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Biomedical subjects

L A Mitscher

Publications and source records attributed to L A Mitscher.

At least 55 records · Page 3Linked to original sources
PubMed1986

Benzanthrins A and B, a new class of quinone antibiotics. II. Isolation, elucidation of structure and potential antitumor activity.

The benzanthrins, which were produced by Nocardia lurida, were extracted from the fermentation broth with CH2Cl2. Subsequent purification on Sephadex LH-20 and diolbonded silica gel, followed by countercurrent chromatography, afforded analytically pure benzanthrins A and B. FAB-MS revealed that benzanthrins A and B were isomeric. It was demonstrated through degradative and spectroscopic studies that the benzanthrins were di-glycosides of a trihydroxy benz[a]anthraquinone chromophore where one of the sugars was linked through carbon and the other through oxygen. Benzanthrins A and B differed in the stereochemistry of the O-glycosidic sugar. Both compounds inhibited the growth of Gram-positive bacteria and 9KB, 9PS and 9ASK tumor cells in tissue culture.

Animals↗
PubMed1985

Antimicrobial and cytotoxic properties of 9,10-dihydrophenanthrenes: structure-activity studies on juncusol.

The antimicrobial and cytotoxic properties of a series of 9,10-dihydrophenanthrenes structurally related to juncusol (1a), a postulated phytoalexin with confirmed cytotoxic properties, are detailed. Two simple 9,10-dihydrophenanthrenes, 2,7-dihydroxy-3,8-dimethyl-9,10-dihydrophenanthrene (2h, desvinyljuncusol) and 2-hydroxy-3-methyl-9,10-dihydrophenanthrene (3h), were found to possess in vitro antimicrobial activity comparable with that of the natural product. Two 9,10-dihydrophenanthrenes substituted with quaternary ammonium salts, 2d and 3d, each containing a reactive benzylic dimethyl[(phenylthio)methyl]ammonio group, were found to be 10-20 times more potent than juncusol (1a). Confirmed in vitro cytotoxic activity that parallels antimicrobial activity was found for juncusol (1a), desvinyljuncusol (2h), 2-hydroxy-3-methyl-9,10-dihydrophenanthrene (3h), and the quaternary dimethyl[(phenylthio)methyl]ammonium salts 2d and 3d in a human lymphoblastic leukemia cell culture (CCRF-CEM, IC50 = nt, 9.3, nt, 0.9 and 1.4 microgram/mL, respectively), B-16 mouse melanoma cell culture (IC50 = 12.5, 17.5, 27.7, 0.3, and 0.5 microgram/mL, respectively), and L-1210 mouse lymphocytic leukemia cell culture (IC50 = 13.8, 10.2, 24.5, 1.3, and 3.7 micrograms/mL, respectively). The comparable potency and spectrum of activity of juncusol (1a), desvinyljuncusol (2h), and 2-hydroxy-3-methyl-9,10-dihydrophenanthrene (3h) suggest that the agents are acting as simple phenols in exerting their antimicrobial and cytotoxic effects.

Animals↗
PubMed1984

Structure-activity relationships among DNA gyrase inhibitors. Synthesis and biological evaluation of 1,2-dihydro-4, 4-dimethyl-1-oxo-2-naphthalenecarboxylic acids as 1-carba bioisosteres of oxolinic acid.

A series of oxolinic acid analogues was synthesized in an attempt to evaluate the role, if any, played by the N-1 atom in putative modes of action of antimicrobial DNA gyrase inhibitors. Carba analogues were prepared because these have no possibility of an internal resonance contribution of the nitrogen atom and yet could otherwise satisfy electronic requirements of putative modes of action. Successful routes were developed involving Friedel-Craft's cycloaddition of suitable aromatic compounds with 4,4-dimethylbutyrolactone, followed by ethoxycarbonylation, oxidation with dichlorodicyanobenzoquinone, and careful saponification. The gem-dimethyl group of these analogues prevents aromatization at the cost of nonplanarity. Only the unsubstituted parent compound, 1,2-dihydro-4,4-dimethyl-1-oxo-2-naphthalenecarboxylic acid, possessed any appreciable antimicrobial activity in vitro. This may be due to a different mode of action, however, since gave no measurable inhibition of DNA gyrase in vitro. Thus, the N-1 atom plays a significant role in enzymic and bacteriological inhibition that cannot be compensated for by the presence of C-6 oxygen atoms.

Magnetic Resonance Spectroscopy↗
PubMed1979

Quinolone antimicrobial agents. 2. Methylenedioxy positional isomers of oxolinic acid.

