Search PubMed⌕ Search

Biomedical subjects

K F Bastow

Publications and source records attributed to K F Bastow.

At least 37 records · Page 2Linked to original sources
PubMed2000

Anti-HIV agents 45(1) and antitumor agents 205.(2) two new sesquiterpenes, leitneridanins A and B, and the cytotoxic and anti-HIV principles from Leitneria floridana.

Two new sesquiterpenes, leitneridanin A (1) and leitneridanin B (2), and seven known compounds, lirioresinol B, (-)-pinoresinal, (+)-lariciresinol, quassimarin (3), simalikalactone D (4), 1-methoxycanthinone (5), and 5-methoxycanthinone (6), were isolated from Leitneria floridana. Their structures were identified on the basis of spectral data. In vitro biological evaluation showed that 5 is a potent anti-HIV agent (EC(50) 0.26 g/mL; TI >39) and that 3-6 suppressed the growth of a panel of human tumor cell lines (KB, A-549, HCT-8, CAKI-1, MCF-7, and SK-MEL-2). Compounds 3 and 4 were significantly active, with ED(50) values in the range of 0.26-0.012 g/mL.

Anti-HIV Agents↗
PubMed2000

Characterization of human lung cancer cells resistant to 4'-O-demethyl-4beta-(2"-nitro-4"-fluoroanilino)-4-desoxypodophyllotoxin , a unique compound in the epipodophyllotoxin antitumor class.

A new semi-synthetic podophyllotoxin derivative, 4'-O-demethyl-4beta-2"-nitro-4"-fluoroanilino)-4-desoxypo dophyllotoxin (compound 1), an analog of GL-331 (compound 2), is a potent and broad-spectrum inhibitor of cultured human cancer and drug-resistant cell growth. In general, 4'-demethylepipodophyllotoxin analogs, including 2, exert anti-tumor activity by targeting the nuclear enzyme DNA topoisomerase II, but 1 is not an enzyme inhibitor. Unlike the cytotoxic activity of compound 2, cell killing by 1 is dose-limiting and a significant fraction of cells (30-40%) survive treatment. As an approach to investigate mechanism of action, 1-resistant A549 (human lung cancer) sub-lines were selected and characterized. Results of the work show that 1-resistant cells: (i) are moderately cross-resistant (2- to 3-fold) to various cytotoxic drugs via a P-glycoprotein-independent mechanism, (ii) have an altered growth habit, (iii) are deficient in normal attachment on plastic and collagen substrata, and (iv) have an altered plasma membrane protein composition including several proteins in the 140->200 kDa molecular mass range and a doublet of phosphoserine-containing proteins of about 135 kDa. Since 1 treatment of cells affects neither cellular attachment or membrane-protein phosphorylation, the changes observed in 1-resistant cells are interpreted as a survival response to drug action.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

The 9-position in berberine analogs is an important determinant of DNA topoisomerase II inhibition.

A current model suggests that the intercalative and minor groove binding components of protoberberines and related compounds are important for DNA topoisomerase I and/or II inhibition. The significance of the 9-substituent in berberine on drug-topoisomerase II interactions is reported here and is based on a comparison of 9-ethoxycarbonyl berberine (compound 1), 9-N,N-dimethylcarbamoyl berberine (compound 2) and 12-bromo berberine (methoxy group at 9-position; compound 3) as enzyme inhibitors. Compound 1 selectively inhibited topoisomerase II and stabilized cleavage complexes predominantly at unique sites and some background sites (depending on the concentration). This agent also allowed partial dissociation of enzyme from the DNA in the absence of religation, indicating unique interactions between 1, enzyme and DNA in the ternary complexes. Compound 2, which had similar DNA binding properties to 1, was not a topoisomerase II poison in the tested concentration range. In contrast, compound 3 was a stronger DNA binding agent but a much weaker enzyme poison both in vitro and in cell-based assays. The results show that the proposed drug domain for DNA intercalation is not a major determinant of enzyme inhibition for simple berberine analogs. Rather, the 9-substituent within the domain has a major influence, presumably by facilitating drug interaction with enzyme and/or enzyme-DNA complexes.

