Search PubMed⌕ Search

Biomedical subjects

T M Allen

Publications and source records attributed to T M Allen.

At least 109 records · Page 6Linked to original sources
PubMed1990

Synthesis and antiviral and cytotoxic activity of iodohydrin and iodomethoxy derivatives of 5-vinyl-2'-deoxyuridines, 2'-fluoro-2'-deoxyuridine, and uridine.

A series of new 5-(1-hydroxy-2-iodoethyl)-2'-deoxyuridine and uridine compounds (11, 16) was synthesized by the regiospecific addition of HOI to the vinyl substituent of 5-vinyl-2'-deoxyuridine (10a), 5-vinyl-2'-fluoro-2'-deoxyuridine (10b), 5-vinyluridine (10c), and (E)-5-(2-iodovinyl)-2'-deoxyuridine (4b). Treatment of the iodohydrins 11a-c with methanolic sulfuric acid afforded the corresponding 5-(1-methoxy-2-iodoethyl) derivatives (12a-c). In contrast, reaction of 5-(1-hydroxy-2-iodoethyl)-2'-deoxyuridine (11a) with sodium carbonate in methanol afforded a mixture of 5-(1-hydroxy-2-methoxyethyl)-2'-deoxyuridine (13) and 2,3-dihydro-3-hydroxy-5-(2'-deoxy-beta-D-ribofuranosyl)- furano[2,3-d]pyrimidin-6(5H)-one (14). The most active compound, 5-(1-methoxy-2-iodoethyl)-2'-deoxyuridine (12a, ID50 = 0.1 micrograms/mL), which exhibited antiviral activity (HSV-1) 100-fold higher than that of the 5-(1-hydroxy-2-iodoethyl) analogue (11a), was less active than IVDU or acyclovir (ID50 = 0.01-0.1 micrograms/mL range). The C-5 substituent in the 2'-deoxyuridine series was a determinant of cytotoxic activity, as determined in the in vitro L1210 screen, where the relative activity order was CH(OH)CHI2 (16) greater than CH(OMe)CH2I (12a) greater than CH(OH)CH2I (11a) congruent to CH(OH)CH2OMe (13). The 2'-substituent was also a determinant of cytotoxic activity in the 5-(1-hydroxy-2-iodoethyl) (11a-c) and 5-(1-methoxy-2-iodoethyl) series of compounds, where the relative activity profile was 2'-deoxyuridine greater than 2'-fluoro-2'-deoxyuridine greater than uridine (11a greater than 11b greater than or equal to 11c; 12a greater than 12b greater than 12c). The most active cytotoxic agent (16), possessing a 5-(1-hydroxy-2,2-diiodoethyl) substituent (ED50 = 0.77 micrograms/mL), exhibited an activity approaching that of melphalan (ED50 = 0.15 micrograms/mL). All compounds tested, except for 13 and 14, exhibited high affinity (Ki = 0.035-0.22 mM range relative to deoxyuridine, Ki = 0.125) for the murine NBMPR-sensitive erythrocyte nucleoside transport system, suggesting that these iodohydrins are good permeants of cell membranes.

Animals↗
PubMed1990

Synthesis and cytotoxic activity of (E)-1-(2-nitrovinyl) and 1-[N-(tert-butylformiminyl)]-substituted 1,4-dihydropyridines and 2-pyridones.

1-(2-Nitrovinyl) derivatives of nuclear substituted 1,4-dihydropyridines (7a-c), and 1-(N-tert-butyl-formiminyl) derivatives of 1,4-dihydropyridines (9a-c) or 2-pyridones (11a-c) were synthesized for evaluation as cytotoxic agents (see Table I for structures). The in vitro cytotoxic activities, determined in the L1210 assay, indicated that the 4-substituent on a 1,4-dihydropyridine ring system was a determinant of activity in both the 1-(2-nitrovinyl) (7) and 1-(N-tert-butylformiminyl) (9) series, the relative activity order being n-Bu > Ph > Me. In the 1-(N-tert-butylformiminyl) series, the 1,4-dihydropyridine derivatives (9) were generally more cytotoxic than the 2-pyridone derivatives (11). The most active compound was 1-(N-tert-butylformiminyl)-3-(4,4-dimethyloxazolin-2-yl)-4-n -butyl-1,4- dihydropyridine (9b), but it was 2-3 log units less active than the reference standard melphalan.

