[Design, synthesis and biological evaluation of fingolimod analogues containing diphenyl ether moiety].

A novel series of fingolimod analogues containing diphenyl ether moiety were designed and synthesized based on the modification of immunosuppressive agent fingolimod used in the treatment of multiple sclerosis. Compounds were evaluated in vivo for lymphopenic activity and heart rate affection. Most compounds showed moderate lymphopenic activity. It is worth noting that compounds 6c, 6d and 14c-14e showed considerable immunosuppressive activities comparable to fingolimod. And compound 14e had no effect on heart rate.

[Effect of a novel selective S1P1 agonist, Syl948, on mouse skin transplantation].

Syl948 is a synthesized selective S1P1 agonist with novel structure. HTRF-IP1 test indicated that Syl948-P, the active form of Syl948 in vitro, has strong activity against S1P1 (EC50: 83 +/- 16 nmol x L(-1)), but its effect on S1P3 was very weak (EC50: 1 026 +/- 90 nmol x L(-1)). In SD rats, oral administration of Syl948 10 mg x kg(-1) significantly decreased the peripheral blood lymphocytes (PBL), with the maximal PBL inhibition rate of 63%, which was as similar as equal dose of fingolimod (FTY720). Oral administration of Syl948 10 mg x kg(-1) had no effect on heart rate of SD rats, which was better than FTY720. Daily oral administration with Syl948 (2 or 4 mg x kg(-1)) significantly prolonged the survival time of the allografts of skin slice on mice. In summary, the above results demonstrated that Syl948 has great selectivity in vitro and good activity in vivo, which indicated its potential use as an anti-rejection drug in skin transplantation.

Resolution and chiral recognition of muscone as well as actions on neural system.

In this letter, (R)-muscone and (S)-muscone were prepared by optical resolution of dl-muscone using N,N'-dibenzyl-l-tartaramide or N,N'-dibenzyl-d-tartaramide, according to the method reported by Kunihiko Takabe. But we separated the diastereomers using EtOH instead of MeOH in the recrystallization step to get the goal product with higher optical purity and yield. The regulatory effect of muscone and its enantiomer on the neural system showed that they could prolong mouse hypoxia tolerance and dose-dependently enhance mouse spinal cord stimulation induced by strychnine nitrate. (R)-muscone and (S)-muscone had a synergistic action on shortening sleep time induced by sodium pentobarbital in mice.

Synthesis and in vitro antitumor activities of novel benzyl urea analogues of sorafenib.

A novel series of benzyl urea analogues based on the structural modification of sorafenib were synthesized. Their in vitro antitumor activities against MX-1, HepG2, Ketr3 and HT-29 were evaluated using the standard MTT assay. While several target compounds showed inhibitory activity against multiple cancer cell lines, compound 9 was of particular interest, demonstrating IC50 values (5.69-13.6 micromol x L(-1)) comparable to those of sorafenib. Furthermore, compounds 20 and 23 showed more potent inhibitory activity against HT-29 and MX-1 when compared to sorafenib. In particular, compound 20 bearing the N-3-pyridyl moiety not only exhibited greater inhibitory activity against HT-29 cell line (IC50 3.82 micromol x L(-1)), but also had improved solubility at pH 7.2, is worthy of further investigation as a lead to identify novel antitumor agents.

Synthesis and anti-tubercular activity of novel alkyl substituted riminophenazine derivatives.

A series of novel riminophenazine derivatives bearing an alkyl substituent attached to N-5 and imino nitrogen at C-3 position of the phenazine ring were obtained through rational drug design, aiming to maintain high anti-tubercular activity, lower toxicity and reduce lipophilicity. All target compounds were prepared by utilizing simple and flexible synthetic route and evaluated against Mycobacterium tuberculosis H37Rv and screened for mammalian cytotoxicity. The results demonstrated that compounds with a cyclopropyl substituent at N-5 position were more active than the reference compound clofazimine. In particular, 2-(4-chloroanilino)-5-cyclopropyl-3-(4-methoxycyclohexyl) imino-3, 5-dihydrophenazine (25) was found to be the most potent compound with low cytotoxicity and lipophilicity. This compound could serve as a valuable lead molecule for further optimization.

[Design, synthesis and in vitro activity of glycinamide-bearing compounds as DPP-IV inhibitors].

To research the structure-activity relationship (SAR) of glycinamide-bearing compounds that used as inhibitors of dipeptidyl peptidase IV (DPP-IV), P32/98 and compound A were chosen as the leading compounds, heterocycles containing nitrogen atom were introduced to form amide, and different residues on a-position of carbonyl were designed. The nineteen designed compounds were synthesized by a simple route and were evaluated as inhibitors of DPP-IV. All of the structures were characterized by 1H NMR and HRMS. The preliminary SAR result was obtained.

