Studies On The Synthesis And In Vitro Antitumor Activities Of Novel D-ring Modified Isosteviol-heterocycle Derivatives

Cancer is one of the serious threat to human health and life. Chemotherapy, thetreatment of cancer through drugs, is an effective treatment method for cancer therapy.Because most of the clinical drugs have the disadvantages of high toxicity and drugresistance, the research of anticancer drugs with high efficiency and low toxicity hasgreat significance. Meanwhile, sturcture modification of bioactive natural products isan effective way for finding new antitumor drugs.In this thesis, five series of novel D-ring modified isosteviol heterocyclederivatives were synthesized via esterification, Tollens reaction, Grob rearrangement,1,3-dipolar cycloaddition, nucleophilic addition and cyclization reaction. All the158synthesized compounds, including133new compounds, were characterized by IR,1HNMR,13C NMR and HRMS spectra, respectively. The absolute configurations of18new compounds were confirmed by X-ray crystallographic analysis. Their in vitroantitumor activities had also been evaluated. The corresponding work was describedas follows:1. Starting from isosteviol,15α-hydroxymethyl-16β-hydroxyl isosteviolderivative3was stereoselectively prepared via esterification and Tollens reaction.Oxidation of3gave compound5, which underwent condensation reaction withhydrazine gave the D-ring fused pyrazole derivative6selectively. Then a series ofnovel phenylthiocarbamyl pyrazole derivatives were facilely synthesized throughnucleophilic addition of compound6to the substituted phenyl isothiocyanates.The in vitro antitumor activities of these compounds were evaluated against fourcancer cell lines, including gastric cancer (SGC7901), lung cancer (A549), lymphomacancer (Raji) and cervical cancer (Hela) with cisplatin as the positive control. Theresults showed that most of these compounds exhibit better cytotoxic activity againstRaji cell line than cisplatin, which was better than the other three cell lines. Themono-substituted compounds were more potent than di-substituted derivatives.Meanwhile, among the mono-substituted pyrazole derivatives, para-substitutedcompounds displayed better cytotoxic activity than the ortho-and meta-substituted derivatives. Specifically, pyrazole derivatives7p exhibited noteworthy cytotoxic activities with IC50value of9.65μM,17.73μM,6.51μM and13.91μM against SGC7901, A549, Raji and Hela cell lines, respectively.2. A series of novel phenylthiocarbamyl substituted isoxazolidine derivatives were facilely prepared via condensation,1,3-dipolar cycloaddition and nucleophilic addition reaction from ring opening product9. Their in vitro antitumor activities of these compounds were evaluated against four cancer cell lines, including SGC7901, A549, Raji and Hela cell lines. In our studies, most of them showed better inhibitory activities against Raji cell line than those in SGC7901, A549and Hela cell lines. The di-substituted compounds were more potent than the mono-substituted derivatives. Specifically, compound12t with2,6-dimethyl substituent exhibited noteworthy antitumor activities with IC50value of27.38μM,41.56μM and19.72μM against SGC7901, A549and Raji cell lines, respectively. 3. A series of novel N-phenyl pyrazoline derivatives were obtained stereoselectively via condensation and1,3-dipolar cycloaddition reaction from ring-opened product9. The in vitro antitumor activities of these compounds were evaluated against four cancer cell lines, including SGC7901, A549, Raji and Hela cells. The results showed that this type of compounds exhibit better inhibitory activities against Raji cell lines than those in SGC7901, A549and Hela cell lines. Meanwhile, compounds containing an electron-donating group on the aromatic ring were more potent against SGC7901cell line than the halogen-substituted compounds. Importantly, several of pyrazole derivatives showed better inhibitory activities against Raji and A549cell lines than cisplatin. Among the mono-substituted pyrazoline derivatives, compound141with p-CH3substituent exhibited better cytotoxic activities with IC50value of29.39μM,13.67μM,3.91μM and29.14μM against SGC7901, A549, Raji and Hela cell lines, respectively.4. A series of N-phenyl pyrazole derivatives were obtained stereoselectively via condensation reaction from compound5and phenylhydrazine hydrochloride containing different substituent group. The in vitro antitumor activities of these compounds were evaluated against four cancer cell lines, including SGC7901, A549, Raji and Hela cell lines. The results showed that these compounds displayed the best antitumor activity against Raji cell line among the four cell lines tested. The mono-substituted compounds were more potent than di-substituted derivatives. Meanwhile, among the mono-substituted derivatives, m-CH3-substituted pyrazole141displayed the best antitumor activity. Interestingly, all the derivatives showed better inhibitory activities against Raji cell line than cisplatin. Specifically, pyrazole derivative14t exhibited noteworthy antitumor activities with IC50value of2.71μM,3.18μM,1.09μM and13.52μM against SGC7901, A549, Raji and Hela cell lines, respectively.5. The thiosemicarbazone derivatives were prepared via condensation and addition reaction with isosteviol as starting material. Then, a series of novel1,3,4-thiadiazoline derivatives were facilely synthesized via oxidation of compound19. The in vitro antitumor activities of these compounds were evaluated against four cancer cell lines, including SGC7901, A549, Raji and Hela cells. Most of compounds showed weak antitumor activity. A few compounds showed better inhibitory activities against Raji cell than those in SGC7901and Hela cell lines. Otherwise, among the derivatives, compound20a displayed better antitumor activity than compound19a. Among the mono-substituted derivatives,p-CH3-substituted,p-OCH3-substituted and p-NO2-substituted compounds showed better antitumor activity against Raji cell with IC50value of25.75μM、32.43μM and27.65μM.