Design,synthesis and activity evaluation of novel 2-indolone derivatives as the c-Met kinase inhibitors / 国际药学研究杂志

Objective To design and synthesize novel 2-indolone derivatives as the c-Met kinase inhibitors. Methods With c-Met kinase inhibitor SU11274 as lead compound,a series of 2-indolone derivatives were designed according to the concept of bioiso-sterism. Then the target compounds(10a-10r)were synthesized from 2-indolone through 5-chlorosulfonation with chlorosulfonic acid, sulfonamidation with intermediate 3,condensation with 6a-6h,7a-7h and 4a-4b,respectively. Their inhibitory activity against c-Met and proliferation of MCF-7 cells were evaluated. Results and Conclusion The designed compounds were successfully prepared and their structures were confirmed by 1H NMR and ESI-MS. Some compounds had certain inhibitory activity against c-Met and prolif-eration of MCF-7 cells. An initial structure-activity relationship analysis of these compounds was performed to provide useful informa-tion for further optimization of their structures.

Synthesis and activity evaluation of novel tyrosine kinase inhibitors / 国际药学研究杂志

Objective To design and synthesize compounds with protein tyrosine kinase(PTK)inhibitory activity with L029 as the lead compound. Methods L029 derivatives were designed and synthesized from L029 by reduction and/or substitution with the 3-dimethylamino-1-propyl,methyl acetate,methyl propionate in its active H and other sites. PTK activity was measured by enzyme-linked immunosorbent assay(ELISA). The inhibitory rate was calculated to screen out the compounds with PTK inhibitory activity. Re-sults Five target compounds were synthesized and their structures were confirmed by 1H NMR and MS. Three compounds T2,T3 and T5 were screened out with strong PTK inhibitory activity. Conclusion The synthetic routes of the target compounds are simple with mild reaction condition,and 3 compounds show strong inhibitory activity by ELISA. These results can provide reference for the further design and synthesis of this kind of molecules.

Synthesis and protein tyrosine kinases inhibitory activity of aroyl derivatives / 国际药学研究杂志

Objective Using Ex-Rad as a lead compound to design and synthesize aroyl derivatives with protein tyrosine ki?nases(PTK)inhibitiory activity. Methods 1-[(4-Fluorophenyl)amioncarbonyl]cyclopropanecarboxylic acid,and 2-oxo-1-phenyl-imidazolidine were used as raw materials to synthesize intermediates 3a-3d,respectively. The target compounds T1-T7 were synthe?sized by chloroformylation reaction with 3a-3d. Enzyme-linked immunosorbent assay(ELISA)was used and inhibitory rate was calcu?lated to screen out the compounds with PTK inhibitory activity. Results Seven new compounds containing aroyl groups were synthe?sized and their structures were confirmed by 1H NMR. The evaluation of the seven compounds demonstrated that PTK inhibitory activi?ty of T2 and T6 were stronger than that of the lead compound. Conclusion The synthetic method is simple,and the materials are cheap and readily available. T2 and T6 show strong PTK inhibitory activity by ELISA.

Multi-mode microwave assisted preparation of PEGylated polystyrene resin / 国际药学研究杂志

Objective To study a method of microwave-assistant PEGylation of polystyrene resin. Methods Modify the commercial Merrifield resin with PEG-200, and study the influence of the yield under different conditions. The self-prepared PEG resin was further derived to PEG-wang resin; kinds of amino acids were anchored, and the loading rates were compared with commercial wang resin. Result A general series react conditions were preferred, which was performed with 5 g resin, 50 ml PEG-200, irradiating for 15 min ×2 at 600 W, preset temperature was 170 ℃. The resin was then transformed to PEGylated Wang resin and anchored with amino acids, the yields were satisfied. Conclusion The multi-mode microwave assistant PEGylation of Merrifield resin method was first reported in this paper. This method has the advantages of simple operation,fast preparation, mild reaction conditions and good yield, which was much better than the traditional method.

