Synthesis and antitumor activity of a series of lactone-opened camptothecin derivatives.

A series of E-ring lactone-opened camptothecin (CPT) derivatives bearing with terminal aza-heterocyclic groups were synthesized, and their antitumor activity was evaluated both in vitro and in vivo. Hydroxyl-amide analogues with morpholin-4-yl displayed excellent antitumor activity in vitro and efficient inhibition on tumor xenograph model in nude mice. Ester-amide compounds acted less active in vitro cytotoxicity and lower inhibition activity in vivo. Substitutions at 7- and 10- positions favored the antitumor activity.

[3,3'-Dihy-droxy-3,3'-bis-(pyridin-3-yl-κN)-1,1'-(pyridine-2,6-di-yl)dipropan-1-one](nitrato-κO,O')silver(I).

In the title compound, a new macrocyclic metal complex, [Ag(NO(3))(C(21)H(15)N(3)O(4))], all non-H atoms are in a close-to-planar geometry (except for the nitrate anion), with a maximum out-of-plane deviation of 0.327 (6) Šfor a pyridine C atom. The dihedral angle between the least-squares plane through the [3,3'-dihy-droxy-3,3'-bis-(pyridin-3-yl)-1,1'-(pyridine-2,6-di-yl)dipropan-1-one]silver(I) fragment and the nitrate anion is 31.29 (13)°. The mol-ecular structure is stabilized by several inter- and intra-molecular O-H⋯O and C-H⋯O hydrogen bonds. The Ag(I) atom is coordinated by two pyridine N atoms and two O atoms of the nitrate anion in a geometry intermediate between tetrahedral and square-planar.

3-(2-Bromo-benz-yl)-1-methyl-1H-imidazol-3-ium bromide.

In the title compound, C(11)H(12)BrN(2) (+)·Br(-), the imidazole and phenyl rings are nearly perpendicular, making a dihedral angle of 87.71 (7)°. The crystal structure is stabilized by non-classical inter-molecular C-H⋯Br hydrogen bonds and inversion-related mol-ecules are linked through π-π inter-actions between the imidazole ring systems [centroid-centroid distance = 3.472 (6) Å].

7-Cycloalkylcamptothecin derivatives: Preparation and biological evaluation.

A series of 7-cycloalkylcamptothecin derivatives were synthesized from camptothecin with two methods. Their biological activities in vitro were evaluated with sulforhodamine-B (SRB) method on four types of human tumor cell lines A549/ATCC, HT29, NCI-H460 and HL60. Most of these camptothecin analogues show higher antitumor activity than the reference compounds SN-38 and Topotecan, with the IC(50) values low to nM level. Structure-activity relationship studies of these compounds mostly match the conclusion we achieved before from quantitative structure-activity relationship (QSAR) research.

Semi-synthesis and biological activity of gamma-lactones analogs of camptothecin.

A series of E-ring gamma-lactone camptothecin derivatives were synthesized by semi-synthesis via a three-step domino reaction. Their biological activity was evaluated on two types of human tumor cell lines A549 and HT-29 with sulforhodamine-B (SRB) method. The antitumor activity of these compounds was lower than SN-38, only compound 12c was found to be close to the activity of Topotecan. The structure-activity relationship (SAR) of these analogs was studied and discussed.

Insight into the mechanism of the asymmetric ring-opening aminolysis of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane catalyzed by titanium/BINOLate/water system: evidence for the Ti(BINOLate)2-bearing active catalyst entities and the role of water.

The mechanism of the enantioselective ring-opening aminolysis of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane with benzylamine, catalyzed by the titanium-BINOLate species generated in situ from a mixture of enantiopure BINOL (1,1'-bi-2-naphthol), Ti(OiPr)4, and H2O in the presence of benzylamine in toluene, was investigated in detail using a combination of reaction profile measurements, nonlinear effect (NLE) studies, solution (1)H NMR analysis, electrospray ionization mass spectrometry (ESI-MS), as well as the results obtained from screening of dynamic catalyst library of complexes L(a)/Ti/L(b) (L(a) or L(b) = chiral diol ligands). The BINOL-to-titanium ratio and the presence or absence of water in the catalytic system were found to exert profound influences on both reactivity and enantioselectivity of the reaction. The NLE studies revealed that the titanium species involved in the catalysis should contain more than one BINOL unit, either within or at the periphery of the catalytic cycle. ESI-MS analysis of the catalytic systems provided strong support in favor of the mechanistic proposal that titanium complexes bearing the Ti(BINOLate)2 moiety should be the active species responsible for the catalysis, which was further confirmed by the observation of synergistic effect of the heteroligand combinations during screening of the dynamic catalyst library. ESI-MS analysis of the reaction system indicated that water does not take part in the catalyst generation, which is an unprecedented finding in contrast to the previous mechanistic understandings in the titanium catalytic chemistry involving the participation of water. Most probably, water functions as a proton shuttle in the catalysis, facilitating the proton transfer between the reactants. Furthermore, the origin of (+)-NLE observed in the present catalytic system is rationalized on the basis of the ESI-MS analysis of the catalyst system prepared from a 1:1 pseudoracemic mixture of (S)-BINOL and (R)-3,3',6,6'-D4-BINOL. Finally, the reactivity differences between several couples of epoxide/amine combinations were tentatively rationalized on the basis of the arguments on their relative coordination preferences, and several other aliphatic amines were also found to efficiently ring-open the titled epoxide in excellent enantioselectivities. The results from this study are expected to shed some light on the often elusive chemistry of Ti(IV)-based catalytic systems where water or molecular sieves (or alcohols, etc.) are found to play an important yet inexplicable role and may help the search for effective asymmetric Ti(IV) catalysts for other types of reactions.

