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1.
Bioorg Med Chem Lett ; 19(15): 4410-5, 2009 Aug 01.
Article in English | MEDLINE | ID: mdl-19500976

ABSTRACT

As a continuation of our efforts to discover and develop the 3-aryl-5-aryl-1,2,4-oxadiazole series of apoptosis inducers as potential anticancer agents, we explored substitutions at the 2- and 3-positions of the 3-aryl group to improve the aqueous solubility properties and identify development candidates. A small substitution such as methyl or hydroxymethyl at the 2-position was well tolerated. This modification, in combination with a 3-substituted furan ring as the 5-aryl group, resulted in 4g and 4h, which have improved solubility properties. Compound 4g was found to have good in vivo efficacy in animal studies via intravenous administration.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Chemistry, Pharmaceutical/methods , Oxadiazoles/chemical synthesis , Animals , Cell Line, Tumor , Combinatorial Chemistry Techniques , Drug Design , Drug Evaluation, Preclinical , Humans , Infusions, Intravenous , Mice , Models, Chemical , Molecular Structure , Neoplasm Transplantation , Oxadiazoles/pharmacology , Solubility , Structure-Activity Relationship , Water/chemistry
2.
Bioorg Med Chem Lett ; 19(13): 3481-4, 2009 Jul 01.
Article in English | MEDLINE | ID: mdl-19467598

ABSTRACT

As a continuation of our efforts to discover and develop the apoptosis inducing 1-benzoyl-3-cyanopyrrolo[1,2-a]quinolines as potential anticancer agents, we explored substitutions at the 4-, 5-, 6-, 7- and 8-positions of pyrrolo[1,2-a]quinoline. SAR studies showed that substitution at the 6-position by a small group such as Cl resulted in potent compounds. Substitutions at the 5- and 8-positions were tolerated while substitutions at the 4- and 7-position led to inactive compounds. Several compounds, including 2c, 3a, 3b and 3f, were found to be highly active against human breast cancer cells T47D with EC(50) values of 0.053-0.080microM, but much less active against human colon cancer cells HCT116 and hepatocellular carcinoma cancer cells SNU398 in the caspase activation assay. Compound 3f also was found to be highly active with a GI(50) value of 0.018microM against T47D cells in a growth inhibition assay.


Subject(s)
Antineoplastic Agents/chemistry , Apoptosis , Caspases/metabolism , Quinolines/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Discovery , Drug Screening Assays, Antitumor , Humans , Quinolines/chemical synthesis , Quinolines/pharmacology , Structure-Activity Relationship
3.
Bioorg Med Chem Lett ; 18(23): 6259-64, 2008 Dec 01.
Article in English | MEDLINE | ID: mdl-18952423

ABSTRACT

1-Benzoyl-3-cyanopyrrolo[1,2-a]quinoline (2a) was identified as a novel apoptosis inducer through our caspase- and cell-based high-throughput screening assay. Compound 2a had good activity against several breast cancer cell lines but was much less active against several other cancer cell lines. SAR studies of 2a found that substitution at the 4-position of the 1-benzoyl group was important for activity. Replacing the 3-cyano group by an ester or ketone group led to inactive compounds. Interestingly, 4-substituted analogs such as 1-(4-(1H-imidazol-1-yl)benzoyl)-3-cyanopyrrolo[1,2-a]quinoline (2k) were found to be broadly and highly active in the caspase activation assay as well as in the cell growth inhibition assay with low nM EC(50) and GI(50) values in human breast cancer cells T47D, human colon cancer cells HCT116, and hepatocellular carcinoma cancer cells SNU398. Compound 2a was found not to inhibit tubulin polymerization up to 50 microM, while 2k was found to inhibit tubulin polymerization with an IC(50) value of 5 microM, indicating that certain substituents at the 4-position of the 1-benzoyl group can change the mechanism of action.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Tubulin Modulators/chemical synthesis , Tubulin Modulators/pharmacology , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Caspases/metabolism , Combinatorial Chemistry Techniques , Drug Screening Assays, Antitumor , Female , HCT116 Cells , Humans , Molecular Structure , Quinolines/chemistry , Structure-Activity Relationship , Tubulin Modulators/chemistry
4.
Bioorg Med Chem ; 16(8): 4233-41, 2008 Apr 15.
Article in English | MEDLINE | ID: mdl-18337106

ABSTRACT

We have reported the discovery of gambogic acid (GA) as a potent apoptosis inducer and the identification of transferrin receptor as its molecular target. In order to understand the basic pharmacophore of GA for inducing apoptosis and to discover novel and simplified derivatives as potential anti-cancer agents, we explored the synthesis of caged 2,3,3a,7a-tetrahydro-3,6-methanobenzofuran-7(6H)-ones (4-oxatricyclo[4.3.1.0]decan-2-ones). Three types of 2,3,3a,7a-tetrahydro-3,6-methanobenzofuran-7(6H)-ones based on xanthone, 2-phenylchromene-4-one and benzophenone, were synthesized using a Claisen/Diels-Alder reaction cascade. All the reactions produced the targeted caged compound as well as its neo-isomer. The caged compounds based on xanthone and 2-phenylchromene-4-one were found to maintain the apoptosis inducing and cell growth inhibiting activity of GA, although with less potency. The caged compounds based on benzophenone were found to be inactive. Our study determined the minimum structure of GA for its apoptosis inducing activity, which could lead to the development of simple derivatives as potential anti-cancer drugs.


