| Following cardiovascular disease, cancer is currently the second majorcause of death in the world. Because of lacking of the selectivity to the drugtarget,traditional chemotherapeutic drugs can kill many normal cells anddamage to normal tissue, even to some serious adverse reactions when they killthe cancer cells,so it has not yet reached satisfactory results. In the clinicaltreatment , resistance of multidrug in tumors has also become the main reasonof chemotherapy failure.Transcriptional regulation of gene is the premise which maintains normalfunction of the heathy cells. When the transcriptional regulation is dysfunctional,the cell may become cancerous. The acetylation status of histone play animportant regulatory role in gene transcription, so it has a close relationshipwith the generation and proliferation of the tumor and expression levels ofoncogene and tumor suppressor gene. Histone acetylation status is decided bythe two types of enzymes: histone acetyltransferase activity (HAT) and histone deacetylase (HDAC). Under normal physiological conditions, the regulation oftwo types of enzymes for histone acetylation is in a state of equilibrium. Whenthe transformation occurred, HDAC activities servously increased which makesHDAC and HAT out of balance and impact cell proliferation and cell cycleregulation molecule expression imbalance and cell deterioration.Histone deacetylase inhibitors because they can effectively inhibit tumorcells proliferation and promote differentiation, induce apoptosis, avoid tumorresistance and have the advantages of high selectivity, specificity, efficiency andlow toxicity, is a new direction for cancer treatment. Histone deacetylaseinhibitors contain two categories: hydroxamic acid and benzamide. Benzamidehave the advantage of high selectivity, low toxicity and good tolerabilityadvantages compared with the hydroxamic acids . Some benzamide drugs haveentered into clinical phase, such as CI994, MS-275,CS055 and MGCD0103.MGCD0103 is another Histone deacetylase inhibitor with oral bioavailabilityand has high anti-cancer activities and selectivity, but its bioavailability for thedog and rat are 1-90% and 47%,Coefficient of variation is big.Based on MGCD0103 as the leading compound, we have used theprinciple of non-classical electronic emission to transformat the structure ofMGCD0103. According to the previous studies in our work, we replacepyrazine, substituted phenyl, benzothiophene or their derivative to pyridinering.,but their water-solubility and biological activities is bad, pharmacokineticresults are not satisfactory too.The heterocyclic groups can be used asstress-activated protein kinase, interleukin-1 receptor-associated kinase,cyclin-dependent kinase, phosphatidylinositol 3 - kinase inhibitors ,benzodiazepine receptors and benzodiazepine ligands, so they are contained in the head of some drugs, they are also good hydrophobic groups and have goodpotential medicinal value. So we took heterocyclic groups or substitutedheterocyclic groups instead of pyridyl group of MGCD0103;improved thehydrophobicity of the enzyme binding sit, increased the combination with thetargets, and maintained the structure of the connection area of the planarstructure or increased the length of the connection area and kept its active siteN-(2 - aminophenyl) benzamide in the enzyme inhibition; pulled fluorine atomsin meta position or ortho position of 2’-Amino; enhance the condensationbetween the amino and carboxylic acid, to improve the stability of the aminoand to examine its impact on the activity. We designed and synthesized 12 newcompounds, and their structures had been verified by 1H-NMR.We used MCF-7 to evalute the activities of target compounds in vitro . Theresults showed that eight of them have some inhibition activity. There are seventarget compounds showed better anti-activity in vitro than MGCD0103, especia-lly compound 2,3 showed the best activity, and their activities are almost theMGCD0103 six times. |
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