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Biomedical subjects

C W Mosher

Publications and source records attributed to C W Mosher.

17 recordsLinked to original sources
PubMed1984

Intensely potent morpholinyl anthracyclines.

3'-Deamino-3'-(3-cyano-4-morpholinyl)doxorubicin is a new analogue that is 100 to 1000 times more potent than doxorubicin against tumors in cell culture or in mice, that is active by intraperitoneal, intravenous, or oral dosing, and that does not produce chronic myocardial lesions in mice. This analogue was encountered in studies on the reductive alkylation of doxorubicin and daunorubicin with 2,2' - oxybis [acetaldehyde], which constructs a morpholino ring incorporating the amino N. The morpholinyl nitrile byproducts are separated by virtue of their nonbasicity from the expected morpholino derivatives. The 13-dihydro and 5-imino derivatives are also described in this important new class of anthracyclines.

Animals↗
PubMed1982

Viscometric analysis of the interaction of bisphenanthridinium compounds with closed circular supercoiled and linear DNA.

The interaction with closed circular supercoiled and linear DNA of bisphenanthridinium compounds substituted through both the meta and para positions of the 6-phenyl group, along with appropriate monomer intercalators as controls, has been investigated by viscometric titration. When CPK models for the phenanthridinium rings of the three bis-compounds are oriented in a parallel manner as a model for intercalation, their ring plane to ring plane distances are approximately 7 to 8 A (SR 2430), 11 A (SR 2193), and 15 A (SR 2166). In SR 2430 the two phenanthridines are linked through the para positions of the 6-phenyl group; this chain allows intercalation of the two rings at adjacent binding sites in DNA, but is not long enough to accommodate an excluded site. The viscometric titrations with both superhelical and linear DNA clearly indicate that SR 2430 gives results close to those of the monomer control compounds while SR 2193 and SR 2166 have approximately twice the unwinding angle and DNA length increase on binding to DNA as the monomer compounds. These phenanthridinium compounds, therefore, are capable of bisintercalation only if their linking groups are of sufficient length to allow an excluded binding site between base pairs. This conclusion is supported by DNA thermal denaturation experiments in the presence of these compounds.

Chemical Phenomena↗
PubMed1982

Enhanced antitumor properties of 3'-(4-morpholinyl) and 3'-(4-methoxy-1-piperidinyl) derivatives of 3'-deaminodaunorubicin.

Reductive N,N-dialkylation of daunorubicin with 2,2'-oxydiacetaldehyde and NaBH3CN occurred in two steps without interruption and with cyclization to form 3'-(4-morpholinyl)-3'-deaminodaunorubicin. This derivative retained the antitumor efficacy of doxorubicin against mouse leukemia P388 but at one-fortieth the dose; hence, it is the most potent anthracycline analogue synthesized so far. The 4-methoxy-1-piperidinyl derivative, similarly prepared with 3-methoxyglutaraldehyde, showed improved efficacy against P388, though at normal doses. Results with a series of analogues indicate that incorporation of the N in the new ring and the presence of an ether O at the 4-position are critical for enhanced activity.

Animals↗
PubMed1981

Nonquaternary cholinesterase reactivators. Dialkylaminoalkyl thioesters of alpha-ketothiohydroximic acids as reactivators of diisopropyl phosphorofluoridate inhibited acetylcholinesterase.

We have prepared a series of alpha-ketothiohydroximic acid thioesters and evaluated them in vitro with respect to their ability to reactivate (diisopropylphosphoryl)acetylcholinesterase. The compounds conform to the general formula RC(=O)C(=NOH)S(CH2)nNR2'.HCl, where R = CH3, C6H5, 4-CH3OC6H4, 4-NO2C6H4; n = 2, 3; and R' = CH3, C2H5, or i-C3h7. We also prepared 4-BrC6H4C(=NOH)S(CH2)2N(C2H5)2.HCl and 4-CH3OC6H4C(=O)C(=NOH)S(CH2)2N(C2H5)2.CH3I for comparison. The alpha-ketothiohydroximates exhibit oxime acid dissociation constants (pKa) in the range 6.9 to 8.4, bracketing the value of pKa = 7.9, believed to be optimal for acetylcholinesterase reactivation. The compounds are also good nucleophiles; bimolecular rate constants (kn) for reaction with p-nitrophenyl acetate follow the expression log (kn) = 6.7 - 0.69(14 - pKa = The reactivation of (diisopropylphosphoryl)acetylcholinesterase is highly dependent on the alpha-ketothiohydroximate structure: 4-h incubation of inhibited enzyme at pH 7.6, 25 degrees C, with 1 x 10(-3) M 4-CH3OC6H4C(=O)C(=NOH)S(CH2)3N(CH3)2.HCl gives no detectable restoration of activity, whereas 4-CH3OC6H4C(=O)C(=NOH)S(CH2)2N(C2H5)2.HCl restores inhibited enzyme activity to 58% of control under identical conditions. With alpha-ketothiohydroximate in excess over inhibited enzyme, the kinetics of reactivation are governed by an equilibrium constant (Kr) for binding alpha-ketothiohydroximate to the inhibited enzyme and a nucleophilic displacement rate constant (kr) for attack on phosphorus.