Berberine↗
PubMed1999

Antitumor agents 201. Cytotoxicity of harmine and beta-carboline analogs.

Twenty-six beta-carbolines were evaluated for in vitro cytotoxicity in a human tumor cell line panel. Harmine (3) showed significant activity against several cell lines including three drug-resistant KB sublines with various resistance mechanisms. Alpha-(4-nitrobenzylidine) harmine (16) had a broad cytotoxicity spectrum (ED50 values from 0.3-1.2 microg/mL against 1A9, KB, SaOS-2, A549, SK-MEL-2, U-87-MG, and MCF-7 cells).

Antineoplastic Agents↗
PubMed1999

Antitumor agents 200. Cytotoxicity of naturally occurring resveratrol oligomers and their acetate derivatives.

Eleven resveratrol oligomers and six acetylated derivatives were evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. The acetate of (-)-ampelopsin A (12) showed potent and selective cytotoxic activity with ED50 values of 0.6, 0.7 and 2.0 microg/mL against KB, 1A9 and MCF-7 cells, respectively. Hopeaphenol (10) and pallidol hexaacetate (13) also showed significant cytotoxicity against KB cells with ED50 values of 1.2 and 1.6 microg/mL, respectively.

Acetates↗
PubMed1999

Antitumor agents. 196. Substituted 2-thienyl-1,8-naphthyridin-4-ones: their synthesis, cytotoxicity, and inhibition of tubulin polymerization.

As part of our continuing search for potential anticancer drug candidates in the 2-aryl-1,8-naphthyridin-4-one series, we have synthesized a series of substituted 2-thienyl-1, 8-naphthyridin-4-ones. Most compounds showed significant cytotoxic effects (log GI(50) < -4.0; log molar drug concentration required to cause 50% growth inhibition) against a variety of human tumor cell lines in the National Cancer Institute's in vitro screen, including cells derived from solid tumors such as non-small-cell lung, colon, central nervous system, melanoma, ovarian, prostate, and breast cancers. The most active compounds (31-33,40) demonstrated strong cytotoxic effects with ED(50) values in the micromolar or submicromolar range in most of the tumor cell lines. The most cytotoxic compounds inhibited tubulin polymerization at concentrations substoichiometric to the tubulin concentration. The most potent inhibitors of polymerization (40,42,43) had effects comparable to those of the potent antimitotic natural products podophyllotoxin and combretastatin A-4 and to that of NSC 664171, a particularly potent, structurally related analogue. Only compound 40 was a potent inhibitor of the binding of radiolabeled colchicine to tubulin, and it was both the most cytotoxic agent and the most effective inhibitor of polymerization among the newly synthesized compounds.

Antineoplastic Agents↗
PubMed1999

Inhibition of DNA topoisomerase II catalytic activity by the antiviral agents 7-chloro-1,3-dihydroxyacridone and 1,3,7-trihydroxyacridone.

Previously we reported that the antiproliferative and antiviral actions of 7-chloro-1,3 dihydroxyacridone (compound 1) and its derivatives may be mediated through the inhibition of mammalian DNA topoisomerase II. In the present work, we have extended our investigation into the mechanism of topoisomerase II inhibition by these agents. Both compound 1 and its 7-OH derivative, compound 2, inhibited topoisomerase II catalytic activity in vitro, yet neither agent affected the activity of topoisomerase I. DNA unwinding assays indicated that compound 1 and compound 2 bound to DNA, although no correlation was found between DNA unwinding and topoisomerase II catalytic inhibition. Neither agent enhanced topoisomerase II-mediated DNA cleavage in vitro; however, both compound 1 and compound 2 antagonized breaks induced by etoposide and amsacrine. Experiments indicate that interference with etoposide-stimulated breaks results from inhibition of topoisomerase II * DNA binding by compound 1. These findings suggest that compound 1 and its derivatives may represent a novel structural class of topoisomerase II catalytic inhibitors.

