ABSTRACT
Ten pharmacophore models of beta-tubulin inhibitors were established from the training set of seventeen beta-tubulin inhibitors (two categories) with comformer analysis by using the Catalyst software. The optimal pharmacophore model with two hydrophobic units and two hydrogen bond acceptor units were confirmed (RMS = 0.43, Correl = 0.98, Weight = 2.06, Config = 15.97). This pharmacophore model is able to predict the activity of known beta-tubulin inhibitors and can be further used to identify structurally diverse compounds with higher activity.
Subject(s)
Benzamides , Chemistry , Computer-Aided Design , Drug Design , Models, Chemical , Models, Molecular , Molecular Conformation , Molecular Structure , Software , Structure-Activity Relationship , Tubulin Modulators , Chemistry , Urea , ChemistryABSTRACT
<p><b>AIM</b>To design and synthesize new compounds of prandial glucose regulator with more simple structure.</p><p><b>METHODS</b>The target compounds were synthesized from diethyl succinate and benzaldehyde or 4-fluorobenzaldehyde by four-step reactions. Thus 18 compounds were synthesized. Their structures were comfirmed by NMR, MS and IR.</p><p><b>RESULTS</b>Seventeen compounds had different hypoglycemic activity in mice, among them, 9 compounds had higher hypoglycemic activity and 6 compounds had character of prandial glucose regulator.</p><p><b>CONCLUSION</b>Part of the compounds have higher hypoglycemic activity deserve to be further investigated.</p>
Subject(s)
Animals , Mice , Benzylidene Compounds , Chemistry , Pharmacology , Blood Glucose , Metabolism , Carbamates , Chemistry , Cyclohexanes , Chemistry , Hypoglycemic Agents , Chemistry , Pharmacology , Indoles , Chemistry , Isoindoles , Molecular Structure , Phenylalanine , Chemistry , Piperidines , Chemistry , Structure-Activity Relationship , Succinates , Chemistry , PharmacologyABSTRACT
Direct DNA delivery procedures (include biolistics method) often resulted in multiple copies of the transgenes in transformants and certain copies of them were rearranged. Integration of multiple copies of the introduced genes was the main reason of gene silencing which meant inhibition or loss of foreign gene expression in filial generations of transformants. In the present work, we compared the influences of maize Ubi-1 promoter and other promoters on copy number of transgenes in maize transgenic plants. Immature embryos from Zea mays L. plants of sib-pollinated of A188 x H99 genotype were used as initial materials. Type- I embryonic calluses derived from preculture of immature embryos were treated on N6 medium containing 0.6 mol/L sucrose for 3 approximately 5 hours and transformed via particle bombardment with PDS1000/He delivery system (Bio-Rad). Bombarded calluses were treated with hyperosmotic N6 medium for 16 approximately 20 hours continuously. Then the cultures were transferred onto normal N6 medium and incubated at 26 degrees C in dark for two weeks and subsequently selected on N6 medium supplemented with 2 or 5 mg/L phosphinothricin (PPT) but without casamino acid for another two weeks. The calluses after selective culture were transferred onto hormone-free MS medium containing 2 or 5 mg/L PPT but without casamino acid, and incubated at 24 degrees C under 16 h illumination for plant regeneration. Regenerated plantlets over 2 cm in height were transferred to Magenta box containing 1/2 hormone-free MS medium. Plantlets over 8 cm in height were transplanted to soil. After growing for one week in greenhouse, the plants were sprayed with 250 mg/L PPT solution. Fertile transgenic maize plants were regenerated and confirmed by Southern blotting and histochemical localization of beta-glucuronidase (GUS) activity. Relations between promoter and copy number of transgenes in transformants were analyzed. Maize transgenic plants possessing an intact copy and another incomplete copy of beta-glucuronidase gene (gus) were obtained in case gus gene under the control of maize Ubi-1 promoter (pUbi:GUS). Simultaneously the co-transformed phosphinothricin acetyltransferase gene (bar) controlled by CaMV 35S promoter in another plasmid (p35S:BAR) also existed with only one copy. When pDB1 and (pUbi:in2) were cobombarded, the regenerated transgenic maize plant exhibited with only one copy of in2 gene too. It suggested that the copy number of transgenes in maize transformants was low if the transgenes controlled by maize Ubi-1 promoter. The possible reason might be that the foreign genes were integrated site-specifically via homologous recombination between Ubi-1 promoter and its endogenous sequences in maize genome, and two cotransformed plasmids had reconstructed as one intact molecule before integrating into maize chromosome. On the contrary, if p35S:BAR was cobom-barded with plasmid pAct:In1 containing rice Act-1 promoter (without maize Ubi-1 promoter), the transgenic maize plants had 4 approximately 8 copies of bar gene. These results reflected that utilization of self gene promoter could reduce the copy number of the transgenes in transgenic plants of certain species itself and avoid the occurrence of gene silencing. T2 seeds have been harvested.