Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmaceutical Chemistry

A series of novel derivatives of hydrazinylpyrimidines, pyrazolylpyrimidines and 3-aminopyrazolo[3,4-d]pyrimidines have been synthesized and tested for their in vitro cytotoxic activity against 60 tumor cell lines by NCI. The IC50 values for the most active compounds were determined against the colon cancer cell line KM12 (5d, 12c and 12d), breast cancer cell line MCF-7 (9a) and melanoma cell line MDA-MB-435 (9h) using 5-fluorouracil (5-FU) as a positive control. Derivatives 5d and 12c were found to be the most potent derivatives against KM12 cell line (IC50 =1.73 and 1.21 oM, respectively) with a high selectivity index (SI) (18.82 and 35.49, respectively) compared to 5-FU (IC50 = 12.26 oM, SI= 1.93). Compounds 5d and 12c were further investigated for their apoptotic behavior in KM12 cell line. The results showed up-regulation of caspase 3/9 and the pro-apoptotic factor Bax. On the other hand, the expression of the anti-apoptotic factor Bcl-2, was down-regulated, as well as its inhibition at a nanomolar concentration. Furthermore, the apoptotic effect for derivatives 5d and 12c in KM12 cells was detected using annexin V-FITC staining method

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