Microbiological Studies on the Mechanism of Action of Sparsomycin

Bannister, Edward R.; Hunt, D. E.; Pittillo, Robert F.

doi:10.1139/m66-085

Cited by 7 publications

(9 citation statements)

References 9 publications

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“…(7? )-2-(Difluoromethyl)dehydroornithine Hydrochloride (10). A mixture of 9a (1.2 g), acetic acid (10 mL), and concentrated hydrochloric acid (30 mL) was heated at reflux temperature for 42 h. After concentration in vacuo, the residue was taken up with water (10 mL).…”

Section: Methodsmentioning

confidence: 99%

“…These were transformed into 17 and 14 via a four-step sequence involving (a) phthaloyation of the amine function; (b) allylic bromination of the methyl group; (c) Gabriel reaction; and (d) hydrolytic cleavage of the protective groups. (E)-a-(Difluoromethyl)dehydroornithine (10) and -putrescine (7) were prepared from ethyl ferf-butyl 2-(difluoromethyl)-2-(2-propenyl)malonate and di-tert-butyl 2-(difluoromethyl)-2-(2-propenyl)malonate, respectively, via a sequence similar to that reported previously for the synthesis of the saturated analogues. Compounds 17,14,10, and 7 proved to be much more potent enzyme-activated irreversible inhibitors of ODC than the corresponding saturated analogues.…”

Section: Articlesmentioning

confidence: 99%

“…Chemistry. Our synthetic approach to (E)-a-(difluoromethyl)dehydroornithine (10) and -putrescine ( 7) is sequence relying on a Curtius rearrangement of appropriately substituted «-(difluoromethyl)malonic acid hemiester and carboxylic acid derivatives that we developed for the preparation of the corresponding saturated analogues of ornithine and putrescine.10 Thus, alkylation of the sodium salt of butenyl-substituted malonate (1) with chlorodifluoromethane provided the olefinic difluoromethyl malonate 2 in excellent yields. Elaboration of the allylamine chain of the target molecules was accomplished efficiently in two steps: allylic bromination of 2 with ZV-bromosuccinimide under light irradiation in benzene gave, after silica gel column chromatography, the rearranged bromides 3 as the major products, which upon treatment with potassium phthalimide in dimethylformamide were converted to the unsaturated phthalimides 4.…”

Section: Articlesmentioning

confidence: 99%

“…As expected from our previous work,10 when subjected to the standard Curtius rearrangement sequence, the hemiester 8 and the acid 5 led to the methyl carbamate derivatives 9 and 6, respectively. Hydrolytic cleavage of the amine and carboxylic acid protecting groups of 9 and 6 under drastic acidic conditions afforded (E)-a-(difluoromethyl)dehydroornithine (10) and -putrescine (7), which were isolated as the hydrochloride and dihydrochloride salts, respectively.…”

Section: Articlesmentioning

confidence: 99%

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.alpha.-(Fluoromethyl)dehydroornithine and .alpha.-(fluoromethyl)dehydroputrescine analogs as irreversible inhibitors of ornithine decarboxylase

Bey¹,

Gerhart²,

Dorsselaer³

et al. 1983

J. Med. Chem.

103

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(E)-Dehydro analogues of alpha-(fluoromethyl)putrescine and -ornithine derivatives were synthesized and evaluated in vitro as irreversible inhibitors of a preparation of ornithine decarboxylase (ODC, EC 4.1.1.17) obtained from rat liver. The key step in the synthesis of (E)-alpha-(fluoromethyl)dehydroornithine (17) and -putrescine (14) was the addition of propenylmagnesium bromide to fluoroacetonitrile. The resulting unstable conjugated imine salt was reduced regioselectively in situ with NaBH4 or was quenched with a solution of NaCN to give the corresponding unsaturated alpha-(fluoromethyl) amine and alpha-amino nitrile, respectively. These were transformed into 17 and 14 via a four-step sequence involving (a) phthaloyation of the amine function; (b) allylic bromination of the methyl group; (c) Gabriel reaction; and (d) hydrolytic cleavage of the protective groups. (E)-alpha-(Difluoromethyl)dehydroornithine (10) and -putrescine (7) were prepared from ethyl tert-butyl 2-(difluoromethyl)-2-(2-propenyl)malonate and di-tert-butyl 2-(difluoromethyl)-2-(2-propenyl)malonate, respectively, via a sequence similar to that reported previously for the synthesis of the saturated analogues. Compounds 17, 14, 10, and 7 proved to be much more potent enzyme-activated irreversible inhibitors of ODC than the corresponding saturated analogues. The increase in potency is particularly marked in the alpha-fluoromethyl series. The apparent dissociation constants (KI) and the times of half-inactivation of enzyme (tau 50) at infinite concentration of inhibitors are 2.7 microM and 2.6 min for 17 and 42 microM and 0.2 min for 14. The KI and tau 50 of the corresponding saturated analogues are 75 microM and 1.6 min for the ornithine derivative and 56 microM and 4.4 min for the putrescine derivative.