Synthesis of N-(4-fluorophenyl)-N-(4-phenoxyphenyl) cyclopropane-1,1-dicarboxamide / 中国生化药物杂志

Objective To synthesize N-(4-fluorophenyl)-N-(4-phenoxyphenyl) cyclopropane-1,1-dicarboxamide (NFNPDB) as small molecular c-Met kinase inhibitor analogue.Methods N-( 4-fluorophenyl )-N-( 4-phenoxyphenyl ) cyclopropane-1, 1-dicarboxamide was synthesized by nucleophilicsubstitution, amidation, etherification, reduction and condensation from diethyl malonate.Results The total yield of target compound was 3.79%, its structure was confirmed by 1 H-NMR.Conclusion The synthesis method of NFNPDB in our research can be easily operated with lost cost and short direction, which lays the foundation for designing the synthetic process of newly small molecular c-Met kinase inhibitor.

Synthesis and protein tyrosine kinases inhibitory activity of aryl benzyl sulfones derivatives / 国际药学研究杂志

Objective To use Ex-Rad as a lead compound to design and synthesize aryl benzyl sulfones derivatives with protein tyrosine kinases(PTK) inhibitory activity. Methods 2-Naphthol was used as a raw material to synthesize intermediates 3a-3f. The target compounds 4a, 4d, and 5a-5f were synthesized by oxidizing 3a-3f in acetic acid with H2O2. Enzyme-linked immunosorbent assay(ELISA) was used and inhibition rate was calculated to screen out the compounds with PTK inhibitory activitity. Results Eight compounds containing a sulfone or sulfoxide group were synthesized and the structures were confirmed by 1H NMR. Preliminary evaluation of the 8 compounds demonstrated that the PTK inhibitory activity of 5c was much stronger than that of the lead compound. Conclusion The synthetic method is simple, and the materials are cheap and readily available. 5c shows strong PTK inhibitory activity by ELISA.

Solid-phase synthesis of Phakellistatin 13 based on photolabile protecting strategy / 国际药学研究杂志

Objective Preparation of the Phakellistatin 13 by using of solid-phase peptide synthesis method and photolabile protecting group. Methods By using of the DHP resin as the solid-phase supporter, a threonine derivative which was protected by the self-prepared photolabile protecting group was anchored to. The linear peptide was assembled via standard procedure with the threonine as the starting amino acid. After that, the photolabile protecting group was removed by UV irradiation, and the cyclization was completed while the peptide was still attached on the beads. The free cyclic peptide was then cut off by acid. Results The photolabile 2-(2-nitrophenyl)-propanol (Npp-OH) was synthesized in one step from o-nitroethylbenzene. With the Npp group, the carboxyl group of threonine was blocked and Phakellistatin 13 was synthesized. The Phakellistatin 13 was identified by high resolution mass spectrometry, indicated that the strategy is quite available, which offer an efficient method for cyclic peptide synthesis. Conclusion The Npp group had the advantages of easy prepared, high yields for protection and deprotection, be stable to the acidic and alkaline conditions, therefore it is an excellent third division protecting group. With this group, the cyclic peptide can be synthesized efficiently.

Drug-resistance and Transferable Mechanism of Integron Mediated in Gram-negative Isolates Causing Nosocomial Infection / 中华医院感染学杂志

OBJECTIVE To investigate the distribution of integron in Gram-negative isolates which are causing nosocomial infection the association with drug resistance,and it′s contribution in horizontal transfer of drug resistance.METHODS Drug resistance test was performed by K-B method.ESBL-positive strains were detected by double-disk synergy test.Integron was determined by PCR assay with integron-specific-primer.Conjugative transfer test,plasmid profile analysis,nested-PCR,and DNA sequence analysis were used to investigate the transferable mechanism of integron mediated.RESULTS 66.4% of Strains were shown to be positive for classes Ⅰ integron,no class Ⅱ and Ⅲ integrons were detected.Profiles of class Ⅰ integron were 11 types,which sized from 700bp to 2300bp,gene cassettes included genes encoding resistance to aminoglycosides(aadA1,aadA2,aadA5 and aacA4),sulfamethoxazole/trimethoprim(dfrA12,dfrA5 and dfrA17) and chloramphenicol(catB8).Strains positive for class Ⅰ integron were highly related to multidrug resistance and ESBLs.Class Ⅰ integron could horizontal transfer along with plasmid among bacteria.CONCLUSIONS Class 1 integron is widespread in Gram-negative isolates which are causing nosocomial infection.Drug resistance is more liable to horizontal transfer via class Ⅰ integron along with plasmid.It implies the necessary for surveillance of horizontal transfer of antibiotic resistance gene among bacteria genus.