Animals↗
PubMed1990

Charge densities of atoms of conjugated styryl ketones having activity against L1210 leukemia cells.

Electron density calculations were undertaken on several atoms in a series of 3-substituted-4-phenyl-3-buten-2-ones in order to gain insight into the molecular features which affect charge densities. The results indicate that substituents at position 3 alter the electron densities of the olefinic group but have little effect on the acetyl function. The compounds were tested against L1210 cells in vitro, and the results suggest that electronic--but not steric--factors are important in affecting cytotoxicity. The most active compound was 3-phenylmethylene-2,4-pentanedione (1c) with an ED50 value of 1.06 x 10(-8) M.

Animals↗
PubMed1989

Liposomes with prolonged circulation times: factors affecting uptake by reticuloendothelial and other tissues.

Many of the applications of liposomes drug-delivery systems have been limited by their short circulation half-lives as a result of rapid uptake into the reticuloendothelial (mononuclear phagocyte) system. We have recently described liposomes formulations with long circulation half-lives in mice (Allen, T.M. and Chonn, A. (1987) FEBS Lett. 223, 42-46). A study of the principal factors important to the attainment of liposomes with prolonged circulation half-lives is presented in this manuscript. Liposomes with the longest circulation half-lives, in mice, had compositions which mimicked the outer leaflet of red blood cell membranes (egg phosphatidylcholine/sphingomyelin/cholesterol/ganglioside GM1, molar ratio 1:1:1:0.14). Several other gangliosides and glycolipids were examined, but none could substitute for GM1 in their ability to prolong circulation half-lives. However, other negatively charged lipids with bulky headgroups, i.e., sulfatides and phosphatidylinositol, had some effect in prolonging circulation half-lives, but GM1 was clearly superior in this regard. Bilayer rigidity, imparted by sphingomyelin or other high-phase-transition lipids, acted synergistically with the negatively charged components, especially GM1, in extending circulation times. Circulation half-lives of liposomes increased with decreasing size, but even larger (0.2-0.4 microns) liposomes of the optimum formulations had significantly prolonged half-lives in circulation. Uptake of liposomes into tissues other than liver and spleen increased with increasing circulation times of the liposomes for i.v. and for i.p. injections. Liposomes appeared to move from the circulation into the carcass between 6 and 24 h post-injection. Our ability to achieve significant prolongation in circulation times of liposomes makes possible a number of therapeutic applications of liposomes which, until now, have not been achievable.

Animals↗
PubMed1989

Properties of lipid complexes with amphipathic helix-forming peptides. Role of distribution of peptide charges.

The peptides [Glu1,8,Leu11,17] 18A and [Glu4,9,Leu11,17] reverse-18A are 18-residue peptides designed to form amphipathic helices with opposite charge distribution; [Glu1,8,Leu11,17] 18A having positively charged residues at the hydrophobic/hydrophilic interface. Both [Glu1,8,Leu11,17] 18A and [Glu4,9,Leu11,17] reverse-18A strongly disrupt the bilayer structure as indicated by the relatively narrow lipid 1H and 31P NMR peaks. In addition, the 1H chemical shift of the quaternary ammonium methyl groups indicates that [Glu1,8,Leu11,17] 18A forms smaller lipoprotein particles with dimyristoylphosphatidylcholine (DMPC) than does [Glu4,9,Leu11,17] reverse-18A. However, motional properties of the lipid head group indicate that no specific salt bridges are formed between the phospholipid head group and the side chains of polar amino acids of either of the two peptides. In addition, the acyl chain conformation for the DMPC complexes with [Glu1,8,Leu11,17] 18A and with [Glu4,9,Leu11,17] reverse-18A are indistinguishable by the criterion of IR spectroscopy. The 2H linewidth of the solvent 2H2O remains narrower in frozen solutions of the DMPC-[Glu1,8,Leu11,17] 18A complexes suggesting the presence of more unfrozen bound water in this case. The two peptides exhibit many similarities in their interaction with lipids. However, [Glu1,8,Leu11,17] 18A can more readily lyse vesicles and activate lecithin:cholesterol acyltransferase. These differences do not appear to result from differences in specific charge interactions between the lipid and peptide but may be manifested through differences in hydration properties.

Calcium↗
PubMed1989

Synthesis of 5-[1-hydroxy(or methoxy)-2-bromo(or chloro)ethyl]-2'-deoxyuridines and related halohydrin analogues with antiviral and cytotoxic activity.