Acridines↗
PubMed1999

Antitumor agents. 194. Synthesis and biological evaluations of 4-beta-mono-, -di-, and -trisubstituted aniline-4'-O-demethyl-podophyllotoxin and related compounds with improved pharmacological profiles.

As a continuation of our structure-activity relationship studies, several new 4-beta-substituted 4'-O-demethyl-4-desoxypodophyllotoxins bearing mono-, di-, or trisubstituted anilines have been synthesized and evaluated as inhibitors of DNA topoisomerase II and tumor cell growth in tissue culture. Selected compounds were further evaluated as cytotoxic agents using a clonogenic survival assay. The target compounds include 4'-O-demethyl-4beta-[(4' '-(benzimidazol-2' '-yl)anilino]-4-desoxypodophyllotoxin (21), 4'-O-demethyl-4beta-(-)-(4' '-camphanamido-anilino)-4-desoxypodophyllotoxin (25), 4-beta-disubstituted-anilino-4'-demethyl-4-desoxypodophyllotoxins (18-20, 26), 4-alpha-disubstituted-anilino-4'-demethyl-4-desoxypodophyllotoxin (27), 4-beta-trisubstituted-anilino-4'-demethyl-desoxypodophyllotoxin (22, 23), and 4'-O-demethyl-4beta-[4' '-(benzimidazol-2' '-yl)amino]-4-desoxypodophyllotoxin (24). Among the target series, 19, 21, and 24 displayed significant growth inhibitory action against a panel of tumor cell lines including human epidermoid carcinoma of the nasopharynx (KB) and its etoposide-resistant (KB7B) and vincristine-resistant (vin20c KB) subclones, lung carcinoma (A549), human ileocecal carcinoma (HCT-8), human kidney carcinoma (CAKI-1), breast adenocarcinoma (MCF-7), and human malignant melanoma (SK-MEL-2) cells. Compounds 19, 21, 24, and 25 were "cleavable-complex"-forming DNA topoisomerase II inhibitors with either improved or similar activity compared with the prototype drug etoposide (VP-16). Compound 21 was the most active analogue, being 10-fold more potent than etoposide in both cell killing and topoisomerase II inhibition in vitro assays. Using mouse models of antitumor activity, 21 was effective against (P388/0) leukemia but not against the growth of a (MCF7) mammary tumor.

Animals↗
PubMed1998

Antitumor agents. 185. Synthesis and biological evaluation of tridemethylthiocolchicine analogues as novel topoisomerase II inhibitors.

Several 1,2,3-tridemethyldeacetylthiocolchicine derivatives have been synthesized and evaluated for cytotoxic activity against various human tumor cell lines and for their inhibitory effects on DNA topoisomerases in vitro. Exhaustive demethylation of thiocolchicine analogues completely changes their biological profiles. Instead of displaying antitubulin activity, most target compounds inhibited topoisomerase II activity. Only compounds with a larger side chain, such as 15a, 23a, and 24a, did not interfere with topoisomerase II enzymatic functions. The cytotoxicity of target compounds was reduced by 3 orders of magnitude compared to that of colchicine in most cell lines. The hydrophilicity of phenolic compounds might prevent drug passage through the cell plasma membrane and, thus, be responsible for the relatively weak cytotoxicity. To test this hypothesis, 27-30 were prepared from 16a by protecting all hydroxy groups with esters with an aim to facilitate drug transportation. In vitro cytotoxicity assays indicated that 27 was more potent than its parent compound in all tested tumor cell lines and showed tissue selective cytotoxicity with a significant inhibitory effect against KB cells (IC50 = 2.7 microg/mL). Therefore, we propose that 27 acts as a prodrug, liberating 16a to exert its antitopoisomerase activity and, finally, to cause cell death.

