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Biomedical subjects

L A Mitscher

Publications and source records attributed to L A Mitscher.

At least 19 recordsLinked to original sources
PubMed1996

Natural antimutagenic agents.

Following a brief review of recent discoveries in the field of natural antimutagenic and tumor chemopreventive agents, contemporary findings in the author's laboratories employing the direct acting mutagen, ethyl methanesulfonate, in modified Ames tests and eukaryotic murine FM3A mammary tumor cells modified to be subject to thymidine-less death are described to illustrate the underlying principles. The EMS studies are illustrated with the isolation of the novel antimutagen, plicatin B, from the medicinal plants, Psoralea juncaea and P. plicata. The FM3A studies are carried out with extracts of Styrax asiatica, a plant previously studied extensively with the EMS system. The FM3A findings closely parallel the earlier work with EMS showing that the responsible agents, cinnamic acid, cinnamoyl ricinoleate and cinnamoyl cinnamate are effective both in prokaryotic and eukaryotic tests and that the new FM3A assay system has useful properties for screening and assay of novel antimutagenic agents.

Acrylates↗
PubMed1995

Novel cytotoxic 3'-(tert-butyl) 3'-dephenyl analogs of paclitaxel and docetaxel.

3'-(tert-Butyl) 3'-dephenyl analogs of paclitaxel were synthesized from 10-deacetylbaccatin III and oxazolidinecarboxylic acid 7 followed by acylation of intermediate amines 10 and 11. Oxazolidinecarboxylic acid 7 was prepared in five steps and in good overall yield from L-tert-leucine. Twelve analogs were synthesized and evaluated for their in vitro ability to stimulate the formation of microtubules and for their cytotoxicity against B16 melanoma cells. Amide, carbamate, urea, and thiourea congeners were prepared. The most potent derivatives found in this study are the docetaxel analog 13, the N-[(tert-amyloxy)carbonyl] analog 17, and the 3'-phenylurea and 3'-tert-butylurea derivatives 20 and 23. Six of these analogs were shown to be ca. 90 times more soluble in water than paclitaxel and ca. 4-5 times more water-soluble than docetaxel.

Antineoplastic Agents, Phytogenic↗
PubMed1994

Wallifoliol, a taxol congener with a novel carbon skeleton, from Himalayan Taxus wallichiana.

A new taxoid, wallifoliol [3], has been isolated, along with five known taxoids (taxol, cephalomannine, 10-deacetylbaccatin III, brevifoliol, 2-acetoxy brevifoliol = taxchinin A) from extracts of the needles of Himalayan Taxus wallichiana. The structure of wallifoliol has been assigned primarily from nmr studies. Wallifoliol [3] is assigned a structure in which rings A and B of the taxane system have undergone putative rearrangements producing a novel skeleton. Wallifoliol is the first diterpene to be found in nature with this particular 5/6/6/6/4 ring system.

India↗
PubMed1994

Alectosarmentin, a new antimicrobial dibenzofuranoid lactol from the lichen, Alectoria sarmentosa.

From the alcoholic extract of the lichen Alectoria sarmentosa, four compounds showing antimicrobial activity were isolated. Of these, (-)-usnic acid and physodic acid are well known lichen products, 8'-O-ethyl-beta-alectoronic acid [2] is believed to be an artifact formed during isolation and fractionation, and alectosarmentin [1] is a new natural product whose structure was shown, by spectroscopy and chemical transformations, to be that of a dibenzofuranoid lactol. The antimicrobial activity of these substances accounts for the activity of the lichen.

Anti-Bacterial Agents↗
PubMed1993

Extracellular interception of mutagens.

