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M Pons

Publications and source records attributed to M Pons.

At least 109 records · Page 6Linked to original sources
PubMed1991

Conformational analysis of bacitracin A, a naturally occurring lariat.

The proton nmr spectra of bacitracin A in H2O and DMSO-d6 have been assigned and the conformational behavior of the peptide in the two solvents has been compared. Although bacitracin A shows a conformational equilibrium between at least two conformations differing in the relative position of the cyclic and linear domains of the molecule, the spectra in water can be interpreted in terms of a preferred conformation in which the linear part is folded over the cyclic moiety and a turn is present around Ile(8)-DPhe(9).

Amino Acid Sequence↗
PubMed1991

Conformational analysis of two cyclic disulfide peptides.

Complete nmr and CD studies of two cyclic tetrapeptides with disulfide bonds, Ac-L-Pen-L-Pro-D-Val-L-Cys-NH2 (1) and Ac-L-Cys-L-Pro-D-Val-L-Cys-NH2 (2) bonds have been carried out in different solvents to investigate the formation and stabilization of beta-turn structures and to determine the stereochemistry of the disulfide linkage. Both peptides have three-dimensional structures with a type II beta-turn, as derived from quantitative nuclear Overhauser effect data. The combined use of CD and nmr indicates that the dihedral angle of the disulfide bridge is different in the two peptides, although the chirality is maintained.

Amino Acid Sequence↗
PubMed1991

A new ionizable chromophore of 1,4-bis(alkylamino)benzo[g]phthalazine which interacts with DNA by intercalation.

The tricyclic heteroaromatic nucleus of 1,4-bis(alkylamino)benzo[g]phthalazine can be protonated at physiological pH, depending on the nature of the side chains. The interaction of the 3-methoxypropyl derivative with calf thymus and closed, circular DNA has been studied with UV-vis spectroscopy and NMR. The effect of drug binding on the topology of closed, circular DNA was determined by topoisomerase-I catalyzed relaxation of the complex followed by gel electrophoresis. The results strongly support intercalative binding and suggest that this series of compounds are promising targets for anticancer activity evaluation.

DNA↗
PubMed1991

Cyclization of disulfide-containing peptides in solid-phase synthesis.

Disulfide-containing peptides may be obtained in good yields and purities when oxidations are carried out on peptide chains anchored to polymeric supports used for solid-phase synthesis. Such approaches take advantage of the pseudo-dilution phenomenon which favors intramolecular processes. A variety of procedures have been demonstrated using the related model peptides Ac-Cys-Pro-D Val-Cys-NH2 and Ac-Pen-Pro-D Val-Cys-NH2 (which both readily assume a type II beta-turn conformation that becomes stabilized by a 14-membered disulfide-containing intramolecular ring), and oxytocin (conformationally mobile 20-membered disulfide ring). Both Boc and Fmoc were used for N alpha-amino protection, the beta-thiols of cysteine or penicillamine were blocked by S-acetamidomethyl (Acm), S-9-fluorenylmethyl (Fm), or S-trityl (Trt), and compatible anchoring linkages included HF-labile 4-methylbenzhydrylamide (MBHA), TFA-labile tris (alkoxy)benzylamide (PAL), and photolabile o-nitrobenzylamide (Nonb). Assemblies of linear sequences proceeded smoothly, and polymer-supported oxidations were carried out in a variety of ways either directly or after deblocking to the resin-bound dithiol. Chains were released from the support without substantial damage to the disulfide bridges, and overall yields were as high as 60-90%.

Amino Acid Sequence↗
PubMed1991

[Retinoic acid has an antiestrogenic effect on different regulated estrogen genes in different cellular types].

In this paper, we confirmed that retinoic acid is an antiestrogenic compound with respect to different chimaeric estrogenic responses and with respect to different cellular types. This was shown by transient transfection of MCF-7 cells with plasmids driving the chloramphenicol acetyl-transferase gene via different estrogenic regulatory part (pS2) and the first promotor of the progesterone receptor gene (PR1); an identical conclusion was obtained in HeLa cells by cotransfecting a plasmid expressing the estrogen receptor. In addition, the inhibitory effect of retinoic acid was not observed for genes regulated by the progesterone receptor and the glucocorticoid receptor. As the antiestrogenic effect of retinoic acid was increased by cotransfecting acid receptor(s) RAR alpha, beta, gamma, we concluded that RAR(s) is(are) involved in the antiestrogenic effect of retinoic acid.

Estrogen Antagonists↗
PubMed1991

[Antiestrogenic effect of retinoic acid in MCF-7 cells].

