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1.  In Vivo Angiogenesis Screening and Mechanism of Action of Novel Tanshinone Derivatives Produced by One-Pot Combinatorial Modification of Natural Tanshinone Mixture from Salvia Miltiorrhiza 
PLoS ONE  2014;9(7):e100416.
Natural products present in low quantity in herb medicines constitute an important source of chemical diversity. However, the isolation of sufficient amounts of these low abundant constituents for structural modification has been a challenge for several decades and subsequently halts research on the utilization of this important source of chemical entities for drug discovery and development. And, pro-angiogenic therapies are being explored as options to treat cardio-cerebral vascular diseases and wound healing recently. The present study investigates the pro-angiogenic potential of tanshinone derivatives produced by one-pot synthesis using zebrafish model.
Methodology/Principal Findings
In order to address the difficulty of chemical modification of low abundant constituents in herb medicines, a novel one-pot combinatorial modification was used to diversify a partially purified tanshinone mixture from Salvia miltiorrhiza. This led to the isolation of ten new imidazole-tanshinones (Compounds 1–10) and one oxazole-tanshinone (Compound 11), the structures of which were characterized by spectroscopic methods in combination with single-crystal X-ray crystallographic analysis. The angiogenesis activities of the new tanshinone derivatives were determined in an experimental model of chemical-induced blood vessels damage in zebrafish. Of all the tested new derivatives, compound 10 exhibited the most potent vascular protective and restorative activity with an EC50 value of 0.026 µM. Moreover, the mechanism underlying the pro-angiogenesis effect of 10 probably involved the VEGF/FGF-Src-MAPK and PI3K-P38 signalling pathways by gene expression analysis and a blocking assay with pathways-specific kinase inhibitors.
Taken together, our study demonstrated the more distinctive pro-angiogenic properties of 10 than other tanshinones and revealed 10 has potential for development as a pro-angiogenic agent for diseases associated with insufficient angiogenesis. Our results highlighted the great potential of adopting a newly modified one-pot approach to enhance the chemical diversity and biological activities of constituents from natural products regardless of their abundances.
PMCID: PMC4081027  PMID: 24992590
2.  De­acetyl­cinobufalactam monohydrate 
The title compound, C24H33NO4·H2O, the reaction product of de­acetyl­cinobufagin with ammonium acetate, consists of three cyclo­hexane rings (A, B and C), one five-membered ring (D), one six-membered lactone ring (E) and an epoxide ring (F). The stereochemistry of the ring junctures are A/B cis, B/C trans, C/D cis and D/F cis. Cyclo­hexane rings A, B and C have normal chair conformations. The five-membered ring D adopts an envelope conformation (with the C atom bearing the lactone ring as the flap) and the lactone ring E is planar. In the crystal, hy­droxy and water O—H⋯O and amine N—H⋯O hydrogen bonds involving carbonyl, hy­droxy and water O-atom acceptors link the mol­ecules into a three-dimensional network.
PMCID: PMC4051091  PMID: 24940236
3.  Epibisde­hydro­neotuberostemonine J 
The title compound, C22H29NO4, a stemona alkaloid, is composed of two lactone rings (A and E), a six-membered ring (B), a pyrrole ring (C) and a seven-membered ring (D). The five-membered rings A and E exhibit envelope conformations (C atoms as flaps) while ring C is planar. Ring B exhibits a twist-chair conformation due to fusion with pyrrole ring C while ring D adopts a chair conformation. The junction between rings A and B is cis. In the crystal, weak C—H⋯O inter­actions involving the two carbonyl groups, a methyl­ene and a methyl group give rise to a three-dimensional network.
PMCID: PMC3884435  PMID: 24427015
4.  3,8-Dimethyl-4-oxo-3,4-dihydro­quinazoline-6-carbonitrile 
In the title compound, C11H9N3O, the quinazoline unit is almost planar, with a mean deviation of 0.006 (1) Å from the least-squares plane defined by the ten constituent atoms. In the crystal, mol­ecules are linked by weak C—H⋯N hydrogen bonds.
PMCID: PMC3379508  PMID: 22719706
5.  14,15-Didehydro­hellebrigenin 
The title compound, C24H30O5, is the didehydro product of the steroid hellebrigenin (systematic name: 3β,5,14-trihy­droxy-19-oxo-5β-bufa-20,22-dienolide). It consists of three cyclo­hexane rings (A, B and C), a five-membered ring (D) and a six-membered lactone ring (E). The stereochemistry of the ring junctions are A/B cis, B/C trans and C/D cis. Cyclo­hexane rings A, B and C have normal chair conformations. The five-membered ring D with the C=C bond adopts an envelope conformation. Lactone ring E is essentially planar with a mean derivation of 0.006 (4) Å and is β-oriented at the C atom of ring D to which it is attached. There is an O—H⋯O hydrogen bond in the mol­ecule involving the hy­droxy groups. In the crystal, O—H⋯O hydrogen bonds link the mol­ecules into chains propagating along [010]. The chains are linked by C—H⋯O contacts into a three-dimensional network.
PMCID: PMC3379221  PMID: 22719419
6.  Brusatol 
The title compound, C26H32O11, is composed of an α,β-unsaturated cyclo­hexa­none ring (A), two cyclo­hexane rings (B and C), a six-membered lactone ring (D) and tetra­hydro­furan ring (E). Ring A exists in a half-chair conformation with a C atom displaced by 0.679 (2) Å from the mean plane through the remaining five atoms. Ring B exists in a normal chair conformation. Both rings C and D exist in a twisted-chair conformation due to the O-atom bridge and the carbonyl group in rings C and D, respectively. Ring E shows an envelope conformation with a C atom displaced by 0.761 (1) Å from the mean plane through the remaining five atoms. The ring junctions are A/B trans, B/C trans, C/D cis and D/E cis. An intra­molecular O—H⋯O hydrogen bond occurs. In the crystal, O—H⋯O hydrogen bonds involving the hy­droxy, lactone and ester groups and C—H⋯O inter­actions are observed.
