ABSTRACT
A series of aminostilbene-arylpropenones were designed and synthesized by Michael addition and were investigated for their cytotoxic activity against various human cancer cell lines. Some of the investigated compounds exhibited significant antiproliferative activity against a panel of 60 human cancer cell lines of the US National Cancer Institute, with 50 % growth inhibition (GI50) values in the range from < 0.01 to 19.9 µM. One of the compounds showed a broad spectrum of antiproliferative efficacy on most of the cell lines, with a GI50 value of < 0.01 µM. All of the synthesized compounds displayed cytotoxicity against A549 (non-small-cell lung cancer), HeLa (cervical carcinoma), MCF-7 (breast cancer), and HCT116 (colon carcinoma) with 50 % inhibitory concentration (IC50) values ranging from 0.011 to 8.56 µM. A cell cycle assay revealed that these compounds arrested the G2/M phase of the cell cycle. Two compounds exhibited strong inhibitory effects on tubulin assembly with IC50 values of 0.71 and 0.79 µM. Moreover, dot-blot analysis of cyclin B1 demonstrated that some of the congeners strongly induced cyclin B1 protein levels. Molecular docking studies indicated that these compounds occupy the colchicine binding site of tubulin.
Subject(s)
Alkenes/chemistry , Drug Design , Stilbenes/chemistry , Tubulin Modulators/chemical synthesis , Tubulin/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin B1/metabolism , Drug Screening Assays, Antitumor , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , M Phase Cell Cycle Checkpoints/drug effects , Molecular Docking Simulation , Protein Structure, Tertiary , Tubulin/metabolism , Tubulin Modulators/chemistry , Tubulin Modulators/toxicityABSTRACT
A library of imidazopyridine-oxindole conjugates was synthesised and investigated for anticancer activity against various human cancer cell lines. Some of the tested compounds, such as 10 a, 10 e, 10 f, and 10 k, exhibited promising antiproliferative activity with GI50 values ranging from 0.17 to 9.31â µM. Flow cytometric analysis showed that MCF-7 cells treated by these compounds arrested in the G2 /M phase of the cell cycle in a concentration-dependent manner. More particularly, compound 10 f displayed a remarkable inhibitory effect on tubulin polymerisation. All the compounds depolarised mitochondrial membrane potential and caused apoptosis. These results are further supported by the decreased phosphorylation of Akt at Ser473. Studies on embryonic development revealed that the lead compounds 10 f and 10 k caused delay in the development of zebra fish embryos. Docking of compound 10 f with tubulin protein suggested that the imidazo[1,2-a]pyridine moiety occupies the colchicine binding site of tubulin.
Subject(s)
Antineoplastic Agents/chemical synthesis , Indoles/chemistry , Microtubules/metabolism , Pyridines/chemistry , Tubulin Modulators/chemical synthesis , Animals , Antineoplastic Agents/metabolism , Antineoplastic Agents/toxicity , Cell Line, Tumor , Cell Proliferation/drug effects , Embryo, Nonmammalian/drug effects , Embryo, Nonmammalian/metabolism , Embryonic Development/drug effects , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , M Phase Cell Cycle Checkpoints/drug effects , MCF-7 Cells , Microtubules/chemistry , Oxindoles , Protein Structure, Tertiary , Signal Transduction/drug effects , Structure-Activity Relationship , Tubulin/chemistry , Tubulin/metabolism , Tubulin Modulators/metabolism , Tubulin Modulators/toxicity , Zebrafish/growth & developmentABSTRACT
A series of new terphenyl benzimidazoles (3a-z and 3aa-ad) were synthesized and evaluated for their anticancer activity. All the 30 compounds have shown moderate to good anticancer potency, however some of the compounds (3j, 3m-t and 3aa-ad) exhibited prominent anticancer potency with GI(50) values ranging from <0.1 to 9.72 µM. These compounds exhibit G2/M phase arrest and the analysis of tubulin by Western blot experiments in case of 3t and 3ad shows the disturbances that are caused in the ratio of soluble versus polymerized tubulin in cells. Compounds 3t and 3ad are the most promising candidates amongst the series and has the potential to be taken up for further detailed studies either alone or in combination with the existing therapies.