We recently developed the cellular model MVLN-15 in which an estrogenic action can be detected by bioluminescence. Using this cellular model, we characterized the inhibitory effect of retinoic acid on the estrogen-dependent induction of luciferase transcription. We present evidence that i) the inhibitory effect of retinoic acid was not due to a simple competition between retinoic acid and estradiol for the estrogen receptor binding site, ii) retinoic acid does not significantly modify the parameters of the estradiol binding to the estrogen receptor, iii) retinoic acid does not act at a post-transcriptional level of the estrogenic action, iv) a DNA sequence restricted to an estrogen responsive element (ERE) was sufficient to observe the antiestrogenic effect of retinoic acid, and v) retinoic acid does not act via a cryptic AP-1 binding site associated with this ERE. We concluded that the antiestrogenic effect of retinoic acid is due to an inhibition of estrogen receptor activity, for example by altering the amount of estrogen receptor protein bound to the ERE or affecting the transcriptional efficiency of this complex.

Estrogen Antagonists↗
PubMed1991

[Cerebral venous angiomas. 12 personal cases and review of the literature].

Cerebral venous angiomas (CVAs) are made up of veins with abnormal structure: thick walls, lumens dilated of irregular calibre that converge radially towards a wide draining vein. The arteries are normal. The veins are separated by a normal nervous tissue. The malformation is thought to develop as a compensatory venous drainage consecutive to the occlusion, or lack of development, of one or several transcerebral veins during the formation of the mature venous system. Together with arteriovenous angiomas, capillary telangiectasias and cavernous angiomas, CVAs belong to the vascular angiomatous malformations, also called hamartomas. The present study is based on 12 cases collected between 1984 and 1989, all explored by CT and angiography, and by MRI in 2 cases. The diagnosis therefore was neuroradiological, except in 1 case where it was obtained by neuropathological examination. The malformation was supratentorial in 10 cases and cerebellar in 2 cases. Most CVAs were discovered in patients whose symptoms could hardly be attributed to these malformations and consequently were termed asymptomatic (6 cases). Two cases were found in subjects with generalized epileptic seizures without clear-cut relationship with the angioma; 4 cases were revealed by haemorrhages: subarachnoidal haemorrhage in 2 cases and supratentorial intraparenchymatous haematoma in 1 case. These 3 cases had a spontaneously favourable outcome after a follow-up of several years. One patient with a cerebellar hematoma died postoperatively of edematous infarction of the cerebellum. One of these patients had two symmetrical CVAs, one in each cerebral hemisphere (multiple venous angiomas), and in another patient the CVA was probably associated with a cavernous angioma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Multiple mechanisms of protein kinase C inhibition by triphenylacrylonitrile antiestrogens.

The activation of type I (gamma), II (beta) and III (alpha) protein kinase C (PKC) subspecies by phosphatidylserine (PS) and diacylglycerol (DAG) is inhibited by micromolar concentrations of triphenylacrylonitrile (TPE) antiestrogens. TPE A (with p-hydroxy and p-diethylaminoethoxy groups on the 3- and 3'-phenyl rings, respectively) interacts with PS-vesicles as well as with the regulatory domain of PKC, probably at a site different from the Ca2+ and DAG binding sites. The interaction of TPE A with the regulatory domain of enzyme is very slow. Apparently, TPE A does not interact with the catalytic domain of PKC. In contrast, another TPE derivative, TPE B (with a p-hydroxy group on each of the three phenyl rings) inhibits the enzyme activity in a competitive manner with respect to ATP, suggesting that this TPE interacts with the catalytically active site of the enzyme. It seems likely that various TPE antiestrogen derivatives may exert their inhibitory action on PKC by multiple different mechanisms.

Acrylonitrile↗
PubMed1990

Hydroxylated triphenylacrylonitriles adopt a unique orientation within the binding site of the estrogen receptor.

The relative binding affinities of a series of twelve para-hydroxylated triphenylethylenes (TPEs) for the estradiol receptor (ER) of calf uterus cytosol were measured by a competition method. The results obtained under equilibrium conditions support the hypothesis of the additivity of the energies corresponding to each of the hydrogen-bond type interactions of di- or tri-hydroxylated TPEs with the estradiol binding site of ER and strongly suggest that, whichever ring is hydroxylated, the orientation of the TPE in the steroid binding site is always the same. A hydroxyl group in a given position always interacts with the same location within the site. Mono-hydroxylation of the highly hydrophobic non-substituted TPE skeleton led to a large increase in relative binding affinity for ER which could be explained by a dual mechanism whereby the interaction specific to the hydroxyl is accompanied by a temperature- or time-dependent binding process that is not related to the hydroxylation position.

Animals↗
PubMed1990

Dual action of hydroxylated diphenylethylene estrogens on protein kinase C1.

