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P Bey

Publications and source records attributed to P Bey.

At least 145 records · Page 8Linked to original sources
PubMed1984

MDL 72145, an enzyme-activated irreversible inhibitor with selectivity for monoamine oxidase type B.

MDL 72145, (E)-2-(3',4'-dimethoxyphenyl)-3-fluoroallylamine hydrochloride, was designed and synthesised as a potential enzyme-activated irreversible inhibitor of monoamine oxidase (MAO). In vitro, the compound displayed time-dependent pseudo-first-order irreversible inhibitory characteristics with high selectivity for the B form of rat brain mitochondrial MAO. At 10 degrees C the Ki and tau 50 values for the B enzyme were 40 microM and 1.7 min, respectively, while these same kinetic constants for the A enzyme were 131 microM and 14.5 min, respectively. Selective protection against inactivation of the two forms of MAO by MDL 72145 was obtained by preincubating the enzyme with suitable concentrations of the selective A and B substrates, 5-hydroxytryptamine and benzylamine.

Allylamine↗
PubMed1983

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

(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.

Animals↗
PubMed1982

alpha-Monofluoromethyl and alpha-difluoromethyl putrescine as ornithine decarboxylase inhibitors: in vitro and in vivo biochemical properties.

In vitro, 5-fluoropentane-1,4-diamine and 5,5-difluoropentane-1,4-diamine are potent enzyme-activated inhibitors of rat liver ornithine decarboxylase (EC 4.1.1.17). The two alpha-fluoromethyl derivatives of putrescine activate to different degrees S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50). The difluoromethyl derivative differs from the monofluoromethyl derivative in that it is not a substrate of diamine oxidase (EC 1.4.3.6), but is a better substrate of mitochondrial monoamine oxidase (EC 1.4.3.4) than the monofluoromethyl derivative. In vivo, a single i.p. injection of 200 mg/kg of 5-fluoropentane-1,4-diamine to rats causes a marked decrease of the ornithine decarboxylase activity in the ventral prostate and to a lesser extent in the thymus, whereas 5,5-difluoropentane-1,4-diamine causes only a slight decrease of this enzyme activity in the prostate and does not affect it in the thymus. Both compounds produce a decrease of 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19) activity in the brain. The differences observed between the biochemical properties of the two alpha-fluoromethyl derivatives of putrescine are discussed in relation to the pKa value of the alpha-amino group which decreases from 7.75 for 5-fluoropentane-1,4-diamine to 6.4 for 5,5-difluoropentane-1,4-diamine.

Animals↗
PubMed1982

DL-a-Monofluoromethylputrescine is a potent irreversible inhibitor of Escherichia coli ornithine decarboxylase.

DL-alpha-Monofluoromethylputrescine (compound R.M.I. 71864) is an enzyme-activated irreversible inhibitor of the biosynthetic enzyme ornithine decarboxylase from Escherichia coli. This compound, however, has much less effect in vitro on ornithine decarboxylase obtained from Pseudomonas aeruginosa. These findings are in contrast with those previously found with the substrate analogue DL-alpha-difluoromethylornithine (compound R.M.I. 71782). The K1 of the DL-alpha-monofluoromethylputrescine for the E. coli ornithine decarboxylase is 110 microM, and the half-life (t1/2) calculated for an infinite concentration of inhibitor is 2.1 min. When DL-alpha-monofluoromethylputrescine is used in combination with DL-alpha-difluoromethylarginine (R.M.I. 71897), an irreversible inhibitor of arginine decarboxylase, in vivo in E. coli, both decarboxylase activities are inhibited (greater than 95%) but putrescine levels are only decreased to about one-third of control values and spermidine levels are slightly increased.

Arginine↗
PubMed1981

DL-alpha-(Difluoromethyl)arginine: a potent enzyme-activated irreversible inhibitor of bacterial decarboxylases.