Cholinesterase Inhibitors↗
PubMed1981

New dimeric analogues of ethidium; synthesis, interaction with DNA, and antitumor activity.

Three new dimeric analogues of ethidium cation in which the monomeric moieties are linked at the 3' positions by alpha,omega-diethers of varying length and composition have been synthesized. The circular dichroism spectra of all three compounds indicate that they double intercalate, and their effects on the thermal helix-coil transition profile of poly(dA-dT) show extremely high affinity for helical DNA, with details of the binding interaction depending on the length and composition of the connecting chain. The ability of the compounds to inhibit nucleic acid synthesis in L1210 cell culture also differed significantly, as did their antitumor effects against P388 leukemia and B16 melanoma. Compound 2, with 10 methylene groups in the connecting chain, is 5-20 times as potent as ethidium against murine P388 leukemia. These results clearly illustrate the advantage gained by incorporating a weak antitumor agent in a double-intercalating analogue.

Animals↗
PubMed1979

A phenazine analogue of actinomycin D.

An analogue of actinomycin D (1), in which the phenoxazone chromophore has been replaced by a phenazine, has been synthesized and characterized. Although this compound (2) lacks the 2-amino group and does not possess the quinoid structure of 1, it does bind to DNA, but less tightly than either 1 or the 2-deamino derivative of 1. NMR and CD spectra indicate that the peptide conformations in 2 are approximately as in 1; there was no apparent asymmetry of the two peptide rings. Compound 2 inhibited nucleic acid synthesis in L1210 cell cultures more effectively than does 2-deaminoactinomycin D, but about one-tenth as well as does actinomycin D.

Animals↗
PubMed1979

7-(Aminoethyl) ether and thioether of daunomycinone.

One-step treatment of daunomycinone with excess 2-aminoethanethiol and 2-aminoethanol in trifluoroacetic acid afforded at C-7 the thioether (77% yield) and ether (30% after recycling), respectively. Stereoselectivity for the natural 7S over the 7R configuration was greater for the ether (97:3) than for the thioether (2.5:1). Esterification of daunomycin at C-7 with beta-alanine was accomplished through the mixed anhydride of Z(OMe)-beta-alanine. Preliminary biological tests suggests that the antitumor and DNA interactive properties of the anthracyclines can be retained in such structures.

Animals↗
PubMed1978

Synthesis, DNA-binding and biological activity of a double intercalating analog of ethidium bromide.

A bis-phenanthridinium salt has been synthesized and its DNA-binding studied. Evidence provided by UV and CD spectra, by thermal denaturation profiles and by equilibrium dialysis of the drug-DNA complex lead to the conclusion that both phenanthridine moieties intercalate in the helix. The double intercalator appears to be less potent than ethidium chloride as an inhibitor of nucleic acid synthesis in cultured L1210 cells, though it is more potent than a monomeric analog. The low potency may be due to a low cell influx rate.

Biological Transport↗
PubMed1977

2-Deaminoactinomycin D, synthesis and interaction with deoxyribonucleic acid.

2-Deaminoactinomycin D has been synthesized and characterized. It binds to DNA by intercalation according to NMR, CD, thermal denaturation, and unwinding studies on the drug-DNA complex. Loss of the 2-amino group does not seriously affect binding parameters relative to actinomycin D; affinity for calf thymus DNA may even be increased, according to deltaTm measurements. The unwinding of circular DNA caused by this compound is at least as large as that effected by actinomycin D and ethidium bromide. Nevertheless, 2-deaminoactinomycin D is less effective than actinomycin D in inhibiting nucleic acid syntheses in L1210 cell culture and in in vivo antitumor activity against P388 leukemia.

Animals↗
PubMed1977

Ethidium analogues with improved resolution in the dye-buoyant density procedure.

Analogues of ethidium chloride with large quaternary side chains have been synthesized and evaluated for improved resolution in the dye-buoyant density system for the separation of open and closed circular DNA. These compounds are similar to propidium which differs from ethidium by the replacement of an ethyl group by a methyldiethylaminopropyl group. The new analogues contain a triethylamino group attached to a methylene chain with 3, 5 or 7 carbons. With PM2 DNA the observed separation for propidium is 1.97 times that of ethidium and the new dyes show separations relative to ethidium of 2.27, 2.66 and 2.77. A correlation is established between the mass of the dye component and the observed separation which is retionalized on the basis of the four component thermodynamics describing this system.

Bacteriophages↗