Four new minor taxanes from cell cultures of Taxus chinensis.

Four new minor taxanes (1-4) have been isolated from Ts-19 cell cultures of Taxus chinensis together with five known taxanes (5-9) by silica gel chromatography combined with semi-preparative HPLC chromatography. On the basis of the analyses of the chemical and spectroscopic (IR, MS, 1D, and 2D NMR) data, the structures of new compounds were elucidated as 5alpha-hydroxy-2alpha,10beta-diacetoxy-14beta-(3-hydroxy-2-methyl-butyryl)oxytaxa-4(20),11-diene (1), 2alpha,5alpha,10beta-triacetoxy-14beta-(2-hydroxy-propionyl)oxytaxa-4(20),11-diene (2), 2alpha,5alpha,10beta-triacetoxy-14beta-(2-hydroxy-3-methyl-butyryl)oxytaxa-4(20),11-diene (3), and 2alpha-benzoxy-4alpha,9alpha,10beta,13alpha-tetraacetoxytax-11-ene (4), respectively. Compounds 1-5 were pharmacologically evaluated for their cytotoxicities against five human cancer cell lines (HCT-8, Bel-7402, BGC-823, A549, and A2780) and their reversing activity towards multi-drug resistance A549/taxol tumor cell line, and the results showed that all of the tested compounds exhibited very low cytotoxicities, while compound 4 possessed twice the reversing activity as that of verapamil at 10 muM.

Overcoming tumor drug resistance with high-affinity taxanes: a SAR study of C2-modified 7-acyl-10-deacetyl cephalomannines.

A series of C2-modified 10-deacetyl-7-propionyl cephalomannine derivatives was designed, prepared, and biologically evaluated. Some C2 meta-substituted benzoate analogues showed potent activity against both drug-sensitive and drug-resistant tumor cells in which resistance is mediated through either P-gp overexpression or beta-tubulin mutation mechanisms. The taxoid 15 b and related compounds are of particular interest, as they are much more cytotoxic than paclitaxel, especially against drug-resistant tumor cells; they are able to kill both drug-resistant and drug-sensitive cells (low R/S ratio), and they have high affinity for beta-tubulin. Our research results led to an important hypothesis, that is, a taxane with very high binding affinity for beta-tubulin is able to counteract drug resistance, which may assist in future taxane-based drug-discovery efforts.

Cytotoxic effect of a non-peptidic small molecular inhibitor of the p53-HDM2 interaction on tumor cells.

AIM: To investigate if non-peptidic small molecular inhibitors of the p53-HDM2 interaction could restore p53 function and kill tumor cells. METHODS: A series of non-peptidic small HDM2 inhibitors were designed by computer-aided model and synthesized by chemical method. Syl-155 was one of these inhibitors. Cytotoxic effect of syl-155 on three tumor cell lines with various states of p53, HT1080 (wild-type p53), KYSE510 (mutant p53), MG63 (p53 deficiency) was evaluated by MTT assay, Western blot and flow cytometry. RESULTS: Syl-155 stimulated the accumulation of p53 and p21 protein in HT1080 cells expressing wild-type p53, but not in KYSE510 and MG63 cells. Consequently, syl-155 induced cell cycle arrest and apoptosis in HT1080 cells. CONCLUSION: Non-peptidic small molecular inhibitors of the p53-HDM2 interaction show promise in treatment of tumors expressing wild-type p53.

[MESH diagrams of Chinese in Beijing and its preliminary application in practice].

OBJECTIVE: To establish the normal MESH diagrams of Chinese in Beijing, and to build a computerized MESH analysis system for orthodontic practice. METHODS: Twenty-eight subjects with normal occlusion were selected in Beijing and their lateral cephalograms were taken at the age of thirteen and eighteen, respectively. Individual MESH diagrams were then established for each subject mainly according to Moorrees' method from the cephalograms orientated in estimated natural head position. Male and female normal MESH diagrams were created. A computerized MESH analysis system was also developed. RESULTS: The normal MESH diagrams of Chinese in Beijing, thirteen and eighteen years old respective, were established. The computerized MESH analysis system was constructed and used in orthodontic patients. CONCLUSIONS: MESH analysis is a proportional analysis method. It can show the results directly, succinctly and holistically. It is also a favorable complement and amendment to the commonly used angle and linear X-ray analysis methods.

