title: Synthesis and biological evaluation of new pyridone-annelated isoindigos as anti-proliferative agents.
abstract: A selected set of substituted pyridone-annelated isoindigos 3a-f has been synthesized via interaction of 5- and 6-substituted oxindoles 2a-f with 6-ethyl-1,2,9-trioxopyrrolo[3,2-f]quinoline-8-carboxylic acid (1) in acetic acid at reflux. Among these isoindigos, the 5'-chloro and 5'-bromo derivatives 3b and 3d show strong and selective antiproliferative activities against a panel of human hematological and solid tumor cell-lines, but not against noncancerous cells, suggesting their potential use as anticancer agents. In all the tested cell lines, compound 3b was a 25%-50% more potent inhibitor of cell growth than 3d, suggesting the critical role of the substitution at 5'-position of the benzo-ring E. The IC50 values after 48 hours incubation with the 5'-chloro compound 3b were 6.60 µM in K562, 8.21 µM in THP-1, 8.97 µM in HepG2, 11.94 µM in MCF-7 and 14.59 µM in Caco-2 cancer cells, while the IC50 values in noncancerous HEK-293 and L-929 were 30.65 µM and 40.40 µM, respectively. In addition, compound 3b induced higher levels apoptosis in K562 cells than 3d, as determined by annexin V/7-AAD flowcytometry analysis. Therefore, further characterization of the antitproliferative mechanisms of compounds 3b and 3d may provide a novel chemotherapeutic agents.
authors.affiliation: Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), P.O. Box 3660, Riyadh 11481, Kingdom of Saudi Arabia. salehay@ngha.med.sa.
authors.forename: Ayman M
authors.initials: AM
authors.lastname: Saleh
authors.affiliation: Chemistry Department, Faculty of Science, The University of Jordan, Amman 11942, Jordan. randaalasad@yahoo.com.
authors.forename: Randa M
authors.initials: RM
authors.lastname: Al-As'ad
authors.affiliation: Chemistry Department, Faculty of Science, The University of Jordan, Amman 11942, Jordan. mustelab@ju.edu.jo.
authors.forename: Mustafa M
authors.initials: MM
authors.lastname: El-Abadelah
authors.affiliation: Chemistry Department, Faculty of Science, The University of Jordan, Amman 11942, Jordan. s.sabri@ju.edu.jo.
authors.forename: Salim S
authors.initials: SS
authors.lastname: Sabri
authors.affiliation: Chemistry Department, Faculty of Science, The University of Jordan, Amman 11942, Jordan. zahra@ju.edu.jo.
authors.forename: Jalal A
authors.initials: JA
authors.lastname: Zahra
authors.affiliation: King Abdullah International Medical Research Center (KAIMRC), National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Kingdom of Saudi Arabia. aljadaa@ngha.med.sa.
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Alaskar
authors.affiliation: Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), P.O. Box 3660, Riyadh 11481, Kingdom of Saudi Arabia. aljadaa@ngha.med.sa.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Aljada
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020014:K562 Cells; D009369:Neoplasms / Q000188:drug therapy*; D000078183:Oxindoles; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D000078183:Oxindoles; D011728:Pyridones; C022960:2-oxindole; C049010:isoindigotin