PMCID: PMC3379203  PMID: 22719401
7.  Secohellebrigeninamide 
The title compound, C26H37NO5, was the reaction product of hellebrigenin with N,N-dimethyl­formamide. It consists of three cyclo­hexane rings (A, B and C), one five-membered ring (D) and one dihydro­pyran ring (E). The stereochemistry of the ring junctions is is A/B cis, B/C trans, C/D cis and C/E trans. The cyclo­hexane rings A, B and C have chair conformations. Both the five-membered ring D and the dihydro­pyran ring adopt an envelope conformation. Two orientations are found for the aldehyde group with occupancies of 0.608 (10) and 0.392 (10). In the crystal, short O—H⋯O hydrogen bonds and short C—H⋯O contacts involving the hy­droxy group, terminal methyl group and carbonyl group link the mol­ecules into a three-dimensional network.
PMCID: PMC3295466  PMID: 22412577
8.  (Nitrato-κ2 O,O′)bis­(tryptanthrin-κN)silver(I) 
In the crystal structure of the title compound, [Ag(NO3)(C15H8N2O2)2], tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione) and silver nitrate form a 2:1 complex. The silver ion is surrounded by two tryptanthrin ligands, each coordinating through the N atoms, with Ag—N bond lengths of 2.247 (3) and 2.264 (3) Å, and an anionic nitrate ligand coordinating through two O atoms, with Ag—O bond lengths of 2.499 (3) and 2.591 (3) Å. The N—Ag—N plane and the O—Ag—O plane are roughly perpendicular, making a dihedral angle of 81.6 (2)°. In the crystal, C—H⋯O inter­actions between aromatic H atoms and keto and nitrate O atoms as well as π–π inter­actions [centroid-centroid distance = 3.706 (4) Å] give rise to a three-dimensional network.
PMCID: PMC3274910  PMID: 22346857
9.  Evodiamide 
The title compound, C19H21N3O, was isolated from the fruits of Evodia rutaecarpa. The indole and benzene rings are both essentially planar with mean derivations of 0.0094 (4) Å and 0.0077 (3) Å, respectively. The dihedral angle between these two planes is 78.24 (9)°. The amide carbonyl plane is roughly parallel to the indole ring with a dihedral angle of 7.0 (2)°, but makes a dihedral angle of 82.9 (3)° with the benzene ring. Inter­molecular N—H⋯O hydrogen-bonding inter­actions involving the amino and carbonyl groups give rise to a three-dimensional network.
PMCID: PMC3274998  PMID: 22346943
10.  Gallic acid pyridine monosolvate 
In the title compound (systenatic name: 3,4,5-trihy­droxy­benzoic acid pyridine monosolvate), C5H5N·C7H6O5, the gallic acid mol­ecule is essentially planar (r.m.s deviation = 0.0766 Å for non-H atoms) and is linked to the pyridine mol­ecule by an O—H⋯N hydrogen bond. An intra­molecular O—H⋯O hydrogen bond occurs in the gallic acid mol­ecule. The gallic acid and pyridine mean planes make a dihedral angle 12.6 (3)°. Inter­molecular O—H⋯O and O—H⋯N hydrogen bonding involving the hy­droxy and carboxyl groups and the pyridine mol­ecule, and π–π inter­actions between inversion-related pyridines [centroid–centroid distance = 3.459 (6) Å] and between pyridine and benzene rings [centroid–centroid distance = 3.548 (6) Å], lead to a three-dimensional network in the crystal.
PMCID: PMC3247482  PMID: 22220100
11.  A statistical investigation of normal regional intra-subject heterogeneity of brain metabolism and perfusion by F-18 FDG and O-15 H2O PET imaging 
The definite evaluation of the regional cerebral heterogeneity using perfusion and metabolism by a single modality of PET imaging has not been well addressed. Thus a statistical analysis of voxel variables from identical brain regions on metabolic and perfusion PET images was carried out to determine characteristics of the regional heterogeneity of F-18 FDG and O-15 H2O cerebral uptake in normal subjects.
Fourteen normal subjects with normal CT and/or MRI and physical examination including MMSE were scanned by both F-18 FDG and O-15 H2O PET within same day with head-holder and facemask. The images were co-registered and each individual voxel counts (Q) were normalized by the gloabl maximal voxel counts (M) as R = Q/M. The voxel counts were also converted to z-score map by z = (Q - mean)/SD. Twelve pairs of ROIs (24 total) were systematically placed on the z-score map at cortical locations 15-degree apart and identically for metabolism and perfusion. Inter- and intra-subject correlation coefficients (r) were computed, both globally and hemispherically, from metabolism and perfusion: between regions for the same tracer and between tracers for the same region. Moments of means and histograms were computed globally along with asymmetric indices as their hemispherical differences.
Statistical investigations verified with data showed that, for a given scan, correlation analyses are expectedly alike regardless of variables (Q, R, z) used. The varieties of correlation (r's) of normal subjects, showing symmetry, were mostly around 0.8 and with coefficient of variations near 10%. Analyses of histograms showed non-Gaussian behavior (skew = -0.3 and kurtosis = 0.4) of metabolism on average, in contrast to near Gaussian perfusion.
The co-registered cerebral metabolism and perfusion z maps demonstrated regional heterogeneity but with attractively low coefficient of variations in the correlation markers.
PMCID: PMC1550222  PMID: 16836759

Results 1-11 (11)