Antineoplastic Agents↗
PubMed1998

Antitumor agents. 181. Synthesis and biological evaluation of 6,7,2',3',4'-substituted-1,2,3,4-tetrahydro-2-phenyl-4-quinolones as a new class of antimitotic antitumor agents.

A novel series of 6,7,2',3',4'-substituted-1,2,3,4-tetrahydro-2-phenyl- 4-quinolones were synthesized and evaluated for interactions with tubulin and for cytotoxic activity against a panel of human tumor cell lines, including ileocecal carcinoma (HCT-8), breast cancer (MCF-7), lung carcinoma (A-549), epidermoid carcinoma of the nasopharynx (KB), renal cancer (CAKI-1), and melanoma cancer (SKMEL-2). Most compounds (18, 20, 22-27) showed potent cytotoxic and antitubulin effects. The most active compounds (23, 26, 27) demonstrated strong cytotoxic effects with ED50 values in the nanomolar or subnanomolar range in almost all tumor cell lines. Three active racemates (20, 22, 25) were separated into the enantiomers, and generally, the optically pure (-)-isomers (20a, 22a, 25a) exhibited greater biological activity than the racemates or (+)-isomers. Cytotoxicity and antitubulin activity were closely correlated, with the most active compounds (23, 26, 27) having effects comparable to those of colchicine, podophyllotoxin, and combretastatin A-4.

Antibiotics, Antineoplastic↗
PubMed1998

The cytotoxicity of 2-formyl and 2-acetyl-(6-picolyl)-4N-substituted thiosemicarbazones and their copper(II) complexes.

2-Acetyl-(6-picolyl)-4N-substituted thiosemicarbazones and their copper(II) complexes were shown to be potent antineoplastic and cytotoxic agents against murine and human cultured cells. Numerous derivatives were as active against solid tumor growth as clinically useful agents. The agents inhibited L1210 DNA and RNA syntheses with inhibition of key regulatory enzyme activities of the purine pathway as well as nucleoside kinase activities. d[NTP] pools were reduced and DNA strand scission occurred. These agents were DNA topoisomerase II inhibitors with lower IC50 values than that of VP-16. However, they did not cause L1210 DNA protein linked breaks and actually protected against those breaks afforded by VP-16. The agents were not synergistic with VP-16 in reducing cell growth or DNA synthesis although they did reduce growth of L1210 cells in agar suspended media.

Animals↗
PubMed1998

Antitumor agents. Part 186: Synthesis and biological evaluation of demethylcolchiceinamide analogues as cytotoxic DNA topoisomerase II inhibitors.

Demethylation of colchiceinamide (2) and its analogues (3-10) afforded a novel class of mammalian DNA topoisomerase II inhibitors (2a-10a) without displaying tubulin inhibitory activity. All target compounds inhibited the catalytic activity of topoisomerase II at drug concentrations at 100 microM. An in vitro cytotoxicity assay indicated that compounds 3a and 8a were strong and tissue-selective cytotoxic agents against the MCF-7 breast cancer cell line (IC50 = 0.36 and 0.48 microgram/mL, respectively) and the CAKI-1 renal cancer cell line (IC50 = 0.72 and 0.96 microgram/mL, respectively).

Antineoplastic Agents↗
PubMed1997

A possible role for topoisomerase II in cell death and N-phosphonoacetyl-L-aspartate-resistance frequency and its enhancement by 1-beta-D-arabinofuranosyl cytosine and 5-fluoro-2'-deoxyuridine.