A series of new 5-(1-hydroxy-2-haloethyl)-2'-deoxyuridines (3, 6, 8) were synthesized in 60-70% yields by addition of HOX (X = Br, Cl, I) to the vinyl substituent of the respective 5-vinyl-2'-deoxyuridines (2, 5, 7). Treatment of 3a,b with methanolic sulfuric acid afforded the corresponding 5-(1-methoxy-2-haloethyl)-2'-(deoxyuridines (4a,b). The 5-(1-hydroxy-2-chloroethyl) (3b), 5-(1-methoxy-2-bromoethyl) (4a), 5-(1-hydroxy-2-bromo-2-(ethoxycarbonyl)ethyl) (6a), and 5-(1-hydroxy-2-iodo-2-(ethoxycarbonyl)ethyl) (6b) derivatives exhibited in vitro antiviral activity (ID50 = 0.1-1 microgram/mL range) against herpes simplex virus type 1 (HSV-1). 5-(1-Hydroxy-2-bromo-2-(ethoxycarbonyl)-ethyl)-2'-deoxyuridine (6a) was the most active cytotoxic agent in the in vitro L1210 screen exhibiting an ED50 of 11 micrograms/mL relative to melphalan (ED50 = 0.15 micrograms/mL).

Animals↗
PubMed1989

Some pharmacological activities of novel adenine-related compounds isolated from a marine sponge Agelas mauritiana.

Agelasimine A and agelasimine B, two novel compounds related to adenine, have been isolated from the orange sponge, Agelas mauritiana, and have been tested for a variety of biological activities. Both compounds inhibited proliferation of cultured L1210 leukemia cells at nanomolar concentrations with accumulation in the G1 stage of the cell cycle. However, no prolongation of life was observed in mice bearing P388 leukemia treated with these compounds. In the rat isolated aorta, micromolar concentrations of agelasimines were very effective in inhibiting contractions elicited by potassium chloride but had little or no effect on responses for prostaglandin F2 alpha and had modest effects on the responses to noradrenaline and significant effects on 5-hydroxytryptamine. Agelsamines A and B appeared to be equipotent in causing relaxation in rabbit jejunum and bovine coronary artery, and they also inhibited nucleoside transport into rabbit erythrocytes in micromolar concentrations.

Adenine↗
PubMed1989

Synthesis, cytotoxic and antiviral activity of uracils containing 5-(1-hydroxy-2-haloethyl)- and 5-(1-methoxy-2-haloethyl) substituents.

5-(1-Hydroxy-2-haloethyl)- (4), 5-(1-methoxy-2-haloethyl)- (5) and 5-(1-hydroxy-2-methoxyethyl)uracils (6) (see Figure 2 for structures) were synthesized to investigate the effect of the C-5 substituents on cytotoxic and antiviral activity. The bromo compounds (4b and 5b) exhibited greater cytotoxic activity than the chloro or iodo analogues in the in vitro L1210 assay. Replacement of the hydroxyl substituent of 4b (bromo) and 4c (iodo) by a methoxyl substituent (5b-c), or substitution of their halogen substituents by methoxyl (providing 6) increased the potency. However, the cytotoxic activity of all the compounds was weak, the most active (6) producing a 45% decrease in cell survival at a concentration of 50 micrograms/ml, as compared with a 97% decrease when the reference standard (melphalan) was tested at 1 microgram/ml. They were inactive antiviral agents against herpes simplex virus type 1 (HSV-1) infected Vero cells at 10 micrograms/ml; in the same test, the reference standard (acyclovir) exhibited an ID50 of 0.01 micrograms/ml.

Animals↗
PubMed1989

Synthesis and cytotoxic activity of pyridylthio, pyridylsulfinyl, and pyridylsulfonyl methyl acrylates.

Nineteen 2-pyridylthio (2), 2-pyridylsulfinyl (3) or 2-pyridylsulfonyl (4) derivatives of (Z)-methyl acrylate were synthesized in order to investigate the effect of the oxidation state of the sulfur atom, and the position and nature of pyridyl substituents on cytotoxic activity. Analogous sulfinyl and sulphonyl derivatives were equipotent, and more potent than analogous thio derivatives, in an vitro L1210 screen. In most cases, incorporation of nuclear trifluoromethyl and chloro substituents at various positions of the pyridyl ring of the sulfinyl derivatives (compounds 3b-3h) decreased activity relative to the unsubstituted sulfinyl 3a (ED50 0.43 micrograms/ml). Compounds 3b, 3d and 3i exhibited weak antineoplastic activity in an in vivo P388 screen at a dose of 5 mg/kg.

