title: Novel 1,5-diphenyl-6-substituted 1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones induced apoptosis in RKO colon cancer cells.
abstract: Novel 1,5-diphenyl-6-substituted-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones were synthesized and characterized. All compounds were screened for their anti-proliferative activities in five different cancer cell lines. The results showed that compounds 7a and 7b comprising aminoguanidino or guanidino moiety at position 6 inhibited proliferation of RKO colon cancer cells with IC50 of 8 and 4 μM, respectively. Compounds 7a and 7b induced apoptosis in RKO cells, which was confirmed by TUNEL and annexin V-FITC assays. Flow cytometric analysis indicated that compounds 7a and 7b arrested RKO cells in the G1 phase and the most active compound 7b increased levels of p53, p21, Bax, ERK1/2 and reduced levels of Bcl2 and Akt. Compound 7b also activates release of cytochrome c, which is consistent with activation of caspase-9. Additionally, compound 7b increased caspase-3 activity and cleaved PARP-1 in RKO cells. Collectively, these findings could establish a molecular basis for the development of new anti-cancer agents.
authors.affiliation: a Biomedical Science Program, Department of Health Sciences, College of Art and Sciences , Qatar University , Doha , Qatar .
authors.forename: Ahmed
authors.initials: A
authors.lastname: Malki
authors.affiliation: b Department of Pharmaceutical Chemistry , Faculty of Pharmacy, Alexandria University , Alexandria, 21521 , Egypt .
authors.forename: Hayam M A
authors.initials: HM
authors.lastname: Ashour
authors.affiliation: b Department of Pharmaceutical Chemistry , Faculty of Pharmacy, Alexandria University , Alexandria, 21521 , Egypt .|c Department of Analytical & Pharmaceutical Chemistry , Faculty of Pharmacy & Drug Manufacturing, Pharos University , Alexandria , Egypt , and.
authors.forename: Rasha Y
authors.initials: RY
authors.lastname: Elbayaa
authors.affiliation: b Department of Pharmaceutical Chemistry , Faculty of Pharmacy, Alexandria University , Alexandria, 21521 , Egypt .|d Department of Pharmaceutical Sciences , Faculty of Pharmacy, Beirut Arab University , Beirut , Lebanon , and.
authors.forename: Doaa A E
authors.initials: DA
authors.lastname: Issa
authors.affiliation: a Biomedical Science Program, Department of Health Sciences, College of Art and Sciences , Qatar University , Doha , Qatar .
authors.forename: Hassan A
authors.initials: HA
authors.lastname: Aziz
authors.affiliation: e Department of Biomedical Sciences , Edison Biotechnology Institute, Molecular and Cellular Biology Program, Ohio University , Athens , Ohio , USA.
authors.forename: Xiaozhuo
authors.initials: X
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology*; D013057:Spectrum Analysis
chemical_list: D000970:Antineoplastic Agents; D011744:Pyrimidinones
keywords: Apoptosis; PARP-1; RKO; caspase-3; p53; pyrazolo[3,4-d]pyrimidin-4(5H)-ones