Subject(s)
Apoptosis/drug effects , Benzofurans/chemistry , Hydrogen/chemistry , Xanthones/chemical synthesis , Xanthones/pharmacology , Caspases/metabolism , Cell Line, Tumor , Enzyme Activation/drug effects , Humans , Molecular Structure , Structure-Activity Relationship , Xanthones/chemistry
5.
J Med Chem ; 48(16): 5215-23, 2005 Aug 11.
Article in English | MEDLINE | ID: mdl-16078840

ABSTRACT

We have identified 5-(3-chlorothiophen-2-yl)-3-(4-trifluoromethylphenyl)-1,2,4-oxadiazole (1d) as a novel apoptosis inducer through our caspase- and cell-based high-throughput screening assay. Compound 1d has good activity against several breast and colorectal cancer cell lines but is inactive against several other cancer cell lines. In a flow cytometry assay, treatment of T47D cells with 1d resulted in arrest of cells in the G(1) phase, followed by induction of apoptosis. SAR studies of 1d showed that the 3-phenyl group can be replaced by a pyridyl group, and a substituted five-member ring in the 5-position is important for activity. 5-(3-Chlorothiophen-2-yl)-3-(5-chloropyridin-2-yl)-1,2,4-oxadiazole (4l) has been found to have in vivo activity in a MX-1 tumor model. Using a photoaffinity agent, the molecular target has been identified as TIP47, an IGF II receptor binding protein. Therefore, our cell-based chemical genetics approach for the discovery of apoptosis inducers can identify potential anticancer agents as well as their molecular targets.


Subject(s)
Antineoplastic Agents/chemical synthesis , Apoptosis , Oxadiazoles/chemical synthesis , Thiophenes/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Caspases/metabolism , Cell Line, Tumor , Cell Proliferation , DNA-Binding Proteins/metabolism , Drug Screening Assays, Antitumor , Enzyme Activation , Flow Cytometry , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Perilipin-3 , Pregnancy Proteins/metabolism , Receptor, IGF Type 2/metabolism , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacology , Vesicular Transport Proteins
6.
Mol Cancer Ther ; 4(5): 761-71, 2005 May.
Article in English | MEDLINE | ID: mdl-15897240

ABSTRACT

A novel series of 3,5-diaryl-oxadiazoles was identified as apoptosis-inducing agents through our cell and chemical genetics-based screening assay for compounds that induce apoptosis using a chemical genetics approach. Several analogues from this series including MX-74420 and MX-126374 were further characterized. MX-126374, a lead compound from this series, was shown to induce apoptosis and inhibit cell growth selectively in tumor cells. To elucidate the mechanism(s) by which this class of compounds alters the signal transduction pathway that ultimately leads to apoptosis, expression profiling using the Affymetrix Gene Chip array technology was done along with other molecular and biochemical analyses. Interestingly, we have identified several key genes (cyclin D1, transforming growth factor-beta1, p21, and insulin-like growth factor-BP3) that are altered in the presence of this compound, leading to characterization of the pathway for activation of apoptosis. MX-126374 also showed significant inhibition of tumor growth as a single agent and in combination with paclitaxel in murine tumor models. Using photoaffinity labeling, tail-interacting protein 47, an insulin-like growth factor-II receptor binding protein, was identified as the molecular target. Further studies indicated that down-regulation of tail-interacting protein 47 in cancer cells by small interfering RNA shows a similar pathway profile as compound treatment. These data suggest that 3,5-diaryl-oxadiazoles may be a new class of anticancer drugs that are tumor-selective and further support the discovery of novel drugs and drug targets using chemical genetic approaches.


Subject(s)
Apoptosis/drug effects , Caspases/metabolism , Drug Screening Assays, Antitumor , Enzyme Activation/drug effects , Gene Expression Profiling , Oxadiazoles/pharmacology , Animals , Antineoplastic Agents , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Cycle Proteins/metabolism , Cell Proliferation/drug effects , Cells, Cultured , Chickens , Cyclin-Dependent Kinase Inhibitor p21 , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Female , Humans , Immunoglobulins/immunology , Mammary Glands, Human/cytology , Mammary Glands, Human/drug effects , Mammary Glands, Human/metabolism , Oligonucleotide Array Sequence Analysis , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Receptor, IGF Type 2/genetics , Receptor, IGF Type 2/immunology , Receptor, IGF Type 2/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta1
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