Reaction of salicylaldehyde thiosemicarbazone (H 2 L 1 ), 2-hydroxyacetophenone thiosemicarbazone (H 2 L 2 ) and 2-hydroxynaphthaldehyde thiosemicarbazone (H 2 L 3 ) (general abbreviation H 2 L, where H 2 stands for the two dissociable protons, one phenolic proton and one hydrazinic proton) with Na 2 [PdCl 4 ] affords a family of polymeric complexes of type [{Pd(L)} n ]. Reaction of the polymeric species with two monodentate ligands (D), viz. triphenylphosphine (PPh 3 ) and 4-picoline (pic), has yielded complexes of type [Pd(L)(D)]. These mixed-ligand complexes have also been obtained from reaction of the thiosemicarbazones with [Pd(PPh 3 ) 2 Cl 2 ] and [Pd(pic) 2 Cl 2 ]. Crystal structures of [Pd(L 1 )(PPh 3 )] and [Pd(L 2 )(pic)] have been determined. The [Pd(L)(D)] complexes show characteristic 1 H NMR spectra and intense absorptions in the visible and ultraviolet region. They also fluoresce in the visible region at ambient temperature. In vitro cytotoxicity screenings of the complexes along with four human clinical drugs viz. cisplatin, BCNU, 5-fluorouracil (5-FU) and hydroxyurea have been carried out in two human tumor cell lines, namely promyelocytic leukemia HL-60 and histiocytic lymphoma U-937. [Pd(L 2 )(PPh 3 )] shows the lowest IC 50 value and is found to be much more cytotoxic than the reference anticancer drugs in both the cell lines. An apoptosis study in HL-60 with [Pd(L 2 )(PPh 3 )] confirms that at 10 mM concentration it induces apoptosis to a greater extent than cisplatin and camptothecin.

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BackgroundAnticancer activities of several substituted naphthalimides (1H-benz[de]isoquinoline-1,3-diones) are well documented. Some of them have undergone Phase I-II clinical trials. Presently a series of ten N-(hydroxyalkyl) naphthalimides (compounds 1a-j) were evaluated as antitumor agents.MethodsCompounds 1a-j were initially screened in MOLT-4, HL-60 and U-937 human tumor cell lines and results were compared with established clinical drugs. Cytotoxicities of compounds 1d and 1i were further evaluated in a battery of human tumor cell lines and in normal human peripheral blood mononuclear cells. Cell cycle analysis of compound 1i treated MOLT-4 cells was studied by flow cytometry. Its apoptosis inducing effect was carried out in MOLT-4 and HL-60 cells by flow cytometry using annexin V-FITC/PI double staining method. The activities of caspase-3 and caspase-6 in MOLT-4 cells following incubation with compound 1i were measured at different time intervals. Morphology of the MOLT-4 cells after treatment with 1i was examined under light microscope and transmission electron microscope. 3H-Thymidine and 3H-uridine incorporation in S-180 cells in vitro following treatment with 8 μM concentration of compounds 1d and 1i were studied.Results6-Nitro-2-(3-hydroxypropyl)-1H-benz[de]isoquinoline-1,3-dione (compound 1i), has exhibited maximum activity as it induced significant cytotoxicity in 8 out of 13 cell lines employed. Interestingly it did not show any cytotoxicity against human PBMC (IC50 value 273 μM). Cell cycle analysis of compound 1i treated MOLT-4 cells demonstrated rise in sub-G1 fraction and concomitant accumulation of cells in S and G2/M phases, indicating up-regulation of apoptosis along with mitotic arrest and/or delay in exit of daughter cells from mitotic cycle respectively. Its apoptosis inducing effect was confirmed in flow cytometric study in MOLT-4 and the action was mediated by activation of both caspase 3 and 6. Light and transmission electron microscopic studies corroborated its apoptosis inducing efficacy at a concentration of 10 μM in MOLT-4 cells. Its apoptosis induction was also observed in HL-60 cells to an extent much greater than well known apoptosis inducing agents as camptothecin and cis-platin at 10 μM concentration each. It significantly inhibited DNA and RNA synthesis in S-180.ConclusionsIn essence, compound 1i showed potential as an antitumor agent.

A new breast-tumor-associated antigen (BTAA) was purified and partially characterized from human breast tumor. By DEAE-cellulose discontinuous NaCl-gradient chromatography of a crude extract of human malignant breast tumor, 3 major protein peaks were obtained. Circulating antibodies against one of the protein peaks, HF1, was observed in breast-cancer patients. The antibodies were absent in patients with carcinoma of the uterine cervix, lung, stomach and liver or with benign breast diseases and in healthy women. Absorption of the sera of breast-cancer patients with normal human breast tissue pellet did not remove the HF1-reactive circulating antibodies. The BTAA was partially purified from HF1 by subjecting the fraction to SDS-PAGE and eluting the band 3 (HF1-3). Western-blot analysis confirmed the presence of the BTAA in HF1-3. Using an affinity column of protein-A-Sepharose-bound IgG, purified from breast-cancer patients' sera, the BTAA was also recovered from HF1. Purification of the BTAA was achieved by subjecting HF1 to size-exclusion high-performance liquid chromatography (SE-HPLC). The antigen was characterized as a glycoprotein with MW of approximately 85 kDa and appeared not to be related either to murine mammary-tumor virus (MuMTV) structural antigens or to human fetal antigens. The BTAA-reactive circulating antibodies in the breast-cancer patients were of IgG, sub-type, and the level of these antibodies significantly decreased in patients following surgical removal of the breast tumors.

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.

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