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.

Parthenium hysterophorus:A Probable Source of Anticancer, Antioxidant and Anti-HIV Agents

“…This brings changes in the mitochondrial membrane that ultimately results in an opening of the mitochondrial permeability transition pore (MPT), loss of mitochondrial transmembrane potential (ΔΨ m ), and release of proapoptotic proteins from the intermembrane space into the cytosol [9]. The normal mechanism of cell cycle check point controls are often disrupted during tumor genesis which gives cells the chance to escape from apoptosis and proliferate continuously [10]. …”

6-Nitro-2-(3-hydroxypropyl)-1H-benz[de]isoquinoline-1,3-dione, a potent antitumor agent, induces cell cycle arrest and apoptosis

“…Both Mitonafide [3,4] and Amonafide [5,6] have undergone Phase I-II clinical trials with limited success. We have recently reported appreciable antitumor activity of some new compounds belonging to N-(2-chloroethyl)- and N-(3-chloropropyl) naphthalimides [7]. From the literature search, it was found that there was no report, to our knowledge, that describes the anticancer potential of known N-(2-hydroxyethyl) and N-(3-hydroxypropyl) naphthalimides (compounds 1a-j) .…”

Evaluation of antitumor efficacy and toxicity of novel 6-nitro-2-(3-chloropropyl)-1H-benz[de]isoquinoline-1,3-dione in vivo in mouse

“…[3] Anticancer drug Endoxan (Cyclophosphamide) was purchased from Sigma-Aldrich Com., USA. Mitonafide was received as a …”

“…1, Table 1] at different doses and schedules. A T/C max value of 138 was obtained for compound in S-180 at the dose of 60 mg/kg for QD [1][2][3][4][5][6][7] [Experiment no.1, Table 1]. Thus the compound has exhibited marginally significant activity in S-180.…”

“…[1,2] We have recently reported the synthesis, in vitro cytotoxicity and mechanism of action of a series of N- [2-(chloroethyl)]-and N- [3-(chloropropyl)]naphthalimides as a new class of antineoplastic agents. [3] Among them 6-nitro-2-(3-chloropropyl)-1H-benz[de]isoquinoline-1,3-dione [compound 1, Figure 1], which revealed excellent cytotoxicity in 15 out of 17 human tumor cell lines tested, was subjected to extensive screening in two murine tumors namely S-180 and EAC in Swiss Albino mice in vivo. Further, its toxicity in normal and S-180 bearing mice was assessed at its optimum dose.…”