Protein kinase C (PKC) I (gamma), II (beta) and III (alpha) subspecies are all activated by 1,1-di-(p-hydroxyphenyl)ethylene derivatives (DPE) at micromolar concentrations. This PKC activation depends on the presence of both Ca2+ and phosphatidylserine (PS) but does not require diacylglycerol (DG). DPEs enhance PKC activity at low PS concentrations, but not at saturating PS concentrations. Like DG, DPEs increase the apparent affinity of PKC for PS as well as for Ca2+, but lead to a decrease in the catalytic activity (Vmax). In the presence of saturating DG concentrations, DPEs exhibit an inhibitory action. The derivatives also inhibit the activity of the proteolytic fragment of PKC, protein kinase M. It is concluded that DPEs are mixed-type inhibitors, probably interacting with the catalytic domain of the enzyme.

Animals↗
PubMed1990

Application of acetamidomethyl and 9-fluorenylmethyl groups for efficient side protection of penicillamine in solid-phase peptide synthesis.

Synthesis of S-acetamidomethyl and S-fluorenylmethyl derivatives of penicillamine is described. Both groups are completely stable to all the usual reagents in solid-phase peptide synthesis, including the HF cleavage step, and show an excellent degree of orthogonality to each other. Treatment of the protected peptides Ac-L-Pen(X)-L-Pro-D-Val-L-Cys(X)-NH2 with thallium (III) trifluoroacetate or iodine for X = Acm or piperidine/DMF (1:1) for X = Fm induced with good yield the formation of the intramolecular disulfide bridge. This cyclic peptide appears to assume a type II beta-turn conformation in d6-DMSO as evidenced by 1H-NMR spectra.

Amino Acid Sequence↗
PubMed1990

A new cellular model of response to estrogens: a bioluminescent test to characterize (anti) estrogen molecules.

With the aim of quickly and easily characterizing new estrogen or anti-estrogen molecules, we developed a cellular model in which estrogenic action can be detected by bioluminescence. This model is based on MCF-7 cells stably transfected with a receptor gene which allows expression of the firefly luciferase enzyme under control of the estrogen regulatory element of the Xenopus vitellogenin A2 gene. A stably transfected cell line (cultured for more than eight months without loss of the chimeric estrogenic response) was established by cotransfection of a neomycin resistance gene and cloning under selective pressure. Subcloning luminescent clones was accomplished by using a single-photon detecting camera. This cellular model allowed the study of an estrogenic activity either in whole-cell or in cell-free experiments by detection of the induced luciferase. Estradiol induced the luciferase activity in a dose-dependent manner at subnanomolar concentrations. The induced luciferase activity reached a maximum level as early as 24 hours after the cells were incubated with estradiol. The antiestrogen 4-hydroxy-tamoxifen inhibited the luciferase activity induced by estradiol. The cross-reactivity of ligands, such as dexamethasone, progesterone, testosterone, aldosterone, calcitriol, oxysterol and retinoic acid, were also studied, showing an estradiol specificity for a 24-hour incubation time.

Animals↗
PubMed1989

Effect of triphenylacrylonitrile derivatives on estradiol-receptor binding and on human breast cancer cell growth.

In a study of a series of 26 triphenylacrylonitrile derivatives (TPEs), we investigated the influence of several possibly interrelated factors on the proliferation of human breast cancer cell lines. (1) Chemical substituents: the test compounds were for the most part para-hydroxylated with increasingly bulky hydrophobic and/or basic side chains [isopropyloxy or (diethylamino)ethoxy] or standard reference compounds. (2) Relative binding affinities (RBAs): they competed diversely for [3H]estradiol (E2) binding to calf uterus cytosol and little, if at all, for binding to the [3H]tamoxifen-labeled antiestrogen binding site (AEBS) in lower speed supernatant. A multiparametric comparison of RBAs recorded for calf, rat, and mouse uterus cytosol estrogen receptor (ER) revealed a possible influence of species-specific receptor conformation and/or environment on binding. (3) Estrogen/antiestrogen potency: their stimulation and inhibition of the proliferation of the ER-positive human breast cancer cell line (MCF7) was measured. Compounds with only hydroxy substituents stimulated proliferation more markedly than methylated derivatives and had a maximum effect at 10(-11)-10(-6) M. Stimulation was related to the RBA for ER. Compounds with isopropyloxy or (diethylamino)ethoxy side chains only weakly stimulated MCF7 cell growth and more powerfully antagonized E2-promoted growth. The extent of inhibition depended upon the bulk of the side chain and could be reversed by 10(-7) M E2. Within the same concentration ranges, the test compounds were without effect on the BT20 ER-negative cell line. (4) Cytostatic and/or cytolytic activity: most compounds could arrest the proliferation of both MCF7 and BT20 cells at concentrations above 3 x 10(-6) M. This activity was thus independent of ER. Nevertheless, those compounds with a charged hydrophobic side chain, which were the most powerful antagonists of E2-promoted cell growth, were also the most cytotoxic. The overall results for all molecules on all parameters were submitted to a multivariate analysis (correspondence analysis) which revealed the progressive influence of increasing substitution by hydroxy and more bulky groups on the generation of antagonist activity and cytotoxicity.