Extracellular interception of mutagens by excreted enzymes or by chemical agents that react with or bind to formed mutagens provides an important means of defense against chemical mutagens/carcinogens. Kada and Shimoi have classified molecules that function in this manner as "desmutagens," and many of them are natural cellular metabolites. Among the specific mechanisms that such agents may employ are: prevention of the activation of "promutagens" to mutagens; stimulation of enzymes (e.g., glutathione-S-transferase) that catalyze the binding/inactivation of damaging electrophiles; direct binding and concomitant inactivation of promutagens or mutagens; interference with uptake of mutagens into cells; etc. De Flora and Ramel have provided an excellent discussion of the mechanisms of these agents and a proposed classification scheme. Drawing on work from our own laboratories and other recent examples in the literature, several examples of mechanistic approaches to these studies using natural plant-derived materials, e.g., humic acid, Glycyrrhiza glabra extract, glutathione, and bioflavonoids, are also described. Antioxidants and agents that conjugate electrophiles will be among the modes of action described for obtaining the goal of intercepting mutagens/carcinogens.

Animals↗
PubMed1993

Antimutagenic activity of extracts of leaves of four common edible vegetable plants in Nigeria (west Africa).

Organic solvent extracts of leaves of 4 common edible vegetable plants--Bryophyllum pinnatum, Dialium guincense, Ocimum gratissimum and Vernonia amygdalina--had inhibitory activity for His- to His+ reverse-mutations induced by ethyl methanesulfonate acting on Salmonella typhimurium TA100. The concentrated ethyl acetate, methanol and petroleum ether extracts were heat-stable when dissolved in dimethyl sulfoxide. The Bryophyllum ethyl acetate extract was fractionated into alkaloidal/water-soluble, acids, polar lipid and non-polar lipid fractions. The polar and non-polar lipid fractions inhibited reversion mutations induced by ethyl methanesulfonate acting on TA100 or TA102, and were also active against reversions induced by 4-nitro-O-phenylenediamine and 2-aminofluorene in TA98. The alkaloidal/water-soluble and the acid fractions had no appreciable antimutagenic activities.

Acetates↗
PubMed1992

Antimutagenicity of secondary metabolites from higher plants.

Higher plants contain both mutagens and antimutagens and are susceptible to mutagenesis but screening programs for detection of antimutagenesis rarely employ higher plant systems. Short-term bacterial and mammalian tissue culture systems are the norm. Using modified screening tests for detecting antimutagenic agents, higher plants have been shown to contain a variety of structurally novel antimutagenic agents. Systematic bioassay-directed methodology resulted in the isolation in pure form and biological and chemical characterization of the responsible individual active components from various plants. The methodology in use is illustrated by the isolation of cinnamic acid, cinnamyl cinnamate and cinnamyl ricinoleate as the active constituents of the classic medicinal plant product, Styrax asiatica. The methods which may be used to reveal structure-activity relationships and to explore putative molecular modes of action are illustrated with excerpts from the same study.

Antimutagenic Agents↗
PubMed1992

Glycyrrhiza glabra extract as an effector of interception in Escherichia coli K12+.

Glycyrrhiza glabra polar lipid extract contains a number of flavonoids and related chemical compounds. Studies on the effectiveness of Glycyrrhiza glabra polar lipid extract in intercepting reactive molecules generated from the illumination of the photosensitizers rose bengal and phenosafranin indicate that it is effective in preventing cytotoxicity against E. coli K12+ in a dose-related fashion using illuminated rose bengal. Since only a modest scavenging of singlet oxygen generated from phenosafranin is observed, the effects of the extracts are less related to singlet oxygen-mediated oxidation of substrate (type II reactions) than non-singlet oxygen-mediated oxidation of substrate (type I reactions). Elevated levels of glutathione observed in exponentially growing cells of E. coli K12 were also observed.

Antioxidants↗
PubMed1992

Dactylocyclines, novel tetracycline derivatives produced by a Dactylosporangium sp. III. Absolute stereochemistry of the dactylocyclines.

The dactylocycline antibiotics were found through circular dichroism measurements, NMR spectroscopy and chemical transformations to possess the usual tetracycline family absolute configuration at carbons 4, 4a, 5a and 12a. The absolute stereochemistry about the C-6 carbon, however, was the reverse of that found with previously investigated tetracyclines.

Actinomycetales↗
PubMed1991

Potential antitumor phenoxazines.

