Biochemical and Molecular Studies on Novel lndoloquinoline Derivatives as DNA­ Intercalating Compounds for Cancer

Abstract

Name of candidate: Samah Ibrahim Mohamed EL-Ghlban Title of thesis: Biochemical and Molecular Studies on Novel lndoloquinoline Derivatives as DNA-rntercalating Compounds for Cancer Treatment. Degree: M.Sc. Master of Science thesis (biochemistry), Faculty of Science, Cairo University, 2010.

Nature provides a great diversity of different kinds of health-promoting compounds and is an important source of new biologically active molecules for drug discovery. These compounds may help to cure or alleviate serious diseases, among them cancer. Towards this direction, this thesis involves the design and synthesis of novel indoloquinoline compounds containing the natural neocryptolepine core with the objective of discovering novel and potent antitumor agents. Structural modifications are made at the II position of the neocryptolepine ring by attaching, haloanilino, tryptamine amino uracilo and piprazino side chains. Preliminary in-vitro evaluation for the tested compounds against EAC cells showed a strong cytotoxic activity in comparison with thalidomide as reference drug. In addition, the in-vivo evaluation of EAC-induced solid tumor in female albino swiss mice of the target compounds revealed a very highly significant reduction in tumor volume (TV), p<O.OOI. In addition. the results also showed that these compounds have antioxidant activity as the level of hepatic lipid pcroxidation decreased and levels of antioxidant enzymes like superoxide dismutase (SOD) and catalase(CAT) were elevated (p<O.OOI). Furthermore, the histopathological investigations revealed that the tested indoloquinoline compounds have antimitotic. apoptotic and necrotic activities against solid tumor with minimum side-effect on the liver. This study also included the investigation of the mechanism of antitumor activity of the tested compounds at the cellular level by flow cytome!Jy. The cell cycle analysis showed that indoloquinoline compounds provoke a massive accumulation of cancer cells in the three cell phases (GO/G I, S and G21M). This led to the appearance of a hypo-diploid DNA content peak (sub•G I) in the cell cycle experiments which is characteristic of the apoptotic cafl population. Furthermore, The immunological study showed a very highly significant elevation in splenic lymphocyte count (p<O.OOl). At the same time, indoloquinoline derivatives elevated the responsiveness of lymphocytes to phytohemagglutinine (PHA) in-vitro. Based on the above mentioned results, these indoloquinoline compounds seem to be a promising a potential targets in cancer prevention and treatment.