752 were grown in the presence of [5',5'-2H2]- or of [2',2',5',5'-2H4]-3-hydroxy-2,4,5-tri(hydroxymethyl)pyridine (i.e., 2'-hydroxypyridoxol). The 2H NMR spectra of the samples of pyridoxamine dihydrochloride and of thiamin chloride hydrochloride that were isolated from the two experiments showed the presence of deuterium at the corresponding sites. Entry of deuterium from the specifically 2H-labeled samples of 2'-hydroxypyridoxol into the predicted sites of pyridoxamine and of the pyrimidine unit of thiamin provides the first unequivocal evidence that, in yeast, 2'-hydroxypyridoxol is an intermediate on the route from a C5-sugar into vitamin B6, and adds to the evidence that pyridoxol serves as a precursor of the pyrimidine unit of thiamin, supplying the C5N unit, C-2',2,N-1,C-6,5,5' as an intact unit.     

Revised structures of gambiriins A1, A2, B1, and B2, chalcane-flavan dimers from gambir (Uncaria gambir extract)

Gambir, the aqueous extract from Uncaria gambir (Rubiaceae), has been used as an astringent medicine in Asian countries. Investigation of the constituents in the extract led to the isolation of four chalcane-flavan dimers, gambiriin A1 (6), A2 (7), B1 (8), and B2 (9), in addition to (+)-catechin (1), (+)-epicatechin (2), and dimeric proanthocyanidins, procyanidin B1 (3), procyanidin B3 (4), and gambiriin C (5). The spectroscopic and chemical data obtained in the present study indicated that their previously proposed structures 6a, 7a, 8a, and 9a should be revised to 6, 7, 8, and 9, respectively.     

Molar absorptivities of aflatoxins B1, B2, G1, and G2 in acetonitrile, methanol, and toluene-acetonitrile (9 + 1) (modification of AOAC Official Method 971.22): collaborative study

Four laboratories participated in a mini-collaborative study of AOAC Official Method 971.22, Standards for Aflatoxins, Thin-Layer Chromatographic Method, to extend the method to 3 replacement solvents for benzene for calibration of standard aflatoxin solutions. Triplicate test sample vials, each containing 25 micrograms of the respective aflatoxin for each of the 4 aflatoxins and for each of the solvents, were prepared and sent to each collaborator. The collaborators dissolved the aflatoxin in each vial in 2 mL solvent, measured the UV spectrum, and reported the absorptivity maxima near 350 nm. The concentrations of the aflatoxins in the test samples were determined by dissolving identical test samples in benzene-acetonitrile (98 + 2) and following the procedure described in AOAC Official Method 971.22. These concentrations were, in turn, used to determine the molar absorptivities in the other 3 solvents (see Table 1). AOAC Official Method 971.22 has been modified to extend its applicability to 3 replacement solvents for benzene for calibration of standard aflatoxin solutions.     

CCl_2(A~1B_1,a~3B_1)自由基被烷烃类分子猝灭动力学

用放电- LIF实验装置 ,对 CCl4/Ar混合气体放电产生 CCl_2自由基 ,再用 541.52 nm激光将电子基态 CCl_2激励到激发态 A~B_1(0,4,0)振动能级上 ,通过检测激发态 CCl_2时间分辨荧光信号 ,测得室温下 CCl_2(A~B_1)被烷烃类分子猝灭的实验结果 ,用我们提出的三能级模型分析处理实验数据 ,获得 CCl_2(A~1B_1)态和 CCl_2(a~3B_1)态的碰撞猝灭速率常数 k_A和 k_a值 .     

Synthesis and optical behaviors of 2-(9-phenanthrenyl)-, 2-(9-anthryl)-, and 2-(1-pyrenyl)-1-alkylimidazole homologues

Eight 2-(9-phenanthrenyl)-, 2-(9-anthryl)- and 2-(1-pyrenyl)-1-alkyl-benzimidazole compounds, three 2-(9-anthryl)-1-alkylphenanthroimidazole compounds and five 4,5-diphenyl-1-alkyl-2-(9-anthryl)imidazole compounds were synthesized by alkylation reactions of the corresponding benzimidazole, phenanthroimidazole or imidazole compounds. 2-(10-Bromo-9-anthryl)-1-alkyl-benzimidazole compounds were prepared by bromination reaction of 2-(9-anthryl)-1-alkylbenzimidazole compounds. All the synthesized compounds were characterized by elemental analysis, ¹H NMR, ¹³C NMR, MS or HRMS; their absorption coefficients (), maximum absorption λ_amax, fluorescence emission maximum λ_em, Stokes shifts and fluorescence quantum yields (Φ_F) in ethyl acetate were determined; their fluorescent lifetimes (T₁ and T₂) were measured in ethyl acetate and in solid state, respectively. The crystal structure of 2-(9-anthryl)-1-n-butyl-4,5-diphenylimidazole (12a) was determined to be triclinic, space group P-1 types, using single crystal X-ray crystallography technique. The results showed that these compounds exhibited moderate fluorescence-emission abilities and higher solubility in most organic solvents than their corresponding starting materials. The relationships between the optical behaviors and structures for these compounds were discussed.     

