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1.
J Med Chem ; 43(22): 4200-11, 2000 Nov 02.
Article in English | MEDLINE | ID: mdl-11063616

ABSTRACT

A series of 3-aryl-1,6-naphthyridine-2,7-diamines and related 2-ureas were prepared and evaluated as inhibitors of the FGF receptor-1 tyrosine kinase. Condensation of 4,6-diaminonicotinaldehyde and substituted phenylacetonitriles gave intermediate naphthyridine-2,7-diamines, and direct reaction of the monoanion of these (NaH/DMF) with alkyl or aryl isocyanates selectively gave the 2-ureas in varying yields (23-93%). For the preparation of more soluble 7-alkylamino-2-ureas, a number of protecting groups for the 2-amine were evaluated (phthaloyl, 4-methoxybenzyl) following selective blocking of the 7-amine (trityl), but these were not superior to the (required) 2-tert-Bu-urea group itself. Direct alkylation of the anion of the (unprotected) 7-amino group with excess 4-(3-chloropropyl)morpholine in DMF gave low (10%) yields of the desired product, but alkylation of the 7-acetamido anion, followed by mild alkaline hydrolysis, raised this to 64%. 3-Phenyl analogues were nonspecific inhibitors of isolated c-Src, FGFR, and PDGFR tyrosine kinases, whereas 3-(2,6-dichlorophenyl) analogues were most effective against c-Src and FGFR, and 3-(3,5-dimethoxyphenyl) derivatives showed high selectivity for FGFR alone. A water-soluble (7-morpholinylpropylamino) analogue retained high FGFR potency (IC(50) 31 nM) and selectivity. Pairwise comparison of the 1, 6-naphthyridines and the corresponding known pyrido[2,3-d]pyrimidine analogues showed little differences in potency or patterns of selectivity, suggesting that the 1-aza atom of the latter is not important for activity. A 7-acetamide derivative inhibited the growth of FGFR-expressing tumor cell lines and was particularly potent against HUVECs (IC(50) 4 nM). This compound was also a very potent inhibitor of HUVEC microcapillary formation (IC(50) 0.01 nM) and Matrigel invasion (IC(50) 7 nM) and showed significant in vivo antitumor effects in a highly vascularized mammary adenocarcinoma 16/c model at nontoxic doses. The compounds are worthy of further evaluation as antiangiogenesis agents.


Subject(s)
Antineoplastic Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Naphthyridines/chemical synthesis , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Urea/analogs & derivatives , Urea/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Mice , Mice, Inbred Strains , Naphthyridines/chemistry , Naphthyridines/pharmacology , Receptor, Fibroblast Growth Factor, Type 1 , Structure-Activity Relationship , Tumor Cells, Cultured , Urea/chemistry , Urea/pharmacology , Xenograft Model Antitumor Assays
2.
J Med Chem ; 41(17): 3276-92, 1998 Aug 13.
Article in English | MEDLINE | ID: mdl-9703473

ABSTRACT

While engaged in therapeutic intervention against a number of proliferative diseases, we have discovered the 2-aminopyrido[2, 3-d]pyrimidin-7(8H)-ones as a novel class of potent, broadly active tyrosine kinase (TK) inhibitors. An efficient route was developed that enabled the synthesis of a wide variety of analogues with substitution on several positions of the template. From the lead structure 2, a series of analogues bearing variable substituents at the C-2 position and methyl or ethyl at N-8 was made. Compounds of this series were competitive with ATP and displayed submicromolar to low nanomolar potency against a panel of TKs, including receptor (platelet-derived growth factor, PDGFr; fibroblast growth factor, FGFr; epidermal growth factor, EGFr) and nonreceptor (c-Src) classes. One of the more thoroughly evaluated members was 63 with IC50 values of 0.079 microM (PDGFr), 0.043 microM (bFGFr), 0.044 microM (EGFr), and 0.009 microM (c-Src). In cellular studies, 63 inhibited PDGF-mediated receptor autophosphorylation in a number of cell lines at IC50 values of 0.026-0.002 microM and proliferation of two PDGF-dependent lines at 0.3 microM. It also caused inhibition of soft agar colony formation in three cell lines that overexpress the c-Src TK, with IC50 values of 0.33-1.8 microM. In in vivo studies against a panel of seven xenograft tumor models with known and/or inferred dependence on the EGFr, PDGFr, and c-Src TKs, compound 63 produced a tumor growth delay of 10.6 days against the relatively refractory SK-OV-3 ovarian xenograft and also displayed activity against the HT-29 tumor. In rat oral bioavailability studies, compound 63 plasma concentrations declined in a biexponential manner, and systemic plasma clearance was high relative to liver blood flow. Finally, in rat metabolism studies, HPLC chromatography identified two metabolites of 63, which were proved by mass spectrometry and synthesis to be the primary amine (58) and N-oxide (66). Because of the excellent potency of 63 against selected TKs, in vitro and in vivo studies are underway for this compound in additional tumor models dependent upon PDGFr, FGFr, and c-Src to assess its potential for advancement to clinical trials.