[Surgical treatment of fibrous dysplasia of the skull with neuro-navagation].

OBJECTIVE: To evaluate the role and effect of neuro-navagation in the surgical treatment of fibrous dysplasia of the skull and to discuss the indication and advantages of transcranial optic nerve decompression are discussed. METHODS: Fifteen patients with fibrous dysplasia of skull, 6 males and 9 females, aged 10.3 (5 approximately 21), were surgically treated by transcranial approach. The location of lesion, symptoms and signs, CT characteristics, surgical approaches, and outcomes were analyzed. The postoperative outcomes of visual acuity were grouped into 5 categories: blindness, light perception, hand motion, counting fingers, and recognizing acuity chart. Improvement of visual acuity of one grade or more or increase of 0.1 by acuity chart, and improvement of visual field were defined as effective. RESULTS: Fibrous dysplasia of skull in children most often involved the frontal, sphenoid, and ethmoid bones and resulted in stenosis of optic canal and superior optic fissure. The most common symptoms were decreased vision, proptosis and facial asymmetry. 13 patients underwent decompression of optic canal in lateral side, and two patients in both side. All the cases had pathological diagnosis of Fibrous dysplasia of the skull. After 3-to-25-month follow-up, improvement was found in 11 eyes (65%), and no improvement was found in 6 eyes (35%). Decreased vision was not seen. CONCLUSION: Transcranial optic nerve decompression is an effective treatment for decreased vision induced by Fibrous dysplasia of the skull.

[Transcranial optic nerve decompression for optic nerve injury].

OBJECTIVE: To discuss the operative indications and advantages of transcranial optic nerve decompression in treatment of optic nerve injury resulted from skull base fracture. METHODS: The data, such as the site of impact, vision, ocular movement, characteristic of CT, and pathologic changes during operation, and the extent of operative decompression of 118 patients with optic nerve injury. According the site of impact on the head, 87 of lateral superciliary arch type, 18 of medial superciliary arch type, and 13 of zygomatic type, undergoing transcranial optic nerve decompression were analyzed retrospectively. The patients were followed up for 6 months after operation. For the purpose of evaluation, the postoperative outcome of visual acuity was classified into five grades: blindness, hand movement, finger count, light perception and visual acuity > 0.05. The visual acuity improvement reaching one grade or more was defined as effective. The improvement of visual field was also considered effective. RESULTS: After follow-up of 6 months, effect was shown in 35 out of the 72 patients with pre-operative blindness (48.6%), and all the 46 patients with residual vision (100%). The total effective rate was 68.6%. The post-operative effective rate was 64.4% in patients with lateral superciliary arch type, 83.3% in patients with medial superciliary arch type injury and 76.9% in patients with zygomatic type injury. CONCLUSIONS: Transcranial optic nerve decompression is worthy recommending to the patients with traumatic optic neuropathy. The operative indications include patients with residual vision; patients with bilateral optic nerve injury; and patients with blindness less than 3 days.

[Synthesis and drug resistant reversal activities of taxane-like multi-drug resistant reversal agents].

AIM: To design and synthesize a series of new taxoids with a 5-O-sidechain, and to test the multi-drug resistant reversal activity of these compound on KB/V200 cells which is 180 times more resistant to vincristine. METHODS: Using Sinenxan A as a common synthetic starting material, three different types of 5-O-sidechain molecules were synthesized through different route. For type I compounds, 14-acetoxy of Sinenxan A was selectively removed by hydrolysis, xanthation and reduction with tributyltin; A C-10-oxo group was introduced by PCC oxidation; 5-O-acetyl group was selectively removed by potassium tert-butoxide and finally the side chain was introduced by acylating with the corresponding acid. For type II compounds, 5-O-sidechain was introduced to the 5-deacetyl Sinenxan A which was obtained by selective hydrolysis with tBuOK. For type III compounds, 9-acetoxy group was introduced, then 5-OH was left free by thorough hydrolysis and reacetylation. Acylation at 5-position, the final product was obtained. Structure of the compounds have been confirmed by FABMS and 2DNMR. The activity of the compounds in vitro was tested on KB/V200 resistant cell line using MTT method. RESULTS: Nine compounds showed resistant reversal activity and enhancing the cytotoxicity of vicristine against KB/V200 cells. Compounds I2, I3, I4 restored the sensitivity of KB/V200 towards vicristine to a level of IC50 at 1 x 10(-8) mol.L-1 which is better than the positive control Verapamil. CONCLUSION: The drug resistant reversal activity of taxane derivatives can be affected by substitution at different positions and the length of side chains of Sinenxan A. It is worthy to be further studied.