ABSTRACT
A series of 2,5-diaryloxadiazole linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates have been prepared and evaluated for their anticancer activity. These conjugates have shown promising activity with GI50 values ranging from <0.1 to 0.29 microM. It is observed that some of these conjugates particularly 4a, 4d, 4i and 4l exhibit significant anticancer activity. Some detailed biological assays relating to the cell cycle aspects associated to Bax and caspases have been examined with a view to understand the mechanism of action of these conjugates.
Subject(s)
Antineoplastic Agents/chemical synthesis , Apoptosis , Benzodiazepines/chemistry , Mitochondria/drug effects , Oxadiazoles/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Benzodiazepines/chemical synthesis , Benzodiazepines/therapeutic use , Caspases/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cyclin-Dependent Kinase 2/metabolism , Humans , Male , Mice , Mice, Inbred NOD , Neoplasms/drug therapy , Oxadiazoles/chemical synthesis , Tumor Suppressor Protein p53/metabolism , Xenograft Model Antitumor Assays , bcl-2-Associated X Protein/metabolismABSTRACT
A series of novel chalcone linked imidazolones were prepared and evaluated for their anti-cancer activity against a panel of 53 human tumour cell lines derived from nine different cancer types: leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate and breast. Some of these hybrids (6, 7 and 8) showed good anti-cancer activity with GI(50) values ranging from 1.26 to 13.9 microM. When breast carcinoma cells (MCF-7) were treated with 10 microM concentration of compounds TMAC, CA-4, 6 and 8 cell cycle arrest was observed in G2/M phase. Surprisingly, the increased concentration of the same compound to 30 microM caused accumulation of cells in G0/G1 phase of the cell cycle.
Subject(s)
Antineoplastic Agents/chemical synthesis , Chalcone/chemistry , Imidazoles/chemistry , Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Imidazoles/chemical synthesis , Imidazoles/therapeutic useABSTRACT
A series of new cinnamido-pyrrolo[2,1-c][1,4]benzodiazepine conjugates (4a-d and 5a-d) and their dimers (6a-d) have been designed, synthesized and evaluated for their biological activity. The anticancer screening of compound 4a by the NCI exhibited significant GI50 values ranging from 68 to 732 nM against 53 of 59 human cancer cell lines tested. Compounds 5a-d and 6a-d have also shown remarkable cytotoxic activity with GI50 values <0.1 microM concentrations in a large number of cell lines. Interestingly, compounds 5b and 6b have been identified as a new class of inhibitors of tubulin polymerization and their action has been rationalized by the cell cycle arrest in G0 and G2/M phase.
Subject(s)
Antimitotic Agents/chemical synthesis , Antimitotic Agents/pharmacology , Benzodiazepines/chemical synthesis , Benzodiazepines/pharmacology , Antimitotic Agents/chemistry , Apoptosis/drug effects , Benzodiazepines/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Humans , Inhibitory Concentration 50 , Protein Multimerization/drug effects , Protein Structure, Quaternary , Tubulin/chemistry , Tubulin/metabolismABSTRACT
New phenanthrylphenol-pyrrolobenzodiazepine (PP-PBD) conjugates have been synthesized and evaluated for their biological activity. One of the compounds 4a has been evaluated for its antiproliferative activity on 57 human tumour cell lines. The growth inhibition of 4a-c has been determined by MTT viability assay on MCF-7 cell line. Among them, 4c showed most potent growth inhibition. Based on this, an attempt was made to rationalize their mechanism of action through cell cycle analysis and DNA interaction studies. The effect of the lead compound 4c on MCF-7 cell growth associated with cell cycle arrest in G1 phase, followed by apoptosis. Our findings suggested the phenanthrylphenol-PBD conjugate 4c, which is a cyclin D1 inhibitor could be considered as a promising lead compound against breast cancer for further investigation.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzodiazepines/chemical synthesis , Benzodiazepines/pharmacology , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Benzodiazepines/chemistry , Caspase 8/metabolism , Caspase 9/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin D1/metabolism , Cytochromes c/metabolism , Cytoplasm/drug effects , Cytoplasm/metabolism , DNA Fragmentation/drug effects , Enzyme Activation/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Humans , Poly(ADP-ribose) Polymerases/metabolism , Restriction MappingABSTRACT
C2-Fluoro substituted DC-81, and its dimers that comprise of two C2-fluoro substituted DC-81 subunits tethered to their C8-position through simple alkane spacers as well as piperazine moiety side-armed with symmetrical alkyloxy spacers have been designed and synthesized. These fluoro substituted pyrrolo[2,1-c][1,4]benzodiazepines have shown remarkable DNA-binding ability and most of them possess promising anticancer activity, having GI(50) values in micromolar to nanomolar concentration range. DNA thermal denaturation studies show that some of these compounds (14a-c and 15) increase the DeltaT(m) values in the range of 28.9-38 degrees C, and this is further confirmed by the restriction endonuclease studies. This study illustrates the importance of introducing fluoro substitution at the C2-position apart from the incorporation of a piperazine ring in between the alkyloxy linker for enhancement of the DNA-binding ability in comparison to DSB-120 and SJG-136 (DeltaT(m)=10.2 and 25.7 degrees C). Moreover, the variations in the DNA-binding ability with respect to fluoro substitution in this class of dimers has been investigated by molecular modeling studies. Some representative C2-fluoro substituted dimers (8a and 14a) have also exhibited significant anticancer activity in the 60 cancer cell line assay of the National Cancer Institute (NCI).
