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1.
Nanoscale ; 8(40): 17506-17515, 2016 Oct 14.
Article in English | MEDLINE | ID: mdl-27714177

ABSTRACT

Recent research efforts about iron oxide nanoparticles has focused on the development of iron oxide-based T1 contrast agents for magnetic resonance imaging (MRI), such as ultrasmall iron oxide nanospheres (USNPs <4 nm) and ultrathin nanowires (NW, diameter <4 nm). In this paper, we report the cellular uptake behaviors of these two types of ultrasmall scale nanostructures on HepG2 cells. Both these two nanostructures were functionalized with tannic acid and their physical and chemical properties were carefully analyzed before cellular tests. Both USNPs and NWs exhibited strong paramagnetic signals, a property suitable for T1 MRI contrast agents. The distinct shapes also caused much difference in their cellular uptake behaviors. Specifically, the uptake of USNPs was five times higher than that of NWs after 72 hours incubation. The shape-dependent cellular uptake can potentially lead to different blood circulation times, and subsequently different applications of these two types of ultrasmall nanostructures.

2.
Mini Rev Med Chem ; 10(2): 138-46, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20105131

ABSTRACT

Aberrant Ret kinase activity has been implicated in multiple carcinomas and disorders. Many strategies have been implemented to identify Ret kinase inhibitors. This review details current efforts to discover novel small molecule Ret kinase inhibitors. Furthermore, we compile a comprehensive list of Ret kinase inhibitors and describe clinical results of advanced assets with Ret inhibitory activity.


Subject(s)
Antineoplastic Agents/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-ret/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Clinical Trials as Topic , Drug Evaluation, Preclinical , Humans , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-ret/metabolism
3.
J Med Chem ; 44(25): 4339-58, 2001 Dec 06.
Article in English | MEDLINE | ID: mdl-11728181

ABSTRACT

Two closely related classes of oxindole-based compounds, 1H-indole-2,3-dione 3-phenylhydrazones and 3-(anilinomethylene)-1,3-dihydro-2H-indol-2-ones, were shown to potently inhibit cyclin-dependent kinase 2 (CDK2). The initial lead compound was prepared as a homologue of the 3-benzylidene-1,3-dihydro-2H-indol-2-one class of kinase inhibitor. Crystallographic analysis of the lead compound bound to CDK2 provided the basis for analogue design. A semiautomated method of ligand docking was used to select compounds for synthesis, and a number of compounds with low nanomolar inhibitory activity versus CDK2 were identified. Enzyme binding determinants for several analogues were evaluated by X-ray crystallography. Compounds in this series inhibited CDK2 with a potency approximately 10-fold greater than that for CDK1. Members of this class of inhibitor cause an arrest of the cell cycle and have shown potential utility in the prevention of chemotherapy-induced alopecia.


Subject(s)
Antineoplastic Agents/chemical synthesis , CDC2-CDC28 Kinases , Cyclin-Dependent Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Hydrazones/chemical synthesis , Indoles/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Crystallography, X-Ray , Cyclin-Dependent Kinase 2 , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , G1 Phase/drug effects , Humans , Hydrazones/chemistry , Hydrazones/pharmacology , Indoles/chemistry , Indoles/pharmacology , Isatin/analogs & derivatives , Isatin/chemical synthesis , Isatin/chemistry , Models, Molecular , Protein Binding , S Phase/drug effects , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Tumor Cells, Cultured
4.
Cancer Res ; 61(19): 7196-203, 2001 Oct 01.
Article in English | MEDLINE | ID: mdl-11585755

ABSTRACT

The type I receptor tyrosine kinases constitute a family of transmembrane proteins involved in various aspects of cell growth and survival and have been implicated in the initiation and progression of several types of human malignancies. The best characterized of these proteins are the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2/neu). We have developed potent quinazoline and pyrido-[3,4-d]-pyrimidine small molecules that are dual inhibitors of ErbB-2 and EGFR. The compounds demonstrate potent in vitro inhibition of the ErbB-2 and EGFR kinase domains with IC(50)s <80 nM. Growth of ErbB-2- and EGFR-expressing tumor cell lines is inhibited at concentrations <0.5 microM. Selectivity for tumor cell growth inhibition versus normal human fibroblast growth inhibition ranges from 10- to >75-fold. Tumor growth in mouse s.c. xenograft models of the BT474 and HN5 cell lines is inhibited in a dose-responsive manner using oral doses of 10 and 30 mg/kg twice per day. In addition, the tested compounds caused a reduction of ErbB-2 and EGFR autophosphorylation in tumor fragments from these xenograft models. These data indicate that these compounds have potential use as therapy in the broad population of cancer patients overexpressing ErbB-2 and/or EGFR.


Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , ErbB Receptors/antagonists & inhibitors , Quinazolines/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Animals , Cell Division/drug effects , Drug Screening Assays, Antitumor , Female , Growth Inhibitors/pharmacology , Humans , Mice , Mice, SCID , Structure-Activity Relationship , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
5.
Science ; 291(5501): 134-7, 2001 01 05.
Article in English | MEDLINE | ID: mdl-11141566

ABSTRACT

Most traditional cytotoxic anticancer agents ablate the rapidly dividing epithelium of the hair follicle and induce alopecia (hair loss). Inhibition of cyclin-dependent kinase 2 (CDK2), a positive regulator of eukaryotic cell cycle progression, may represent a therapeutic strategy for prevention of chemotherapy-induced alopecia (CIA) by arresting the cell cycle and reducing the sensitivity of the epithelium to many cell cycle-active antitumor agents. Potent small-molecule inhibitors of CDK2 were developed using structure-based methods. Topical application of these compounds in a neonatal rat model of CIA reduced hair loss at the site of application in 33 to 50% of the animals. Thus, inhibition of CDK2 represents a potentially useful approach for the prevention of CIA in cancer patients.


Subject(s)
Alopecia/chemically induced , Alopecia/prevention & control , Antineoplastic Agents/toxicity , CDC2-CDC28 Kinases , Cyclin-Dependent Kinases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hair Follicle/drug effects , Indoles/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Sulfonamides/pharmacology , Animals , Animals, Newborn , Antineoplastic Combined Chemotherapy Protocols/toxicity , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line , Cyclin-Dependent Kinase 2 , Cyclin-Dependent Kinases/metabolism , Cyclophosphamide/toxicity , Cytoprotection/drug effects , DNA/biosynthesis , Doxorubicin/toxicity , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Epithelium/drug effects , Etoposide/toxicity , Hair Follicle/cytology , Humans , Indoles/chemical synthesis , Indoles/chemistry , Mice , Mice, SCID , Phosphorylation , Protein Serine-Threonine Kinases/metabolism , Rats , Retinoblastoma Protein/metabolism , Scalp/transplantation , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Transplantation, Heterologous
6.
Mol Cancer Ther ; 1(2): 85-94, 2001 Dec.
Article in English | MEDLINE | ID: mdl-12467226

ABSTRACT

The epidermal growth factor receptor (EGFR) and ErbB-2 transmembrane tyrosine kinases are currently being targeted by various mechanisms in the treatment of cancer. GW2016 is a potent inhibitor of the ErbB-2 and EGFR tyrosine kinase domains with IC50 values against purified EGFR and ErbB-2 of 10.2 and 9.8 nM, respectively. This report describes the efficacy in cell growth assays of GW2016 on human tumor cell lines overexpressing either EGFR or ErbB-2: HN5 (head and neck), A-431 (vulva), BT474 (breast), CaLu-3 (lung), and N87 (gastric). Normal human foreskin fibroblasts, nontumorigenic epithelial cells (HB4a), and nonoverexpressing tumor cells (MCF-7 and T47D) were tested as negative controls. After 3 days of compound exposure, average IC50 values for growth inhibition in the EGFR- and ErbB-2-overexpressing tumor cell lines were < 0.16 microM. The average selectivity for the tumor cells versus the human foreskin fibroblast cell line was 100-fold. Inhibition of EGFR and ErbB-2 receptor autophosphorylation and phosphorylation of the downstream modulator, AKT, was verified by Western blot analysis in the BT474 and HN5 cell lines. As a measure of cytotoxicity versus growth arrest, the HN5 and BT474 cells were assessed in an outgrowth assay after a transient exposure to GW2016. The cells were treated for 3 days in five concentrations of GW2016, and cell growth was monitored for an additional 12 days after removal of the compound. In each of these tumor cell lines, concentrations of GW2016 were reached where outgrowth did not occur. Furthermore, growth arrest and cell death were observed in parallel experiments, as determined by bromodeoxyuridine incorporation and propidium iodide staining. GW2016 treatment inhibited tumor xenograft growth of the HN5 and BT474 cells in a dose-responsive manner at 30 and 100 mg/kg orally, twice daily, with complete inhibition of tumor growth at the higher dose. Together, these results indicate that GW2016 achieves excellent potency on tumor cells with selectivity for tumor versus normal cells and suggest that GW2016 has value as a therapy for patients with tumors overexpressing either EGFR or ErbB-2.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Division/drug effects , Enzyme Inhibitors/pharmacology , ErbB Receptors/antagonists & inhibitors , Furans/pharmacology , Neoplasms, Experimental/drug therapy , Quinazolines/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Animals , Apoptosis , Blotting, Western , Cell Cycle/drug effects , Epidermal Growth Factor/pharmacology , ErbB Receptors/metabolism , Female , Fibroblasts/drug effects , Humans , Infant, Newborn , Mice , Mice, Nude , Mice, SCID , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Phosphorylation , Precipitin Tests , Receptor, ErbB-2/metabolism , Signal Transduction/drug effects , Skin/cytology , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/metabolism , Xenograft Model Antitumor Assays
7.
Anticancer Drug Des ; 16(1): 1-6, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11762640