Subject(s)
Antineoplastic Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Ovarian Neoplasms/drug therapy , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidinones/chemical synthesis , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , 3T3 Cells , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Biotransformation , Cell Division/drug effects , Cisplatin/therapeutic use , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Female , Humans , Male , Mice , Mice, Nude , Molecular Conformation , Molecular Structure , Platelet-Derived Growth Factor/pharmacology , Pyrimidinones/chemistry , Pyrimidinones/pharmacokinetics , Pyrimidinones/pharmacology , Rats , Structure-Activity Relationship , Transplantation, Heterologous , Tumor Cells, Cultured
3.
Eur J Cancer ; 32A(2): 311-5, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8664047

ABSTRACT

Stout and colleagues [Proc Am Assoc Cancer Res 1993, 34, p. 298] previously reported that both hydrocortisone and tamoxifen increased the free fraction of suramin in human plasma. We examined several corticosteroids as well as tamoxifen for their effects on suramin protein binding and also evaluated hydrocortisone for its ability to modulate suramin activity in PC-3 and MCF-7 cells. Greater than 99% of the suramin was protein bound in undiluted human plasma. However, the free fraction of suramin was increased with the reduced plasma protein levels and increased suramin concentrations. At concentrations ranging from 1 to 30 microM, neither tamoxifen, hydrocortisone, prednisone nor dexamethasone had any effect on the binding of suramin to human plasma, regardless of protein concentrations. Similar results were observed with fetal calf serum. Hydrocortisone also had no effect on suramin activity against PC-3 and MCF-7 cell in vitro. We conclude from these studies that neither corticosteroids nor tamoxifen affect suramin protein binding or its cytotoxic activity.


Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Antineoplastic Agents/metabolism , Blood Proteins/metabolism , Glucocorticoids/pharmacology , Suramin/metabolism , Tamoxifen/pharmacology , Tumor Cells, Cultured/drug effects , Anti-Inflammatory Agents/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Female , Humans , Hydrocortisone/pharmacology , Male
4.
Int J Cancer ; 62(5): 636-42, 1995 Sep 04.
Article in English | MEDLINE | ID: mdl-7665238

ABSTRACT

The mechanism of action of the novel anti-cancer compound CI-994 was studied in C26 murine colon tumor and HCT-8 human colon adenocarcinoma cells. Treatment of either cell line resulted in the specific loss of a 16-kDa phosphoprotein in a time- and concentration-dependent manner. Treatment with salicylanilide, CI-940, mimosine, aphidicolin, quercetin or ciclopirolxalamine, which, like CI-994, block cells in the G1-S phase of the cell cycle, did not affect the production of this protein. Loss of the 16-kDa protein preceded the block in cell proliferation induced by CI-994 treatment, and recovery of this protein was evident prior to the resumption of cell growth. Cellular fractionation studies demonstrated that the 16 kDa phosphoprotein is confined to the nuclear compartment. Our data indicate that loss the 16-kDa nuclear phosphoprotein appears to be a direct effect of CI-994 treatment and that the inhibition of this phosphoprotein may play a critical role in the mechanism of action of CI-994.


Subject(s)
Antineoplastic Agents/pharmacology , Phenylenediamines/pharmacology , Phosphoproteins/metabolism , Adenocarcinoma/drug therapy , Animals , Benzamides , Cell Cycle/drug effects , Cell Nucleus/metabolism , Colonic Neoplasms/drug therapy , Humans , In Vitro Techniques , Mice , Molecular Weight , Phosphoproteins/chemistry , Salicylanilides/pharmacology , Tumor Cells, Cultured
5.
Mol Pharmacol ; 34(2): 180-5, 1988 Aug.
Article in English | MEDLINE | ID: mdl-2901030