The synthesis and antimicrobial activity of the methylenedioxy positional isomers, 1-ethyl-1,4-dihydro-5,6-methylenedioxy-4-oxo-3-quinolinecarboxylic acid (9) and 1-ethyl-1,4-dihydro-7,8-methylenedioxy-4-oxo-3-quinolinecarboxylic acid (17), of oxolinic acid (18) have been accomplished. Isomer 9 was prepared by the reaction of N-ethyl-6,7-methylenedioxyisatoic anhydride with sodioethyl formylacetate [L. A. Mitscher, H. E. Gracey, G. W. Clark III, and T. Suzuki, J. Med. Chem., 21, 485 (1978)], while isomer 17 was prepared by thermal cyclization of diethyl 2-[(2,3-methylenedioxyanilino)methylene]malonate [D. Kaminsky and R. I. Meltzer, J. Med. Chem., 11, 160 (1968)]. Both of the new isomers are less active in vitro when compared to oxolinic acid (18) itself.

Isomerism↗
PubMed1978

Quinolone antimicrobial agents. 1. Versatile new synthesis of 1-alkyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids.

A flexible reaction sequence has been developed which starts with readily available anthranilic acids or isatoic anhydrides and leads regiospecifically to 1-alkyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids after reaction with 1,3-dicarbonyl compounds. The sequence is superior to earlier published methods by allowing electron-releasing and -withdrawing groups in any position on the aro;atic ring, by allowing convenient substitution at C2, and better overall yield. A number of new and known antimicrobial agents were prepared and tested in vitro, demonstrating, inter alia, that substitution of the H at C2 abolished antibacterial activity.

Anti-Infective Agents↗
PubMed1977

Rate and proposed mechanism of anhydrotetracycline epimerization in acid solution.

The pathway through which the toxic tetracycline degradation product epianhydrotetracycline forms in solution was studied using high-performance liquid chromatography and circular dichroism, taking advantage of the large difference in ellipticity between the reactant and the product at 285 nm. The epimerization of anhydrotetracycline followed a reversible first-order process, and both analytical methods yielded the same rate constants. The rate constants indicate that anhydrotetracycline epimerization is faster than tetracycline epimerization. The equilibrium favored anhydrotetracycline, and the activation energies for the forward and reverse rates were almost the same as those for tetracycline epimerization. The epimerization was catalyzed by phosphate. Activation energies in 0.1 and 1 M phosphate were essentially the same. The equilibrium constants for both anhydrotetracycline and tetracycline favored the natural configuration rather than the epi series. Possible rationalization based on conformational and hydrogen bonding effects is presented.

Chemical Phenomena↗
PubMed1977

A new aminoglycoside antibiotic complex--the seldomycins. III. The structures of seldomycin factors 1 and 2+.

The structures of seldomycin factors 1 and 2 have been determined by consideration of chemical degradation and spectral properties. Factor 1, also known as XK-88-1, is shown to be 6-O-(2-amino-2-deoxy-alpha-D-xylopyranosyl) paromamine (1) and factor 2, also known as XK-88-2, is shown to be 4'-deoxy-neamine (2). Mass spectral evidence has been obtained that suggests the most probable structure for seldomycin factor 3, also known as XK-88-3, is 6'-amino-6'-deoxyseldomycin factor 1 (12).

Amino Sugars↗
PubMed1977

Fortimicins A and B, new aminoglycoside antibiotics. III. Structural identification.

The structures of fortimicins A and B have been determined by PMR, CMR, mass spectra and CD combined with chemical degradations. Both antibiotics are pseudodisaccharides and incorporate a novel aminocyclitol, fortamine. In contrast to the diaminocyclitol moieties of known aminoglycosides, fortamine is a 1,4-diamine, contains both N- and O-methyl groups and possesses chiro stereochemistry. Both antibiotics are glycosides of 6-epi-purpurosamine B, but fortimicin A differs from fortimicin B by being a glycyl amide.

Aminoglycosides↗
PubMed1977

Modern instrumental methods for identification of antibiotics.

Modern screening for antimicrobial agents and the characterization of their transformation products are not only extremely competitive but highly labor intensive activities. The use of specialized instrumental techniques for rapid identification of molecular species shows promise of becoming an essential part of this process. At the earliest stages, microseparation methods coupled with modern methods of ion production are particularly useful. Applications of various methods of chromatography, including high performance liquid chromatography, with various methods of ion production using mass spectrometers, particularly under computer control, are exceptionally powerful, though expensive, means of addressing this problem. Some present and potential uses of this technique are discussed along with a consideration of the strengths and weaknesses now apparent and a projection is made of the future of this method. A brief review of the use of a variety of physical methods of structural characterization for a variety of specialized purposes is also given along with a bibliography of recent applications to specific antibiotics. The scope and limitations of these methods is also treated.

Anti-Bacterial Agents↗