Pretreatment of cells with AraC markedly enhances the frequency of resistance to PALA, methotrexate and 5-fluoro-2'-deoxyuridine (FdUrd) (D.V. De Cicco, A.C. Spradling, Localization of a cis-acting element responsible for the developmentally regulated amplification of Drosophila chorion genes. Cell 38 (1984) 45-54). As a part of studies to elucidate the mechanism for this effect of AraC, the SV40 transformed baby hamster kidney cell line SV28 was treated with either AraC, etoposide or etoposide plus verapamil (to avoid selection for P-glycoprotein-mediated resistance) to isolate cells resistant to AraC or etoposide, respectively. The cells isolated for resistance to AraC (500) were cross-resistant to etoposide and the cells isolated for resistance to etoposide (V5ER and 20ER) were cross-resistant to AraC as well as FdUrd (only V5ER were tested). Enhancement of PALA-resistance frequency by pretreatment with various AraC concentrations and exposure times was greatly attenuated in the three resistant cell lines. Pretreatment with FdUrd markedly enhanced PALA-resistance frequency in SV28 cells, but only weakly did so in V5ER cells. All three resistant cell lines had diminished topoisomerase II as measured by immunoblotting and which was reflected in increased LC50s for etoposide. A comparison of either the etoposide LC50 values or the amount of cellular topoisomerase II, as measured by immunoblotting, with the PALA-resistance frequency in the SV28 and resistant cell lines showed a clear correlation. Increased etoposide LC50 or decreased topoisomerase II correlate with increased PALA-resistance frequency. This holds true for cells treated or not pretreated with AraC. Cells with reduced topoisomerase II are more resistant to the lethal actions of not only etoposide, but also AraC and FdUrd, drugs with different primary sites of action. Cells with reduced topoisomerase II have a higher frequency of resistance to PALA by gene amplification and reduced enhancement of gene amplification frequency when treated with AraC or FdUrd. This suggests two different mechanisms responsible for the increased frequency of resistance and the reduced enhancement of resistance frequency, respectively. These data suggest a role for topoisomerase II in cell death and gene amplification. Possible mechanisms are discussed and a scheme is presented.

Animals↗
PubMed1997

Antitumor agents--CLXXIII. Synthesis and evaluation of camptothecin-4 beta-amino-4'-O-demethyl epipodophyllotoxin conjugates as inhibitors of mammalian DNA topoisomerases and as cytotoxic agents.

Two conjugates composed of a camptothecin and a 4'-O-demethyl epipodophyllotoxin derivative joined by an imine linkage were prepared and evaluated as inhibitors of mammalian DNA topoisomerases I and II. Target compounds stimulated cleavable complex formation with both types of enzyme in vitro although activities were reduced at least twofold relative to the activity of unconjugated constituents. The behavior of the most active conjugate as an inhibitor of cell growth closely resembled both topoisomerase I- and II- inhibitory components in that the compound displayed a combined spectrum of activity against various drug-resistant KB sublines. Cytotoxic activity and selectivity were largely retained through conjugation, the exception being a lower than expected activity against a pleiotrophic multidrug-resistant subline. The induced levels and the properties of cellular protein-associated DNA complexes were consistent with topoisomerase involvement and with the in vitro cleavage assay results. Based on the present findings, conjugation afforded cleavable complex-forming topoisomerase inhibitors which display dual target specificity and a broad spectrum of cytotoxic activity against drug-resistant cells.

Animals↗
PubMed1996

Antitumor agents. 166. Synthesis and biological evaluation of 5,6,7,8-substituted-2-phenylthiochromen-4-ones.

As a continuation of our structure--activity relationship study of substituted 2-phenyl-4-quinolones and flavonoids as antitumor and antiviral agents, a series of 5,6,7,8-substituted-2-phenylthiochromen-4-ones has been synthesized by condensation of substituted thiophenols and ethyl benzoylacetates. Target compounds were evaluated for biological activity. Among them, compounds 7, 10, 12, and 13 displayed significant growth inhibitory action against a panel of tumor cell lines including human ileocecal carcinoma (HCT-8), murine leukemia (P-388), human melanoma (RPMI), and human central nervous system tumor (TE671) cells. Compounds 10, 12, and 19 displayed DNA topoisomerase I inhibitory activity in vitro and compound 11 was an in vitro, inhibitor of DNA topoisomerase II. Compound 11 was most active (ED50 value, 0.65 microM) against HIV in acutely infected H9 lymphocytes and had a therapeutic index of about 5.