DL-alpha-(Difluoromethyl)arginine (RMI 71 897) is an irreversible inhibitor of both the biosynthetic and biodegradative arginine decarboxylases of Escherichia coli and of the biosynthetic arginine decarboxylases of Pseudomonas aeruginosa and Klebsiella pneumoniae. The Ki is close to 800 muM for the biosynthetic decarboxylase of E. coli and 140 muM for the biodegradative enzyme while the respective half-lives (t1/2) calculated for an infinite concentration of inhibitor are 1.0 and 2.1 min. The inhibitor also blocks the arginine decarboxylase activity of E. coli and Pseudomonas aeruginosa in vivo, indicating that the compound is transported into the cell. DL-alpha-Methylarginine (RMI 71 699) was found to be a competitive inhibitor of both arginine decarboxylases from E. coli. These results suggest that it may be possible to use an arginine decarboxylase inhibitor in conjunction with known inhibitors of ornithine decarboxylase to block all putrescine biosynthesis in prokaryotic cells and thus to study the effects of such inhibition in these organisms.

Arginine↗
PubMed1981

omega-Fluoromethyl analogues of omega-amino acids as irreversible inhibitors of 4-aminobutyrate:2-oxoglutarate aminotransferase.

omega-Monofluoromethyl and omega-difluoromethyl analogues of the known substrates of GABA-T, beta-alanine, gamma-aminobutyric acid, and 5-aminopentanoic acid, are time-dependent inhibitors of purified 4-aminobutyrate: 2-oxoglutarate aminotransferase (GABA-T). The inhibitory activity decreases with increasing chain length. In vitro, inhibitory activity decreases with increasing fluorine substitution of the methyl group. In vivo, beta-difluoromethyl-beta-alanine and 2,4-difluoro-3-aminobutyric acid are the most potent GABA-T inhibitors ever reported. Trifluoromethyl derivatives are devoid of GABA-T inhibitory activity in vitro or in vivo.

4-Aminobutyrate Transaminase↗
PubMed1981

[Epidermoïd carcinoma of uterine cervix with bone metastases in lower limbs (author's transl)].

Bone lesions are infrequent in the evolution of epidermoïd carcinoma of the uterine cervix. Direct bone invasion from the primary tumor, extension from lymph node metastases and distant metastases can be seen. The frequency of these lesions is about 3 to 4%. Hematogen bone metastases are very uncommon. They are often located in the lower limb. We report a case of a patient with a cervical carcinoma who developed isolated bone metastases in all the bones of a lower limb.

Bone Neoplasms↗
PubMed1981

[Carcinoma of a nasopharynx. Apropos of 42 cases treated between 1968 and 1977].

As reporting 42 cases of carcinoma of the nasopharynx, the main characteristics of these tumors which are different of the other carcinomas of the head and neck are exposed. In this series, there are 31 men and 11 women with ages between 13 and 75. The diagnosis was late (80% of palpable lymph nodes and 40% with bone invasion or nerve palsy at diagnosis). The radiocurability is good even for big tumors. The actuarial crude survival is 39% at 5 years (50% of local control at 2 years). 40% of the deaths are due to metastatic disease. It seems that in certain cases, a systematic chemotherapy could be useful.

Adolescent↗
PubMed1981

[Combined hyperthermia, radiotherapy and chemotherapy: preliminary clinical results (author's transl)].

Results of treating superficial cancerous nodules by hyperthermia, alone or combined with radiotherapy or chemotherapy, over a period of one year, are presented. Twenty-five patients with multiple cutaneous or subcutaneous metastatic tumors were treated by 1 to 3 MHz ultrasound hyperthermia or 434 MHz microwave hyperthermia. Good local tolerance was observed, even in regions previously treated with high doses of irradiation. Regression of the tumors was assessed by comparison with unheated nodules. Two out of 11 tumors treated by hyperthermia alone, 10 out of 17 tumors treated by conventional chemotherapy combined with hyperthermia showed significant regression.

Hot Temperature↗
PubMed1980

Further studies on the inhibition of monoamine synthesis by monofluoromethyldopa.

1 alpha-Monofluoromethyldopa (MFMD, RMI 71963), a potent and selective enzyme-activated irreversible inhibitor of aromatic L-amino acid decarboxylase produces a substantial and long-lasting decrease in the catecholamine content of mouse brain, heart and kidney. 2 Single doses of MFMD reduce the 5-hydroxytryptamine concentration of mouse brain without altering the tryptophan concentration. 3 In animals treated with MFMD, peripheral but not brain noradrenaline is restored within 1 h to control levels by an intraperitoneal injection of dopamine.

Animals↗