ABSTRACT

Earlier we reported potent cRaf1 kinase inhibitors with a key acidic phenol pharmacophore that had, at best, adequate cellular efficacy. To improve the cellular potency, phenol isosteres and prodrugs were investigated. Many phenol isosteres were synthesized and tested, but failed to provide adequate enzyme potency. A prodrug approach resulted in a 2- to 17-fold improvement over the parent compound in cell-based efficacy.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Prodrugs , Proteins/metabolism , Proto-Oncogene Proteins c-raf/metabolism , Cells, Cultured , Down-Regulation/drug effects , Humans , Indicators and Reagents , Mitogen-Activated Protein Kinases/biosynthesis , Phenols/chemical synthesis , Phenols/pharmacology , Structure-Activity Relationship , TNF Receptor-Associated Factor 3
8.
Bioorg Med Chem Lett ; 10(3): 223-6, 2000 Feb 07.
Article in English | MEDLINE | ID: mdl-10698440

ABSTRACT

A series of benzylidene-1H-indol-2-one (oxindole) derivatives was synthesized and evaluated as cRaf-1 kinase inhibitors. The key features of the molecules were the donor/acceptor motif common to kinase inhibitors and a critical acidic phenol flanked by two substitutions. Diverse 5-position substitutions provided compounds with low nanomolar kinase enzyme inhibition and inhibited the intracellular MAPK pathway.


Subject(s)
Enzyme Inhibitors/pharmacology , Proto-Oncogene Proteins c-raf/antagonists & inhibitors , Enzyme Inhibitors/chemistry , MAP Kinase Signaling System , Structure-Activity Relationship
9.
J Med Chem ; 41(11): 1894-908, 1998 May 21.
Article in English | MEDLINE | ID: mdl-9599239

ABSTRACT

The design, synthesis, and evaluation of dipeptide analogues as ligands for the pp60c-src SH2 domain are described. The critical binding interactions between Ac-Tyr-Glu-N(n-C5H11)2 (2) and the protein are established and form the basis for our structure-based drug design efforts. The effects of changes in both the C-terminal (11-27) and N-terminal (51-69) portions of the dipeptide are explored. Analogues with reduced overall charge (92-95) are also investigated. We demonstrate the feasibility of pairing structurally diverse subunits in a modest dipeptide framework with the goal of increasing the druglike attributes without sacrificing binding affinity.


Subject(s)
Dipeptides/pharmacology , Enzyme Inhibitors/pharmacology , Proto-Oncogene Proteins pp60(c-src)/antagonists & inhibitors , src Homology Domains , Crystallography, X-Ray , Dipeptides/chemical synthesis , Dipeptides/chemistry , Dipeptides/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Enzyme-Linked Immunosorbent Assay , Humans , Ligands , Models, Molecular , Molecular Conformation , Proto-Oncogene Proteins pp60(c-src)/metabolism , Structure-Activity Relationship
10.
J Med Chem ; 39(3): 713-9, 1996 Feb 02.
Article in English | MEDLINE | ID: mdl-8576914

ABSTRACT

Eleven water soluble 7-substituted quaternary ammonium salt derivatives of 10,11-(methylenedioxy)- and 10,11-(ethylenedioxy)-(20S)-camptothecin were synthesized via the Friedlander reaction followed by nucleophilic displacement with an aromatic amine. All of these compounds were more potent than camptothecin in the in vitro cleavable complex assay. These inherently charged camptothecin derivatives were cytotoxic against three different human tumor cell lines (SKOV3, an ovarian adenocarcinoma; SKVLB a multidrug resistant ovarian adenocarcinoma; and HT-29, a colon carcinoma). A selected group of five compounds was evaluated in the nude mouse HT-29 xenograft model. Two of these quaternary salts (17 and 18) were more efficacious than Topotecan in delaying tumor growth. In an extended in vivo model, 18 demonstrated tumor regression.