From the various studies cited, spanning more than forty years, it is clear that some members of the phenoxazine and benzophenoxazine dye family selectively stain certain tumors and, when given in suitable concentrations in the feed, can prolong life and shrink tumors. In addition, some use has been made of these compounds as carriers for other antitumor agents based upon the idea of selective accumulation into tumor tissue. Although many analogs have been made and examined, the work has been done in a relatively unfocused manner and the field could benefit from a systematic study of the effect of structure on biological activity. None of the synthetic materials prepared and tested to date has the potency of the outstanding antitumor natural products bearing the ring system of the actinomycins. Advances in our understanding of the molecular mode of action of the actinomycins, based in large measure upon x-ray studies, suggest some avenues for future exploitation. To date, attempts to prepare simplified actinomycins or elaborate phenoxazines to accomplish this have been disappointing.

Animals↗
PubMed1989

Mechanism of inhibition of DNA gyrase by quinolone antibacterials: a cooperative drug--DNA binding model.

We have proposed a cooperative quinolone-DNA binding model for the inhibition of DNA gyrase. The essential feature of the model is that bound gyrase induces a specific quinolone binding site in the relaxed DNA substrate in the presence of ATP. The binding affinity and specificity are derived from two unique and equally important functional features: the specific conformation of the proposed single-stranded DNA pocket induced by the enzyme and the unique self-association phenomenon (from which the cooperativity is derived) of the drug molecules to fit the binding pocket with a high degree of flexibility. Supporting evidence for and implications of this model are provided.

Anti-Bacterial Agents↗
PubMed1987

Streptonigrin and lavendamycin partial structures. Probes for the minimum, potent pharmacophore of streptonigrin, lavendamycin, and synthetic quinoline-5,8-diones.

The preparation and evaluation of 7-amino-5,8-dioxo-2-(2'-pyridyl)quinoline-6'-carboxylic acid (5a) and 7-amino-2-(2'-aminophenyl)-5,8-dioxoquinoline-5'-carboxylic acid (6a) constituting potential minimum, potent pharmacophores of streptonigrin (1a) and lavendamycin (2a), two structurally related naturally occurring antitumor antibiotics, are detailed. In contrast to observations associated with streptonigrin and lavendamycin in which the C-ring C-6' carboxylic acid potentiates the antitumor, antimicrobial, and cytotoxic properties of the naturally occurring, substituted 7-aminoquinoline-5,8-dione AB ring systems, the C-6'/C-5' carboxylic acid of 5a/6a diminishes the observed antimicrobial and cytotoxic properties of the 2-(2'-pyridyl)- and 2-(2'-aminophenyl)-7-aminoquinoline-5,8-diones. A direct comparison of the antimicrobial and cytotoxic properties of a complete set of streptonigrin and lavendamycin partial structures is detailed in efforts to define the role peripheral substituents play in potentiating the biological properties of the naturally occurring and synthetic agents bearing the 7-aminoquinoline-5,8-dione AB ring system and in efforts to define the minimum, potent pharmacophore of the naturally occurring antitumor antibiotics. The relationship of these observations to a chemical mechanism of cellular toxicity is discussed.

Animals↗
PubMed1987

Chiral DNA gyrase inhibitors. 2. Asymmetric synthesis and biological activity of the enantiomers of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H- pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (ofloxacin).

A short and efficient synthesis, starting with (R)- and (S)-alaninol, of the two optical antipodes of the quinolone antimicrobial agent ofloxacin has been devised. Testing in vitro of the products against a range of bacteria and in an assay system incorporating purified DNA gyrase from different bacterial species demonstrates that the S-(-) enantiomer is substantially the more active.

Anti-Bacterial Agents↗
PubMed1987

In vitro susceptibility of Coxiella burnetii to antibiotics, including several quinolones.