Subject(s)
Benzimidazoles/chemical synthesis , Cell Cycle/drug effects , Cell Proliferation/drug effects , Neoplasms/drug therapy , Tubulin Modulators/chemical synthesis , Tubulin/metabolism , Benzimidazoles/pharmacology , Blotting, Western , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Structure-Activity Relationship , Tubulin Modulators/pharmacology , Tumor Cells, CulturedABSTRACT
A series of anilino substituted pyrimidine sulfonamides were prepared and evaluated for their anticancer activity. These sulfonamides showed promising activity with IC(50) values ranging from 5.6 to 12.3 µM. The detailed biological aspects of some of the promising compounds (3d, 3e and 3g) on the K562 cell line were studied. Interestingly, compounds induced G1 cell cycle arrest and down regulation of G1 phase cell cycle regulatory proteins such as cyclin D1, CDK4. These compounds also exhibited inhibition of NF-κB as well as its downstream target gene Akt1 and the phosphorylated form of AKt ser 474 proteins. One of the representative compound 3e could be considered as the potential lead for its development as a new anticancer agent.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cyclin D1/metabolism , Down-Regulation/drug effects , G1 Phase/drug effects , Humans , NF-kappa B/genetics , Neoplasms/drug therapyABSTRACT
A library of new aryl-substituted naphthalene C8-linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates with various linker architectures were designed, synthesized, and evaluated for their anticancer activity against a panel of 11 human cancer cell lines. All 32 conjugates show anticancer potential, with some of them exhibiting particularly high activity (0.01-0.19â µM). Thermal denaturation studies showed effective DNA binding capacity relative to DC-81. In assays for biological activity relating to cell-cycle distribution, these PBD conjugates induce G0/G1-phase arrest and also cause an increase in the levels of p53 and caspase-9 proteins, followed by apoptotic cell death. One conjugate in particular is the most promising candidate of the series, with the potential to be selected for further studies, either alone or in combination with existing anticancer therapies.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Benzodiazepines/pharmacology , Naphthalenes/pharmacology , Neoplasms/drug therapy , Pyrroles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzodiazepines/chemical synthesis , Benzodiazepines/chemistry , Caspase 9/metabolism , Cell Line, Tumor , Drug Design , Humans , Naphthalenes/chemistry , Neoplasms/metabolism , Neoplasms/pathology , Pyrroles/chemical synthesis , Pyrroles/chemistry , Tumor Suppressor Protein p53/metabolismABSTRACT
A series of new estradiol linked pyrrolo[2,1-c][1,4]benzodiazepine (E(2)-PBD) conjugates (3a-f, 4a-f and 5a-f) with different linker architectures including a triazole moiety have been designed and synthesized. All the 18 compounds have been evaluated for their anticancer activity and it is observed that some of the compounds particularly 4c-e and 5c,d exhibited significant anticancer activity. The detailed biological aspects relating to the cell cycle effects and tubulin depolymerization activity have been examined with a view to understand the mechanism of action of these conjugates. Among all these conjugates, one of the compound 5c could be considered as the most effective compound particularly against MCF-7 breast cancer cell line.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzodiazepines/chemical synthesis , Antineoplastic Agents/pharmacology , Benzodiazepines/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Cycle/drug effects , Cell Line, Tumor , Estradiol , Estrogens , Female , Humans , Pyrroles , Structure-Activity Relationship , Tubulin/drug effectsABSTRACT
A series of new 3,5-diaryl isoxazoline/isoxazole linked 2,3-dihydro quinazolinone hybrids with different linker architectures have been designed and synthesized. These compounds have been evaluated for their anticancer activity. One of the compounds 4c amongst this series has shown promising anticancer activity. Further some detailed biological assays relating to the cell cycle aspects and tubulin depolymerization activity have been examined with a view to understand the mechanism of action of this conjugate.
Subject(s)
Antineoplastic Agents/pharmacology , Isoxazoles/pharmacology , Quinazolinones/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Molecular Structure , Quinazolinones/chemical synthesis , Quinazolinones/chemistry , StereoisomerismABSTRACT
A series of new anilino substituted pyrimidine linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates were prepared and evaluated for their anticancer activity. The effects of four promising PBD conjugates on cell cycle of cancerous cell line A375 were investigated. These compounds showed the characteristic features of apoptosis like enhancement in the levels of p53, release of cytochrome c, and cleavage of PARP.
Subject(s)
Aniline Compounds/chemistry , Benzodiazepines/chemical synthesis , Benzodiazepines/pharmacology , Pyrimidines/chemistry , Benzodiazepines/chemistry , Cell Line, Tumor , Drug Evaluation, Preclinical , Drug Screening Assays, Antitumor , HumansABSTRACT
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).