Animals↗
PubMed1988

A model of antiglucocorticoid action for designing a potent glucocorticoid antagonist.

We have previously shown that the biological efficacy of an antiglucocorticoid is directly related to its affinity for the glucocorticoid receptor in whole cells at 37 degrees C. We have also shown that RU 486-receptor complexes differ from other antiglucocorticoid-receptor complexes in so far as their affinity is as high at 37 degrees C in whole cells as at 0 degree C in a cell-free system, whereas a decrease by a factor of 5-10 is observed with the other antagonists. The aim of the present paper was to evaluate the contributions of temperature and cellular integrity (or the biological events linked to temperature and cellular integrity) to the affinity of a steroid for its receptor for the purpose of determining the parameters favorable to high affinity, which is the prerequisite of a potent antagonist. We provide evidence showing that: (1) an increase in temperature has an unfavorable effect on the affinity of a glucocorticoid for its receptor (4-6-fold decrease between 0 and 37 degrees C), (2) RU 486, like an agonist, forms a complex with the cytosolic glucocorticoid receptor, which satisfies the criteria for an "activated" complex under "in vitro activating treatment", (3) these biological post-binding events (either agonistic or otherwise nature), which change the nature of the complexes, contribute to compensating for the negative effect of rising temperatures on their apparent dissociation constant. We conclude that potent antiglucocorticoids must have a chemical structure allowing them to induce biological post-binding events, such as receptor activation, but in an abortive form which thus effectively "traps" the receptor in a non-functional state.

Animals↗
PubMed1988

Analogies and differences in the modulation of progesterone receptor induction and cell proliferation by estrogens and antiestrogens in MCF-7 human breast cancer cells: study with 24 triphenylacrylonitrile derivatives.

Structure-activity relationships in a homogeneous series of 24 triphenylacrylonitrile derivatives were examined with respect to the stimulation of progesterone receptor induction and cell proliferation in MCF-7 cells. In general, triphenylacrylonitrile derivatives were found to be full or partial agonists for both responses; the partial agonists were also able to antagonize the stimulatory action of estradiol. The agonistic activities of these molecules decreased as the size of the lateral side chain increased, but the side-chains correlated with partial agonism of progesterone receptor induction were bulkier than those correlated with partial agonism of cell proliferation. Agonistic and antagonistic effects on both responses were correlated with affinity for the estrogen receptor. Half maximal effects on the two responses occurred at different concentrations (4-fold) of the compounds. It can be concluded that in MCF-7 cells, triphenylacrylonitrile modulation of progesterone receptor induction and cell proliferation are mediated by the estrogen receptor; the two effects, which occur at different concentrations and with slightly different substituents of the compounds, are differentially modulated.

Breast Neoplasms↗
PubMed1988

Description and analysis of differential sensitivity to glucocorticoids in Fao cells.

This study shows that the derived hepatoma cell line Fao displays different sensitivities for glucocorticoid induction of tyrosine aminotransferase (TAT), alanine aminotransferase (AAT) and gamma-glutamyltransferase (GGT). This was seen in the different behaviors of nine steroids with respect to these three effects: (1) in the presence of full agonists (dexamethasone or deacylcortivazol), half-maximal induction of GGT occurred at approx 5- to 6-fold higher agonist concentrations than those required for half-maximal induction of AAT and TAT; (2) in the presence of full antagonists (RU 486, R5020, or progesterone) the GGT response induced by an equal agonist concentration was inhibited at concentrations approx 4- to 5-fold lower than those required for an equivalent inhibition of TAT response; (3) in the presence of cortexolone, deoxycorticosterone, 11 beta-hydroxyprogesterone and dexamethasone-3'-oxetanone, there was a partial agonistic effect (30-50%) on TAT and AAT responses, whereas there was a mainly antagonistic effect (very weak agonistic effect: 0-10%) on GGT response; (4) regardless of the steroid or its full or partial agonist activity, a given TAT induction level (50%, for example) always corresponded to the same AAT and GGT induction levels (50 and 10% respectively). We provide evidence showing that the three above-mentioned biological responses are mediated via the same type of glucocorticoid receptor binding site. Consequently, this differential behavior probably originates from a phenomenon occurring after the common steps (activation, translocation) that follow the formation of the steroid-receptor complex. This leads us to propose a model in which this phenomenon is assumed to originate from a difference in the affinities of the activated receptor for the nuclear acceptor sites of the TAT and GGT genes.

Alanine Transaminase↗