Antitumor Activity And DNA Interaction Of Several Steroidal Compounds

The steroidal compounds bearing aromatic rings or heterocycles have been widelyreported due to their good biological activity. It has been found that the steroidalcompounds bearing aromatic rings or heterocycles show different biological activitycompared with the parent compounds. In this thesis, three steroidal compoundsbearing aromatic rings or heterocycles, dehydroepiandrosteronequinoline-4-methanylidenehydrazone (A)， dehydroepiandrosterone naphthalen-2-methanylidenehydrazone(B)and pregnenolone naphthalen-2-methanylidenehydrazone(C)，were synthesized through the introduction of the corresponding aromatic ringsand heterocycles on pregnenolone or dehydroepiandrosterone.In addition, the cytotoxicity of three steroidal compounds had been investigatedby using SGC-7901, HeLa, Bel-7404and HT-29cancer cell lines as model cancercells. The results indicated that three steroidal compounds exhibited good anticanceractivity, and the IC50values of compound (B) against SGC-7901cells and HT-29cellswere1.0μM and5.9μM, respectively. The mechanism of the cell death for threesteroidal compounds was further analyzed using Annexin V Assessment Method. Theresults showed that three steroidal compounds inhibited the growth of tumor cellsmainly through inducing apoptosis manner.In order to further study the inhibiting mechanisms of steroidal compounds onmolecular level, the interactions between these steroidal compounds and herringsperm DNA(hsDNA) were investigated. The results were shown below.1. Through UV-Vis absorption spectrum, the interaction between hsDNA andsteroidal compounds A or B could result in the subtractive effect of hsDNA, while theinteraction between hsDNA and steroidal compound C could result in thehyperchromic effect of hsDNA.2. Through iodide quenching experiments, we could further confirm that theintercalation between three steroidal compounds and hsDNAwas existed. 3. The double helix structure of hsDNA and the interaction between three steroidalcompounds and hsDNAwere varied by the change of ionic strength.4. Through the calculation of the binding constants under different temperaturefrom Stern-Volmer equation, the quenching mechanism between three steroidalcompounds and hsDNA was mainly the static quenching. Three steroidal compoundscould react with hsDNA and formed a complex. The hydrogen bonds and van derWaals forces were exhibited to be the main forces through the calculatedthermodynamic parameters.5. Through hsDNA thermal denaturation experiments, three steroidal compoundscould combine with the bases of hsDNA.6. The non-covalent interactions between three steroidal compounds and hsDNAwere also confirmed by the changing of the pH values.Our results showed that these three steroidal compounds could bind with hsDNAby different degrees. The binding mode included the intercalation binding,electrostatic binding, hydrogen bonds and van der Waals interactions. In addition, themain binding mode was the intercalation binding. These three steroidal compoundsmight be used as a novel fluorescent probe for DNA in the furture. These results willprovide an important theoretical basis for the design and the development of newanticancer steroidal drugs.