ABSTRACT

The effect of lysosomotropic agents and secretory inhibitors were compared with verapamil for their effect on the activity of doxorubicin (DOX) in multiple drug-resistant (MDR) P388 leukemia cells (P388R) and in blocking anthracycline efflux from these cells. Agents known to interact with the plasma membrane did not potentiate DOX activity in P388R cells unless these same agents were also capable of interacting with acidic compartments within the cell. The lysosomotropic detergent Triton WR-1339, for example, potentiated DOX activity in P388R cells and stimulated the net accumulation of daunorubicin (DAU) in P388R cells by inhibiting drug exodus. However, another detergent, deoxycholate, and two membrane active antibiotics, amphotericin B and filipin, had no effect on DOX activity and/or DAU efflux in P388R cells. Lysosomotropic agents such as chloroquine and secretory inhibitors such as monensin, cytochalasin B, and vinblastine all inhibited DAU efflux from P388R cells. In a MDR B16 melanoma cell line, the activity of DOX was potentiated by both verapamil and reserpine. These same two agents also inhibited melanin secretion from this same cell line. Based on these observations, we propose that secretory vesicles derived from the Golgi apparatus might be involved in the MDR phenomenon. We further suggest that drugs such as DOX might be concentrated in these acidic vesicles, where they would be released to the outside of the cell by exocytosis.


Subject(s)
Drug Resistance , Lysosomes/physiology , Membrane Glycoproteins/physiology , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Amines/pharmacology , Animals , Antibiotics, Antineoplastic , Cell Line , Cell Membrane Permeability , Cytoskeleton/drug effects , Ionophores/pharmacology , Melanins/metabolism , Mice , Monensin/pharmacology , Naphthacenes/metabolism , Nigericin/pharmacology , Reserpine/pharmacology , Secretory Rate/drug effects , Verapamil/pharmacology
6.
Cancer Res ; 48(11): 3025-30, 1988 Jun 01.
Article in English | MEDLINE | ID: mdl-3365692

ABSTRACT

The insensitivity of colon tumors to various anticancer agents was studied in vitro. The activity of Adriamycin (ADR) in several colon tumor cell lines was potentiated by the calcium channel blocker verapamil (VER). In the HCT-8 human colon adenocarcinoma cell line, VER potentiation of the activities of ADR and the anthrapyrazole CI-937 appeared to be related to its ability to enhance the net accumulation of both drugs and inhibit their efflux. VER, which potentiated ADR activity in HCT-8 cells by 4-fold, caused a 3.5-fold stimulation of ADR accumulation and 3.5-fold inhibition of ADR efflux, when compared to non-VER-treated cells. The low level of VER potentiation of CI-937 activity in HCT-8 cells (1.4-fold) was also reflected in CI-937 transport studies which demonstrated a 1.5-fold enhancement of CI-937 accumulation and a 1.4-fold inhibition of its efflux. VER was also found to stimulate ADR activity and accumulation in a normal small intestinal crypt cell line (IEC-6). The mechanism of drug efflux was examined in HCT-8 cells. Agents known to increase the permeability of the plasma membrane did not alter ADR accumulation or its efflux in HCT-8 cells unless these same agents were also capable of interacting with the lysosome. Tween 80 and the lysosomotropic detergent Triton WR-1339 as well as proton ionophores and lysosomotropic amines all stimulated ADR uptake and/or inhibited its efflux from HCT-8 cells. ADR efflux was also partially blocked by cytochalasin B. Based on these observations, we suggest that at least part of the inherent drug resistance of colon tumor cells results from the retention of an enhanced drug efflux mechanism which is found in normal intestinal epithelium where this property may provide protection from plant alkaloids and other xenobiotic agents ingested in the diet. The mechanism of this drug efflux from HCT-8 cells may involve drug partitioning into acidic vesicles within the cell and their subsequent release from these cells by exocytosis.