The 1 (2)A(1), 1 (2)B(2), and 1 (2)A(2) states of the SO(2) (+) ion studied using multiconfiguration second-order perturbation theory

The 1 (2)A(1), 1 (2)B(2), and 1 (2)A(2) electronic states of the SO(2) (+) ion have been studied using multiconfiguration second-order perturbation theory (CASPT2) and two contracted atomic natural orbital basis sets, S[6s4p3d1f]/O[5s3p2d1f] (ANO-L) and S[4s3p2d]/O[3s2p1d] (ANO-S), and the three states were considered to correspond to the observed X, B, and A states, respectively, in the previous experimental and theoretical studies. Based on the CASPT2/ANO-L adiabatic excitation energy calculations, the X, A, and B states of SO(2) (+) are assigned to 1 (2)A(1), 1 (2)B(2), and 1 (2)A(2), respectively, and our assignments of the A and B states are contrary to the previous assignments (A to (2)A(2) and B to (2)B(2)). The CASPT2/ANO-L energetic calculations also indicate that the 1 (2)A(1), 1 (2)B(2), and 1 (2)A(2) states are, respectively, the ground, first excited, and second excited states at the ground-state (1 (2)A(1)) geometry of the ion and at the geometry of the ground-state SO(2) molecule. Based on the CASPT2/ANO-L results for the geometries, we realize that the experimental geometries (determined by assuming the bond lengths to be the same as the neutral ground state of SO(2)) were not accurate. The CASPT2/ANO-S calculations for the potential energy curves as functions of the OSO angle confirm that the 1 (2)B(2) and 1 (2)A(2) states are the results of the Renner-Teller effect in the degenerate (2)Pi(g) state at the linear geometry, and it is clearly shown that the 1 (2)B(2) curve, as the lower component of the Renner splitting, lies below the 1 (2)A(2) curve. The UB3LYP/cc-pVTZ adiabatic excitation energy calculations support the assignments (A to (2)B(2) and B to (2)A(2)) based on the CASPT2/ANO-L calculations.     

Unexpected formation of clusters with a nortricyclene-containing carborane ligand, 1-(η6-arene)-3-(C7H9CH2O)-isonido-1,2,4-RuC2B8H9, in the reaction of 1,1,3-(PPh3)3-1-H-1,2,4-RuC2B8H9 with 2-(hydroxymethyl)norbornadiene in arene solvents

Heating of 1,1,3-(PPh₃)₃-1-H-1,2,4-RuC₂B₈H₉ with 2-(hydroxymethyl)bicyclo[2.2.1]hepta-2,5-diene in arene solvents (benzene, toluene, or mesitylene) unexpectedly afforded the ruthenium arene complexes 1-(η⁶-arene)-3-(C₇H₉CH₂O)-isonido-1,2,4-RuC₂B₈H₉ containing the nortricyclene fragment in the carborane ligand.     

Sterically-induced low temperatur polyhedral rearrangements of carbaplatinaboranes: Synthesis and crystal structures of 1-Ph-3,3-(PMe2Ph)2-3,1,2-PtC2B9H10, 1-Ph-3,3-(PMe2Ph)2-3,1,11-PtC2B9H10, 11-Ph-3,3-(PMe2Ph)2-3,1,11-PtC2B9H10 and 1,11-Ph2-3,3-(PMe2Ph)2-3,1,11-PtC2B9H9

Reaction of cis-Pt(PMe₂Ph)₂Cl₂ with Tl₂[7-Ph-7,8-nido-C₂B₉H₁₀] affords 1-Ph-3,3-(PMe₂Ph)₂-3,1,2-PtC₂B₉H₁₀, mild thermolysis (55°C) of which yields 1-Ph-3,3-(PMe₂Ph)₂-3,1,11-PtC₂B₉H₁₀ and 11-Ph-3,3-(PMe₂Ph)₂-3,1,11-PtC₂B₉H₁₀. Both of the latter compounds are produced by the microwave irradiation of a mixture of cis-Pt(PMe₂Ph)₂Cl₂ and [HNMe₃][7-Ph-7,8-nido-C₂B₉H₁₁]. When cis-Pt(PMe₂Ph)₂Cl₂ is allowed to react with Tl₂[7,8-Ph₂-7,8-nido-C₂B₉H₉] at room temperature the only isolable species is 1,11-Ph₂-3,3-(PMe₂Ph)₂-3,1,11-PtC₂B₉H₉. The generation of rearranged products with 3,1,11-PtC₂B₉ architectures is inconsistent with a diamond-square-diamond mechanism for the isomerisation of icosahedral heteroboranes.