Phosphorylation of HsMis13 by Aurora B kinase is essential for assembly of functional kinetochore.

Chromosome movements in mitosis are orchestrated by dynamic interactions between spindle microtubules and the kinetochore, a multiprotein complex assembled onto centromeric DNA of the chromosome. Here we show that phosphorylation of human HsMis13 by Aurora B kinase is required for functional kinetochore assembly in HeLa cells. Aurora B interacts with HsMis13 in vitro and in vivo. HsMis13 is a cognate substrate of Aurora B, and the phosphorylation sites were mapped to Ser-100 and Ser-109. Suppression of Aurora B kinase by either small interfering RNA or chemical inhibitors abrogates the localization of HsMis13 but not HsMis12 to the kinetochore. In addition, non-phosphorylatable but not wild type and phospho-mimicking HsMis13 failed to localize to the kinetochore, demonstrating the requirement of phosphorylation by Aurora B for the assembly of HsMis13 to kinetochore. In fact, localization of HsMis13 to the kinetochore is spatiotemporally regulated by Aurora B kinase, which is essential for recruiting outer kinetochore components such as Ndc80 components and CENP-E for functional kinetochore assembly. Importantly, phospho-mimicking mutant HsMis13 restores the assembly of CENP-E to the kinetochore, and tension developed across the sister kinetochores in Aurora B-inhibited cells. Thus, we reason that HsMis13 phosphorylation by Aurora B is required for organizing a stable bi-oriented microtubule kinetochore attachment that is essential for faithful chromosome segregation in mitosis.

2,6-Bis(3-phenyl-1H-pyrazol-5-yl)pyridine monohydrate.

In the title compound, C(23)H(17)N(5)·H(2)O, the pyrazole rings are slightly twisted from the central pyridine ring, forming dihedral angles of 5.3 (2) and 3.5 (2)°. The pyrazole and phenyl rings on each side of the pyridine ring are also approximately coplanar, making dihedral angles of 6.0 (2) and 4.5 (2)°. In the crystal structure, 2,6-bis-(3-phenyl-1H-pyrazol-5-yl)pyridine and water mol-ecules are linked together via N-H⋯O and O-H⋯N hydrogen bonds, forming a column running parallel to the a axis.

QSAR study of the enantiomeric excess in asymmetric catalytic reactions with topological indices and an artificial neural network.

The relationships between the enantiomer excess of product in catalytic asymmetric reactions and the structures of the catalysts or reagents in several asymmetric reactions were studied using a backpropagation (BP) neural network with topological indices and their chiral expansions. The trained network can be used to screen new asymmetric catalysts, estimate catalytic effects, design reaction environments, and prove or improve the proposed reaction mechanism.

Anti-inflammatory and immunomodulatory activities of the extracts from the inflorescence of Chrysanthemum indicum Linné.

Chrysanthemum indicum Linné (CI) has a long history for the treatment of inflammation, hypertension and respiratory diseases in China. The purpose of the present study was to investigate the anti-inflammatory and immunomodulatory properties of the inflorescence or bud of CI extracts. The ethanol extract of CI (CIEE) was fractionated to a petroleum ether soluble fraction (CIPF), an ethyl acetate soluble fraction (CIEF), a butanol soluble fraction (CIBF) and a water soluble fraction (CIWF) successively. CIBF (150 mg/kg, p.o.) caused a significant inhibition on the auricle edema in mice. CIBF (150, 300 mg/kg, p.o.) not only significantly increased the delayed-type hypersensitivity (DTH) reaction induced by 2,4-dinitro-fluorobenzene (DNFB) but also significantly enhanced antibody generation by splenic cells of mice and IgG and IgM levels in mice sera in response to sheep red blood cells (SRBC) in cyclophosphamide (CP)-induced mice. Furthermore, CIBF (150, 300 mg/kg, p.o.) obviously potentiated the function of the mononuclear phagocytic system in CP-induced mice. The above results reveal that CIBF possesses anti-inflammatory, humoral and cellular immunomodulatory and mononuclear phagocytic activities, probably due to the presence of flavonoids.

QSAR study of catalytic asymmetric reactions with topological indices.

The relationships between the e.e.% of product in catalytic asymmetry reaction and the structures of the catalyst and reagents in several asymmetric reactions were studied by using topological indices and their chiral expansions. The general regression method used can be applied to designing or screening a new asymmetric catalyst, predicting catalytic effects, and proving or improving the reaction mechanism supposed.

Asymmetric cyclopropanation catalyzed by a series of copper-(Schiff-base) complexes with two chiral centers.

A series of copper(Schiff-base) complexes with two chiral centers derived from 1,2-diphenyl-2-amino-ethanol were synthesized and applied to catalyze the asymmetric cyclopropanation of ethenes with diazoacetates. A mechanism that can explain the observed results was proposed. Some of these complexes were also efficient catalysts for asymmetric cyclopropanation of 1,1-diphenylethene with ethyl diazoacetate, affording high e.e. of up to 98.6%. An e.e. of 80.7% was achieved when no solvent was used.