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Section: Methodsmentioning

confidence: 99%

Section: Articlesmentioning

confidence: 99%

Section: Articlesmentioning

confidence: 99%

Section: Articlesmentioning

confidence: 99%

See 2 more Smart Citations

.alpha.-(Fluoromethyl)dehydroornithine and .alpha.-(fluoromethyl)dehydroputrescine analogs as irreversible inhibitors of ornithine decarboxylase

Bey¹,

Gerhart²,

Dorsselaer³

et al. 1983

J. Med. Chem.

103

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“…Isolated in 1962 from Streptomyces sparsogenes , , sparsomycin was quickly identified as a universal translation inhibitor with activity against a variety of eukaryotic and prokaryotic cells. − The structure of the sparsomycin–ribosome complex was solved and demonstrated that it binds simultaneously with the P-site tRNA mimic (3′-CCA-Phe) (Figure ). It also demonstrated a π-stacking interaction with A2637 and prohibits the movement of A2637, a critical residue facilitating the movement of tRNAs between the A- and P-site.…”

Section: Ribosomal P-site Inhibitors: the Universal Antibioticsmentioning

confidence: 99%

Dissecting the Nucleoside Antibiotics as Universal Translation Inhibitors

2021

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Metrics & MoreArticle Recommendations CONSPECTUS: Without question, natural products have provided the lion share of leads, if not drugs themselves, for the treatment of bacterial infections. The bacterial arms race, fueled by selection and survival pressures has delivered a natural arsenal of small molecules targeting the most essential of life processes. Antibiotics that target these critical intracellular processes face the formidable defense of both penetrating a bacterial cell membrane and avoiding efflux to exert their effect. These challenges are especially effective in Gramnegative (Gram-(−)) bacteria, which have a double membrane structure and efficient efflux systems from the combination of outer-membrane porins and inner membrane proton pumps. In this landscape of offense and defense, our clinically used antibiotics have only successfully targeted three intracellular processes for therapeutic intervention in Gram-(−) bacteria: dihydrofolate biosynthesis, transcription, and translation. Not surprisingly, such critical survival machinery is a popular target for bacterial warfare, and eight of our 14 classes of commonly used antibiotics target translation with the bacterial ribosome remaining one the most vetted targets for antimicrobial therapy. On the plus side, its anionic character attracts cationic inhibitors, which are generally more capable of penetrating the bacterial cell wall, and clinical resistance rates are usually manageable as mutation of such a highly evolved machine is difficult. On the down side, this highly evolved machine renders it difficult to inhibit selectively, and the inhibition of prokaryotic translation versus both eukaryotic cellular and mitochondrial translation is critical for clinical development and minimization of undesired toxicities.A class of natural products known as the "nucleoside antibiotics" have historically been recognized as universal inhibitors of the ribosome and can inhibit translation in prokaryotes, eukaryotes, and archaea. While they have served an essential role in dissecting the biochemical underpinnings of the enzymatic functions of the ribosome, they have not proven therapeutically useful as they target the highly conserved rRNA in the P-site and are toxic to mammalian cells. In this Account, we describe our studies on the natural product amicetin, a nucleoside antibiotic that we have demonstrated to break the rule of being a universal translation inhibitor. While the cytosine of amicetin mimics C75 of the 3′-CCA tail of the P-site tRNA akin to other nucleoside antibiotics, we advance a hypothesis that amicetin's unique interaction with the ribosomal protein uL16 exploits an untapped mechanism for selectively targeting the bacterial ribosome. A complex molecule comprised of a nucleoside, carbohydrates and amino acids, amicetin is also chemically unstable. Our initial attempts to stabilize and simplify this scaffold are presented with the ultimate goal of rebuilding the compound with improved penetrance to bacterial cells. If successful, this scaffold ...

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