Antineoplastic Agents↗
PubMed1996

Antitumor agents. 164. Podophenazine, 2'',3''-dichloropodophenazine, benzopodophenazine, and their 4 beta-p-nitroaniline derivatives as novel DNA topoisomerase II inhibitors.

We report here the synthesis and biological evaluation of novel DNA topoisomerase II inhibitors, podophenazine (8), 2'',3'' "-dichloropodophenazine (9), and benzopodophenazine (10), and their 4beta-p-nitroaniline derivatives 13-15. Among these, 4'-0-demethyl-4beta-(4'''- nitroanilino)-4-desoxypodophenazine (13) and 4'-O-demethyl-2'',3''-dichloro-4beta-(4-'''-nitroanilino)-4- desoxypodophenazine (14) were found to inhibit KB cells at sub-micromolar concentrations (IC50 = 0.11 +/- 0.03 and 0.48 +/- 0.17 microM, respectively. Against KB/7d cells (a pleiotrophic multiple drug-resistant subclone selected with etoposide which has reduced level of topoisomerase II), only compound 13 out of a target series maintained activity in the sub-micromolar concentration range with a IC 50 value of 0.56 +/- 0.13 mu M. The differential toxicity ratio for 13 [IC 50 (KB/7d)/IC 50 (KB)] was approximately 5. Unlike etoposide and its congeners, compounds 13 and 14 were found to be weak inhibitors of the catalytic activity of topoisomerase II (IC100 = > 100 and > 150 microM, respectively). In vitro protein-linked DNA complex formation assay revealed that 13 and 14, respectively, induced marginal response (13 at 1 microM, 320.3 +/- 124.5 cpm; 13 at 50 microM, 308.8 +/- 139.9 cpm; 13 at 100 mu M, 446.0 +/- 153.5 cpm) and no response (14 at 1 microM, 104.9 +/- 52.6 cpm; 14 at 50 microM, 103.3 +/- 42.6 cpm; 14 at 100 microM, 101.4 +/- 35.2 cpm) compared to the enzyme control. On the basis of these results, we conclude that the mechanism of enzyme inhibition of these compounds is distinct from that of etoposide and its congeners. We are currently investigating the mechanism(s) of action of compounds 13 and 14 as well as synthesizing other derivatives in order to better characterize structure-activity relationships of this series of compounds.

Antineoplastic Agents↗
PubMed1994

Antiproliferative actions of 7-substituted 1,3-dihydroxyacridones; possible involvement of DNA topoisomerase II and protein kinase C as biochemical targets.

7-Chloro-1,3-dihydroxyacridone (1) reversibly inhibited growth of KB and vero cell lines with IC50's of 35 and 40 microM, respectively, and a topoisomerase II-mediated multidrug resistant KB sub-clone was found to be about three-fold more susceptible to 1. In contrast, two cell lines of lymphoid origin were killed following treatments with 60 microM and at higher concentrations of 1. KB cell growth inhibition correlated with a rapid, reversible suppression of thymidine incorporation. Uridine but not leucine incorporation was also rapidly suppressed. The in vitro activities of DNA topoisomerase II and novel protein kinase C-subtype delta were inhibited at effective concentrations in tissue-culture, but 1 did not stimulate intracellular protein-associated DNA breaks nor interfere initially with topoisomerase II-mediated DNA cleavage in KB cells. In addition to antiproliferative effects against cells, the compound was weakly virustatic for herpes simplex virus type I with an IC50 of 8 microM. Limited studies comparing three 1-congeners and citpressine-I, an acridone alkaloid with reported antiherpes activity, demonstrated that 7-substituted 1,3-dihydroxyacridones are novel antiproliferative agents which share similar biological and biochemical properties.

Acridines↗