Study On Synthesis And Antitumor Activity Of Drug Molecules Based On Multi-target Of Tumor

Current cancer has become the leading cause of global mortality,and billions of dollars are used to study how to cure cancer or improve the level of medical treatment of cancer each year.Small molecule targeted drugs have been developed,which is based on the current research of cell biology and signal transduction pathways.The new harmfulless molecular targeted drugs have been shown to be effective on the treatment of tumors,and it can be sure that the drugs will replace traditional chemotherapy medicine.Using computer aided drug design,we can more quickly design structures with higher specificity and efficacy,as well as good pharmacokinetic efficacy,functional properties and mechanisms,which is based on corresponding targets,leading to the discovery of anticancer drugs.Compared to the previous blindness of tumor pharmacology research,it becomes more scientific.In this paper,five novel anti-tumor compounds with anti-tumor drug small molecule as the nucleus were designed and synthesized by computer-aided drug design and natural drug small molecule skeleton as a reference.The antitumor activity of synthesized compounds was tested and analyzed,which provides the basis for the future design of antitumor compounds with better activity and less side effects.These studies mainly include the following parts:Chapter 1 Advances in Molecular Biology of Antitumor DrugsThis part summarizes the mechanism of tumorigenesis,some methods of treating tumor playing an important role of chemical drugs in the treatment of tumor process.It also introduces a tool to design novel drug-targeting small molecule(Computer Assisted Drug Design).Chapter 2 Study on Design Synthesis and Activity of Triarylacrylamide Tubulin InhibitorsA class of tubulin inhibitor with phenylacetamide as the parent nucleus was designed by means of computer aided drug design.Substituting benzaldehyde 1 and substituted phenylacetic acid 2 as raw materials,acrylic acid intermediate 3 was obtained,and then intermediate 3 reacted with substituted aniline under the condensation of condensing agent to form amide bond and a series of novel phenylacetamide tubulin inhibitor 4.Biological activity of these compounds was tested and analyzed,indicating that the compound 4h has a good anti-tumor activity(IC50[A549]=8.9 ?M,IC50[SKNMC]=6.4 IC50[SK-OV-3]=5.3 ?M).Chapter 3 Study on Synthesis and Activity of Novel VEGFR-2 Tyrosine Kinase InhibitorsTwo types of VEGFR-2 tyrosine kinase inhibitors were designed by computer-aided drug design.(1)By using the substituted benzoic acid 1 and formamide as raw materials,intermediate 2 was obtained,and then through the fuming nitric acid nitrification,quinazolinone intermediate 3 was obtained.Compound 3 and substituted aniline 4 were carried out by nucleophilic substitution reaction,intermediate 5 was obtained.In the presence of H2,the nitro group of 5 was reduced to amino group by Pd/C catalysis,intermediate 6 was obtained.Compound 6 was reacted with phenyl isocyanate 7 to obtain a series of novel quinazolinones VEGFR-2 Tyrosine kinase inhibitor 8.The compounds were tested for antitumor activity,in which compound 8e(IC50?6.10 ?M)and 81(IC50=6.39 ?M)showed better cytotoxic activity against Hela cells.(2)o-Phenylenediamine 1 was reacted with 1,4-dibromo-butanedione 2 by the cyclization reaction,which was carried out and produced an intermediate 3,which has a quinoxaline nucleus.Compound 3 was subjected to nucleophilic substitution reaction with phenol 4 to obtain a series of novel VEGFR-2 tyrosine kinase inhibitor 5 with quinoxaline as parent nucleus,and the anti-tumor activity test was carried out.Compounds 5i and 5n on OVCAR8 cells showed better activity at the concentration of 10 ?M,the inhibition rates were 57.15%and 53.69%.Chapter 4 Synthesis Polycyclic Oxadiazole Heterocyclic Compounds with Antitumor Activity(1)The reaction was carried out with chloromethoxime 1 and substituted isatin 2 without the use of any metal catalyst under relatively mild reaction conditions,a series of novel 1,2,4-oxadiazolo-indolone antitumor compounds 3 were obtained.Antitumor activity of compounds was tested,among which compound 3a(IC50[OVCAR8]=3.65?M)and 3e(IC50[SKOV3]=0.79 ?M)showed good antitumor activity.2a-d:R2=H,F,OCH3,CH3(2)The reaction was carried out with N-hydroxybenzimidoyl chloride 1 and 2-chlorobenzimidazole or 2-chloro-4-nitroimidazole by a simple one-step procedure.A series of novel imidazole fused 1,2,4·oxadiazole heterocyclic skeleton compounds were obtained.We tested and analyzed the anti-tumor activity of these novel compounds,and some of them exhibited excellent antitumor activity,in which compound 4y had 90.83%inhibition of NCI/ADR-RES tumor cell at a concentration of 10 ?M.