Antibiotic susceptibility testing of the rickettsial Q fever agent Coxiella burnetii was performed by using persistently infected L929 fibroblast cells. The efficacies of a variety of antibiotics with different metabolic targets were tested and compared. The most effective antibiotics in bringing about the elimination of the parasite from infected cells included several quinolone compounds and rifampin. Of the quinolone compounds tested, difloxacin (A-56619) was the most effective, followed by ciprofloxacin and oxolinic acid. These three quinolones were apparently rickettsiacidal. After 48 h of exposure to microgram amounts of the compounds (ranging from 2 micrograms of difloxacin per ml to 5 micrograms of the other two antibiotics per ml), the number of intracellular parasites markedly declined; after 10 days of treatment, very few intracellular rickettsiae were detected. Rifampin (1 microgram/ml) was also very effective in eliminating the parasites. Some of the 13 other antibiotics tested that were somewhat effective included chloramphenicol, doxycycline, and trimethoprim. The persistently infected L929 cells were found to provide a convenient system for the relatively rapid determination of the susceptibility of C. burnetii to antibiotics.

Animals↗
PubMed1986

Total chemical synthesis and antitumor evaluation of the 9-aza analogue of N-(trifluoroacetyl)-4-demethoxydaunomycin.

The 9-aza analogue of N-(trifluoroacetyl)-4-demethoxydaunomycin has been synthesized from 2,5-dimethoxybenzaldehyde. Pomeranz-Fritsch condensation followed by borohydride reduction and acid-catalyzed cyclization led smoothly to 4-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline. Selective N-acetylation and subsequent Friedel-Crafts acylation with phthalic anhydride produced 2-acetyl-5,12-dihydroxy-1,2-dihydro-2-azanaphthacene-6,11-dione, which was protected as its dimethyl ether and epoxidized to an acylated aza Brigl's anhydride. This was converted to (+/-)-2-acetyl-4-hydroxy-5,12-dimethoxy-1,2,3,4-tetrahydro-2- azanaphthacene-6,11-dione by dehydration to the 4-keto analogue followed by cyanoborohydride reduction either stepwise or in situ. The protecting groups were removed with boron trichloride and the resulting aglycone glycosidated with optically active N,O-bis(trifluoroacetyl)daunosamine bromide and silver trifluoromethanesulfonate. The resulting diastereoisomers were separated by column chromatography and their structures established by CD and NMR spectroscopy. Unexpectedly it was not possible to remove the N-trifluoroacetyl blocking group without aromatization to the azanaphthaquinone. Both (R)- and (S)-acetyl-4-O-[N-(trifluoroacetyl)daunosaminyl]-5,12-dihydroxy-2- azanaphthacene-6,11-dione were inactive ip in mice carrying the P388 tumor. Drugs were given at various concentrations on days 0, 5, and 9.

Animals↗
PubMed1986

Chiral DNA gyrase inhibitors. 1. Synthesis and antimicrobial activity of the enantiomers of 6-fluoro-7-(1-piperazinyl)-1-(2'-trans-phenyl-1'-cyclopropyl)-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid.

New quinolone antimicrobial agents (racemic, (1'S,2'R)- and (1'R,2'S)-6-fluoro-7-(1-piperazinyl)-1-(2'-trans-phenyl-1'-cyclopropyl)- 1, 4-dihydro-4-oxoquinoline-3-carboxylic acids) were synthesized, and their in vitro antimicrobial potencies and spectra were determined. As compared to their conceptual parents, these agents retained a considerable amount of the antimicrobial potency and spectra of ciprofloxacin and of 6-fluoro-1-phenyl-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxy lic acid against Gram-positives. Gram-negatives were considerably less sensitive. The (-)-(1'S,2'R) analogue was the more potent of the enantiomers, but the degree of chiral discrimination by most bacteria was only 4-fold. The 4-fold chiral discrimination was observed also using purified DNA gyrase obtained from Micrococcus luteus, whereas the two enantiomers were essentially equiactive against the enzyme derived from Escherichia coli. These results confirm that there is a substantial degree of bulk tolerance available at N-1 of quinolone antimicrobial agents and suggest that electronic factors controlled by substitution at that site are of considerable importance. On the other hand, chiral recognition brought about by attachment of optically active groups to the N-1 position in these derivatives is relatively small.

Anti-Bacterial Agents↗