title: Antitumor efficacy and apoptotic activity of substituted chloroalkyl 1H-benz[de]isoquinoline-1,3-diones: a new class of potential antineoplastic agents.
abstract: A series of ten chloroalkyl 1H-benz[de]isoquinoline-1,3-diones (naphthalimides) were synthesized and evaluated for antitumor activity. Amongst them, new compounds 2d and 2i carrying a 6-NO(2) substituent in the aromatic portion of the molecule possessed significant antineoplastic activity. The most active compound 2i had elicited significant cytotoxicity in 15 human tumor cell lines namely Leukemia: MOLT-4, HL-60; Lymphoma: U-937; Colon: 502713, HT-29, SW-620, HCT-15, COLO-205; Liver: Hep-2; Prostate DU-145, PC-3; Breast: MCF-7; Neuroblastoma: IMR-32, SK-N-SH and Ovary: OVCAR-5 out of the 17 cell lines screened. Flow cytometric analysis performed to study the effect of compound 2i on the progression of cell cycle of MOLT-4 cells, revealed rise in sub-G(1) fraction and concomitant accumulation of cells in S and G(2)/M phases, indicating apoptosis, mitotic arrest and/or delay in exit of daughter cells from mitotic cycle respectively. It also induced caspase-mediated apoptosis of MOLT-4 cells in a dose dependant manner. Light and electron microscopic studies revealed characteristic morphology of apoptotic MOLT-4 cells after in vitro treatment with 10 μM concentration of the compound. Apoptosis induction was also observed in HL-60 cells by compounds 2d and 2i to an extent much greater than camptothecin and cis-platin at 10 μM concentration. Both the compounds have shown minimal suppressive effect on human PBMC having high IC(50) values of 3,582 and 1,536 μM respectively. These compounds inhibited DNA and RNA synthesis in murine ascites Sarcoma-180 tumor cells in vitro at 8 μM concentration. Above results indicate promising chemotherapeutic potential of the key compound 2i.
authors.affiliation: Department of Anticancer Drug Development, Chittaranjan National Cancer Institute, Kolkata, 700026, India.
authors.forename: Asama
authors.initials: A
authors.lastname: Mukherjee
authors.forename: Suva
authors.initials: S
authors.lastname: Hazra
authors.forename: Sushanta
authors.initials: S
authors.lastname: Dutta
authors.forename: Shanmugavel
authors.initials: S
authors.lastname: Muthiah
authors.forename: Dilip Manikrao
authors.initials: DM
authors.lastname: Mondhe
authors.forename: Parduman Raj
authors.initials: PR
authors.lastname: Sharma
authors.forename: Shashank Kumar
authors.initials: SK
authors.lastname: Singh
authors.forename: Ajit Kumar
authors.initials: AK
authors.lastname: Saxena
authors.forename: Gulam Nabi
authors.initials: GN
authors.lastname: Qazi
authors.forename: Utpal
authors.initials: U
authors.lastname: Sanyal
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D053644:Naphthalimides / Q000737:chemistry / Q000494:pharmacology; D011419:Propidium / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013194:Staining and Labeling; D016896:Treatment Outcome
chemical_list: D017304:Annexin A5; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007546:Isoquinolines; D053644:Naphthalimides; D012334:RNA, Neoplasm; C019215:mitonafide; D011419:Propidium; D020169:Caspases; D016650:Fluorescein-5-isothiocyanate; C039109:isoquinoline