Subject(s)
Antineoplastic Agents/pharmacology , Camptothecin/pharmacology , Topoisomerase I Inhibitors , Adenocarcinoma/enzymology , Adenocarcinoma/pathology , Animals , Antineoplastic Agents/chemistry , Camptothecin/analogs & derivatives , Colonic Neoplasms/enzymology , Colonic Neoplasms/pathology , Female , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Mice, Nude , Ovarian Neoplasms/enzymology , Ovarian Neoplasms/pathology , Solubility , Structure-Activity Relationship , Tumor Cells, Cultured , Water
11.
J Med Chem ; 38(6): 906-11, 1995 Mar 17.
Article in English | MEDLINE | ID: mdl-7699706

ABSTRACT

Substituted 8-ethyl-2-(2-oxo-1,2-dihydroindol-3-ylidene)-8-hydroxy-2,3,5,8- tetrahydro-6-oxa-3a-azacyclopenta[b]naphthalene-1,4,7-triones were synthesized and evaluated as topoisomerase I inhibitors in an in vitro cleavable complex assay. The activity of these compounds may be attributed to their rigid, planar geometry, and an attempt was made to correlate the SAR in this series to known attributes of camptothecin.


Subject(s)
Alkaloids/chemical synthesis , Alkaloids/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Camptothecin/analogs & derivatives , Topoisomerase I Inhibitors , DNA/metabolism , Isomerism , Models, Molecular , Molecular Structure , Structure-Activity Relationship
12.
J Med Chem ; 38(3): 395-401, 1995 Feb 03.
Article in English | MEDLINE | ID: mdl-7853331

ABSTRACT

The synthesis and antitumor activities of the novel water soluble camptothecin derivatives 7-[(4-methylpiperazino)methyl]-10,11-(methylenedioxy)-(20S)-campto thecin trifluoroacetate (6) and 7-[(4-methylpiperazino)methyl]-10,11-(ethylenedioxy)-(20S)-camptot hecin trifluoroacetate (7) are described. The solubilities of compounds 6 and 7 were measured to be 4.5 and 5.8 mg/mL, respectively, in pH 5 acetate buffer in contrast to < 0.003 mg/mL for camptothecin in the same buffer. In the purified topoisomerase I cleavable complex enzyme assay, compounds 6 and 7 demonstrated potent inhibition of topoisomerase I with IC50's of 300 and 416 nM, respectively, in comparison to 679 nM for camptothecin and 1028 nM for topotecan. In human tumor cell cytotoxicity assays, compounds 6 and 7 demonstrated potent antitumor activity against ovarian (SKOV3), ovarian with upregulated MDRp-glycoprotein (SKVLB), melanoma (LOX), breast (T47D), and colon (HT29) with IC50's ranging from 0.5 to 102 nM. Compounds 6 and 7 induced tumor regressions in the HT29 human colon tumor xenograft model and demonstrated similar rank order of potency compared to in vitro assay results.


Subject(s)
Antineoplastic Agents/chemical synthesis , Camptothecin/analogs & derivatives , Topoisomerase I Inhibitors , Animals , Antineoplastic Agents/pharmacology , Camptothecin/chemical synthesis , Camptothecin/pharmacology , Cell Survival/drug effects , Female , Humans , Mice , Solubility , Tumor Cells, Cultured , Water/chemistry
13.
Psychol Rep ; 72(3 Pt 2): 1167-70, 1993 Jun.
Article in English | MEDLINE | ID: mdl-8337322

ABSTRACT

Estimations of some relationships among scores on the "General Purpose Abbreviated Battery" of the Stanford-Binet: Fourth Edition and the Wechsler Intelligence Scale for Children-III were based on the responses of 14 boys and 18 girls enrolled in Grades 3, 4, and 5 and who took both tests. Of 13 Pearson correlations between the Binet IV composite score and the Wechsler subtest scores and IQs 12 were statistically significant (rs = .45 to .74). The new Wechsler scale appears to be a valid instrument for the 32 children (8-8 to 11-11) who were tested.


Subject(s)
Intelligence , Stanford-Binet Test/statistics & numerical data , Wechsler Scales/statistics & numerical data , Child , Female , Humans , Male , Psychometrics , Reference Values
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