Subject(s)
Antineoplastic Agents/pharmacology , Colonic Neoplasms/drug therapy , Intestinal Mucosa/metabolism , Animals , Antineoplastic Agents/therapeutic use , Cell Line , Cell Survival/drug effects , Drug Resistance , Drug Screening Assays, Antitumor , Humans , Inactivation, Metabolic , Mice , Verapamil/pharmacology
7.
Cancer Res ; 46(9): 4352-6, 1986 Sep.
Article in English | MEDLINE | ID: mdl-3460695

ABSTRACT

A series of anthrapyrazoles was examined for their cytotoxic effect on P388 cells resistant (P388R) to anthracyclines, N-[4-(9-acridinylamino)-3-methoxyphenyl] methanesulfonamide, trimetrexate, and vinblastine. The degree of resistance of P388R cells to Adriamycin (ADR) and daunomycin was 50-fold and 38-fold, respectively, when compared to the parent cell line (P388S). The Adriamycin-resistant cells were highly cross-resistant to some anthrapyrazoles, but the degree of cross-resistance was not uniform and was less than 3-fold for one member of the series. The lipophilicity of these compounds appeared to correlate to some extent with the level of resistance. The calcium channel blockers verapamil (VER) and diltiazem and the calmodulin antagonist trifluoperazine potentiated the cytotoxicity of the anthrapyrazoles and ADR in P388R. This potentiating effect was concentration dependent with VER being the most efficacious. VER increased ADR cytotoxicity by greater than 10-fold and CI-937 by almost 40-fold. However, VER, diltiazem, and trifluoperazine had no effect on ADR or anthrapyrazole activity in P388S cells. The antiarrhythmic drug, quinidine, and the detergent, Tween 80, also potentiated ADR activity in P388R cells to the same extent as VER. Both the net accumulation and efflux of [3H]daunomycin were altered in P388R cells by nontoxic concentrations of Tween 80 in a fashion virtually identical to that demonstrated for VER. These data suggest that agents which potentiate drug cytotoxicity in P388R cells may do so by their interaction with the lipid domain of the plasma membrane. In addition, these results demonstrate that some members of the new series of DNA binding drugs, the anthrapyrazoles, may be active against anthracycline-resistant tumors and that, where cross-resistance to them occurs, it can be partially reversed by agents such as VER.


Subject(s)
Anthracenes/pharmacology , Antineoplastic Agents/pharmacology , Calcium Channel Blockers/pharmacology , Calmodulin/antagonists & inhibitors , Drug Resistance/drug effects , Leukemia P388/physiopathology , Leukemia, Experimental/physiopathology , Pyrazoles/pharmacology , Animals , Antibiotics, Antineoplastic , Biological Transport/drug effects , Cell Line , Daunorubicin/metabolism , Mice , Naphthacenes/pharmacology , Polysorbates/pharmacology , Quinidine/pharmacology , Solubility , Structure-Activity Relationship
8.
Cancer Lett ; 31(3): 253-60, 1986 Jun.
Article in English | MEDLINE | ID: mdl-2941142

ABSTRACT

Several antifolate compounds were examined for their cytotoxic activity in a pleiotropically resistant P388 cell line (P388R). The sensitivity of P388R cells to methotrexate (MTX) and the lipophilic antifols, metoprine and methotrexate gamma-mono t-butyl ester (MTX-gamma-t-butyl ester) were comparable with that activity observed in the parental cell line (P388S). P388R cells were, however, resistant to 2 other lipophilic antifols, trimetrexate (TMQ) and BW 301U. The degree of resistance to TMQ and BW 301U was 22-fold and 15-fold, respectively and could be partially overcome by the calcium channel blocker, verapamil (VER) or the detergent Tween 80. Transport studies showed that net accumulation of trimetrexate was markedly reduced in P388R cells resulting in a steady-state level which was 25% of the sensitive line. This impaired uptake was reversed by 5 micrograms/ml VER which increased the steady-state to a level comparable to P388S. P388R also exhibited a 50% reduction in the unindirectional influx rate, however, this defect could not be reversed by VER. The resistance of P388R cells to TMQ and BW 301U and their potentiation by VER extends pleiotropic resistance to yet another class of drugs which have important clinical implications.


Subject(s)
Folic Acid Antagonists/therapeutic use , Pyrimidines/therapeutic use , Quinazolines/therapeutic use , Animals , Drug Resistance , Leukemia P388/drug therapy , Leukemia P388/pathology , Methotrexate/therapeutic use , Mice , Trimetrexate
9.
Eur J Cancer Clin Oncol ; 22(2): 205-10, 1986 Feb.
Article in English | MEDLINE | ID: mdl-3084263

ABSTRACT

Polyacrylamide gel electrophoresis of galactosyltransferase (GT) extracted from a human colon adenocarcinoma cell line, HCT-8, demonstrated the presence of two peaks of activity: a slow-moving peak, referred to as GT-II, and a more anodally migrating peak, designated as GT-I, which was also found for normal human serum. However, if GT solubilized from HCT-8 cells was separated by isoelectric focusing, no unique isoenzymes could be detected. Total GT activity from HCT-8 cells was purified by alpha-lactalbumin-Sepharose affinity chromatography followed by ion exchange chromatography on either DEAE-cellulose or FPLC using a Mono Q anion exchange resin. Three major peaks of activity were resolved from anion exchange chromatography. Electrophoresis of each peak revealed a GT pattern identical with that originally observed for the crude (detergent) solubilized homogenate. No enrichment of either GT-I or GT-II was observed in the three enzyme fractions. The data suggest that GT-II may be an artifactual activity of cancer cells composed of GT-I associated with some contaminating protein.