Animals↗
PubMed1989

Synthesis and cytotoxic activity of tetrahydropyridylidene-2- and -4-sulfonamides.

1,2,3,4-Tetrahydropyridylidene-4-sulfonamides, 1,2,3,4-tetrahydropyridylidene-2-sulfonamides, and 1,2,3,6-tetrahydropyridylidene-2-sulfonamides, of structures 10, 12 and 14, respectively (given in Table I), were synthesized in order to investigate the effect of nuclear substituents and the position of the sulfonamido group on cytotoxicity. The relative potency order was 12 greater than 10 greater than 14. Compounds possessing an R1 CONEt2 substituent were more potent than those possessing a R1 CN substituent. The nature of the aryl(alkyl)-sulfonamido substituent was a determinant of activity, the relative potency order being 4-chlorophenyl greater than phenyl, 4-methoxy- or 4-nitrophenyl greater than methyl. 1-Methyl-4-tert-butyl-5-diethylaminocarbonyl-1,2,3,4-tetrahydro pyridylidene- 2-(4-chlorophenyl)sulfonamide (12c) was the most active cytotoxic agent, exhibiting an ED50 of 5.4 micrograms/ml in the L1210 in vitro screen.

Animals↗
PubMed1988

Fluorometric detection of the bilayer-to-hexagonal phase transition in liposomes.

We have used the fluorescent probe N-(7-nitro-2,1,3-benzoxadiazol-4-yl)phosphatidylethanolamine (NBD-PE) to detect the bilayer-to-hexagonal phase transition. The fluorescence intensity of the probe was found to increase during the bilayer-to-hexagonal transition. The bilayer-to-hexagonal transitions of various types of phosphatidylethanolamine or cardiolipin measured by this method are consistent with results obtained by differential scanning calorimetry. To establish this method for wider use, agents known to alter the bilayer-to-hexagonal transition were examined, and the results are comparable with the published data. The added advantage of this fluorometric method over other currently available techniques is that it is applicable not only for aggregated lipid samples but also for dilute liposome suspensions. This is especially important when one of the components of the system under study can partition between lipid and aqueous phase. Since NBD is located near the headgroup region of the bilayer, it most likely detects the change of the environment surrounding that region. On the basis of our present study, it appears that NBD-PE is sufficiently sensitive to detect bilayer-to-hexagonal phase transition.

Fluorescent Dyes↗
PubMed1988

Phosphatidylserine as a determinant of reticuloendothelial recognition of liposome models of the erythrocyte surface.

Liposomes formulated to resemble the outer leaflet of the erythrocyte membrane were found to substantially avoid recognition and clearance by the reticuloendothelial system. When these models of the erythrocyte surface were modified by the incorporation of greater than 2 mol % of phosphatidylserine (PtdSer), their ability to remain in the circulation of mice was greatly reduced. To examine whether this altered behavior was the consequence of an alteration in bilayer organization induced by PtdSer, a method utilizing the fluorescent dye merocyanine 540 was used to assess the packing of external phospholipids. No significant difference in overall membrane lipid organization was detected between liposomes containing 2 or 3 mol % of PtdSer, at which dramatic differences in recognition and clearance occurred. These results exclude alterations in phospholipid packing as an indirect cause of increased clearance of PtdSer-containing liposomes and implicate PtdSer directly in recognition by the reticuloendothelial system.

Animals↗
PubMed1988

Synthesis and cytotoxic activity of 1-(3-oxoprop-1-enyl)-2-pyridones.

1-(3-Oxoprop-1-enyl) derivatives of nuclear substituted 2-pyridones (7a-i), 2-pyridinethione (7j), 1-isoquinolone (9), and the 1,4-dihydropyridine (11) have been synthesized and tested for biological activity. The 2-pyridones (7) and the 1-isoquinolone (9) were all active cytotoxic agents as determined in the in vitro L1210 screen, exhibiting activity in the ED50 0.5-3.5 micrograms/ml range. The nature and position of nuclear substituents present in 7 and 9 did not alter activity significantly. The unsubstituted (7a) and 5-ethoxycarbonyl-2-pyridones (7g), and the 1-isoquinolone derivative (9) were active antineoplastic agents (%T/C = 133-135) in vivo exhibiting activity comparable to 5-fluorouracil.