Subject(s)
Colonic Neoplasms/enzymology , Galactosyltransferases/metabolism , Isoenzymes/metabolism , Adenocarcinoma/enzymology , Cell Line , Chromatography, Affinity , Chromatography, Ion Exchange , Drug Contamination , Electrophoresis, Polyacrylamide Gel , Galactosyltransferases/isolation & purification , Humans , Isoelectric Focusing , Isoenzymes/isolation & purification
10.
J Natl Cancer Inst ; 75(2): 353-9, 1985 Aug.
Article in English | MEDLINE | ID: mdl-3860688

ABSTRACT

Proline analogues such as cis-4-hydroxy-L-proline (CHP) and L-azetidine-2-carboxylic acid (A2C) were tested for their antitumor activity in tissue culture and in vivo. In culture, CHP specifically inhibited those tumor cells that synthesized basement-membrane collagen. CHP appeared to selectively inhibit collagen biosynthesis with only a slight effect on protein synthesis. Culturing cells on type IV collagen matrix did not alter the antiproliferative effect of CHP. The inhibition of 450.1 mouse mammary tumor cells was fully reversible when cultures were incubated for 6 or 12 hours with 25 micrograms CHP/ml but was irreversible after 24 hours of exposure. Of the proline analogues tested against 450.1 tumor cells, A2C and CHP were the most potent inhibitors of cell growth. These two compounds were therefore tested in vivo using 3 transplantable tumors, all of which synthesized basement-membrane collagen. CHP and A2C were given twice daily to mice for 7 to 10 days at doses ranging from 50 mg/kg (body wt) to 600 mg/kg (body wt) per injection. Both CHP and A2C were completely inactive against the 450.1 mammary tumor and the EHS sarcoma. Both compounds also caused considerable liver toxicity. Against CD8F1 mammary tumors, treatment with maximum tolerated doses of CHP and A2C resulted in a slight but insignificant inhibition of tumor growth. While our studies confirmed previous findings that CHP specifically inhibited those tumor cells that synthesized basement-membrane collagen, CHP and A2C did not appear to be efficacious antitumor agents.


Subject(s)
Antimetabolites, Antineoplastic , Collagen/biosynthesis , Proline/analogs & derivatives , Animals , Azetidinecarboxylic Acid/pharmacology , Basement Membrane/metabolism , Cell Division/drug effects , Cell Line , Humans , Hydroxyproline/pharmacology , Mammary Neoplasms, Experimental/drug therapy , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neoplasm Transplantation , Proline/pharmacology , Sarcoma, Experimental/drug therapy
11.
Am J Trop Med Hyg ; 33(4): 526-33, 1984 Jul.
Article in English | MEDLINE | ID: mdl-6236702

ABSTRACT

The duration of protection from blood-stage malarial challenge following single injections of pyrimethamine pamoate was assessed in mice and monkeys. This duration was dose-related and ranged from several weeks in mice to over 4 months in the monkeys. Comparisons with the previously reported repository drugs, cycloguanil pamoate and acedapsone (diacetyldiaminodiphenyl sulfone), in mice demonstrated that pyrimethamine pamoate provides an equal or greater duration of protection. Studies with mixtures containing acedapsone gave good protection against a pyrimethamine-resistant strain of Plasmodium berghei.


Subject(s)
Malaria/prevention & control , Pyrimethamine/analogs & derivatives , Pyrimethamine/therapeutic use , Acedapsone/therapeutic use , Animals , Dapsone/therapeutic use , Drug Combinations , Female , Injections, Intramuscular , Macaca fascicularis , Male , Mice , Plasmodium berghei , Pyrimethamine/administration & dosage , Pyrimethamine/adverse effects , Pyrimethamine/toxicity , Time Factors , Triazines/therapeutic use
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