Animals↗
PubMed1987

Lipid mixing during membrane aggregation and fusion: why fusion assays disagree.

The kinetics of lipid mixing during membrane aggregation and fusion was monitored by two assays employing resonance energy transfer between N-(7-nitro-2,1,3-benzoxadiazol-4-yl)phosphatidylethanolamine (NBD-PE) and N-(lissamine Rhodamine B sulfonyl)phosphatidylethanolamine (Rh-PE). For the "probe mixing" assay, NBD-PE and Rh-PE were incorporated into separate populations of phospholipid vesicles. For the "probe dilution" assay, both probes were incorporated into one population of vesicles, and the assay monitored the dilution of the molecules into the membrane of unlabeled vesicles. The former assay was found to be very sensitive to aggregation, even when the internal aqueous contents of the vesicles did not intermix. Examples of this case were large unilamellar vesicles (LUV) composed of phosphatidylserine (PS) in the presence of Mg2+ and small unilamellar vesicles (SUV) composed of phosphatidylserine in the presence of high concentrations of Na+. No lipid mixing was detected in these cases by the probe dilution assay. Under conditions where membrane fusion (defined as the intermixing of aqueous contents with concomitant membrane mixing) was observed, such as LUV (PS) in the presence of Ca2+, the rate of probe mixing was faster than that of probe dilution, which in turn was faster than the rate of contents mixing. Two assays monitoring the intermixing of aqueous contents were also compared. The Tb/dipicolinic acid assay reported slower fusion rates than the 1-aminonaphthalene-3,6,8-trisulfonic acid/N,N'-p-xylylene-bis(pyridinium bromide) assay for PS LUV undergoing fusion in the presence of Ca2+. These observations point to the importance of utilizing contents mixing assays in conjunction with lipid mixing assays to obtain the rates of membrane destabilization and fusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemical Phenomena↗
PubMed1987

Large unilamellar liposomes with low uptake into the reticuloendothelial system.

Particulate drug carriers, including liposomes, are rapidly removed from blood by cells of the reticuloendothelial system (RES) with resulting adverse effects on this important host defense system. In order to overcome this and other major disadvantages of liposomes, we have altered liposome composition in an effort to achieve prolonged circulation half-lives. Gangliosides and sphingomyelin act synergistically to dramatically diminish the rate and extent of uptake of liposomes by macrophages in vivo. The significantly extended circulation times achieved by these modified large unilamellar liposomes overcome an important barrier to the targeting of particulate drug carriers to specific tissues in vivo.

Cholesterol↗
PubMed1987

Effects on the murine mononuclear phagocyte system of chronic administration of liposomes containing cytotoxic drug or lipid A compared with empty liposomes.

In experiments designed to examine the adverse effects of chronic liposome administration in vivo on the mononuclear phagocyte system (reticuloendothelial system), the presence of drug entrapped in the liposomes may increase the level of reticuloendothelial impairment. We have compared the effects on the mononuclear phagocyte system in mice of chronic administration of empty liposomes with the effects of liposomes containing the anti-leishmanial drug meglumine antimoniate. We have also examined the effect on the mononuclear phagocyte system of continued injections of liposomes containing lipid A, a component of bacterial lipopolysaccharide, which is responsible for macrophage activation. Ten intravenous injections of multilamellar liposomes composed of dipalmitoylphosphatidylcholine and cholesterol (1:0.75 M ratio) were given to ICR mice over a 25-day period. Two individual groups of mice received endotoxin-free liposomes in which meglumine antimoniate was either present or absent. One addition group received liposomes containing lipid A derived from Escherichia coli lipopolysaccharide. A control group received sterile saline injections. In each group, a depression of the phagocytic index, as measured by reduction of uptake of particulate carbon, was observed among some of the individual animals 24 h after the first injection. In many mice a marked splenomegaly was observed. A depressed phagocytic index and splenomegaly were most marked for mice receiving lipid A liposomes. However, there was a large individual variability among mice receiving these preparations and some mice in each group had normal spleen size and a nearly normal phagocytic index. Tissue distribution of liposomes containing [14C]dipalmitoylphosphatidylcholine as a phospholipid marker was examined in all groups in mice 24 h after the last injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