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P Ducrot

Publications and source records attributed to P Ducrot.

12 recordsLinked to original sources
PubMed2001

CoMFA and CoMSIA 3D-quantitative structure-activity relationship model on benzodiazepine derivatives, inhibitors of phosphodiesterase IV.

Recently, we reported structurally novel PDE4 inhibitors based on 1,4-benzodiazepine derivatives. The main interest in developing bezodiazepine-based PDE4 inhibitors is in their lack of adverse effects of emesis with respect to rolipram-like compounds. A large effort has thus been made toward the structural optimization of this series. In the absence of structural information on the inhibitor binding mode into the PDE4 active site, 2D-QSAR (H-QSAR) and two 3D-QSAR (CoMFA and CoMSIA) methods were applied to improve our understanding of the molecular mechanism controlling the PDE4 affinity of the benzodiazepine derivatives. As expected, the CoMSIA 3D contour maps have provided more information on the benzodiazepine interaction mode with the PDE4 active site whereas CoMFA has built the best tool for activity prediction. The 2D pharmacophoric model derived from CoMSIA fields is consistent with the crystal structure of the PDE4 active site reported recently. The combination of the 2D and 3D-QSAR models was used not only to predict new compounds from the structural optimization process, but also to screen a large library of bezodiazepine derivatives.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2000

3D-QSAR CoMFA on cyclin-dependent kinase inhibitors.

Several series of cyclin-dependent kinase inhibitors previously prepared in our laboratory were compared using 3D-QSAR (CDK1) and docking (CDK2) techniques. Evaluation of our own library of 93 purine derivatives served to establish the model which was validated by evaluation of an external library of 71 compounds. The best predictions were obtained with the CoMFA standard model (q(2) = 0.68, r(2) = 0.90) and with the CoMSIA combined steric, electrostatic, and lipophilic fields (q(2) = 0.74, r(2) = 0.90). The CDK1 3D-QSAR model was then superimposed to the ATP/CDK2 binding site, giving direct contour maps of the different fields. Although too few compounds were evaluated on CDK5 to derive a 3D-QSAR model, some interesting SARs have been deduced. Comparison of the results obtained from both methods helped with understanding the specific activity of some compounds and designing new specific CDK inhibitors.

Adenosine Triphosphate↗
PubMed2000

Cyclin-dependent kinase inhibition by new C-2 alkynylated purine derivatives and molecular structure of a CDK2-inhibitor complex.

A new series of 2,6,9-trisubstituted purines, characterized by the presence of a common alkynyl substituent at C-2 and a range of different anilino/benzylamino groups at C-6, were synthesized. These compounds were evaluated for their capacity to inhibit cyclin-dependent kinase activity (CDK1-cyclin B) in vitro. Compounds 4e (N-6-p-Cl-benzylamino derivative) and 5e (N-6-m-Cl-anilino derivative) exhibited the strongest inhibitory activity with an IC(50) of 60 nM. The structure of compound 4b (N-6-p-methoxybenzylamino derivative) in complex with human CDK2 was determined by X-ray crystallography, revealing the molecular basis of inhibition by this molecule. Subsequent molecular modeling studies allowed us to rationalize the SAR observed for these compounds.

Adenine↗
PubMed2000

Diphenyl quinolines and isoquinolines: synthesis and primary biological evaluation.

The synthesis of a series of 35 substituted 3,4-diphenyl quinolines and isoquinolines is described. The majority of these molecules differ from all other triphenylethylene based antiestrogens by a different spatial location of the aminoalkyl side chain. The binding affinity of the most representative molecules (8, 9, 19, 20, 21, 23 and 25), including analogues 8 and 21 without the side chain, for the estrogen receptor alpha (ER) was determined. The ability of these molecules to induce the progesterone receptor was also studied. Antiproliferative activity was evaluated on MCF-7 human breast cancer cells, while intrinsic cytotoxic/cytostatic properties resulting from interaction with other targets than ER were assayed on L1210 murine leukemia cells. Introduction of an aminoalkylamino side chain at carbon 2 confers strong cytotoxic properties to diphenylquinolines 9 and 10 as well as pure antiestrogenic activities. However, cytotoxicity is so high with respect to antiestrogenicity that the latter was clearly observable only in one case (9b). The structure of compound 9b was determined by X-ray crystallography. Molecular modeling of its docking within the hormone-binding domain of the receptor was subsequently undertaken. According to our results, the design of molecules with the side chain bound to the ethylene part of the triphenyl ethylene skeleton might generate compounds of potential pharmacological interest.

Animals↗
PubMed1992

[Fatal poisoning caused by African viper's bite (Echis carinatus)].

The case is reported of a 44-year-old European who was bitten on the foot in Djibouti, probably by an African viper. Unusually, there wasn't any pain, nor any cardiovascular collapse nor any local swelling. An oedema of the lower limb started the day afterwards. Two days after the bite, the patient presented a generalized haemorrhagic syndrome, which led to his admission. There was a consumption of fibrinogen and prothrombin, without any decrease in the platelet count. Heparin was started (100 IU.kg-1.day-1), as well as fluid replacement (albumin, fresh frozen plasma, packed red cells). This allowed him to be transferred to France, where he arrived in anuria, with hyperpyrexia, and severe lower limb oedema and a haemorrhagic syndrome. There was a major extensive retroperitoneal haematoma spreading to the perineum. The four limbs were ischaemic. The patient's condition continued to worsen, developing hypoxic pulmonary oedema. He died on the seventh day after the bite, during a session of haemodialysis, from cardiovascular failure resistant to all the usual drugs. The principles of anti-venom therapy are recalled. Indeed, this should be started early enough and relies on large amounts of serum (greater than 50 ml).

Adult↗
PubMed1991

[Value of the nucleolar organizers (AgNOR) in brain gliomas].

The aim of the study was to evaluate the feasibility and possible contribution of silver stained nucleolar organizer regions (AgNORs) to prognostic considerations, in a series of 55 supratentorial gliomas: eight grade II astrocytomas, twelve grade III astrocytomas, thirty grade IV astrocytomas, two glioblastomas, one anaplastic oligodendroglioma, one oligodendroglioma and one ependymoma. Silver NORs (AgNORs) were demonstrated according to the method of Crocker et al. A difference between AgNOR sizes in peritumor and tumor tissue is noted. The mean NOR numbers in the tumor areas range from 0.871 to 2.677, without overlap between peritumor gliosis and glial tumors. A comparative analysis reveals significant correlations between the mean NOR number per nucleus and histological grading. This technique can play a practical role in the diagnosis and grading of tumors sampled by stereotactic biopsies: a count higher than 0.8 is highly suggestive of malignancy. In addition, the distribution of NORs may be important: intratumoral heterogeneity expresses various degrees of transcriptional activity between different glial tumors of the same grade. This technique provides information about the biological behaviour of glial tumors supplementary to that obtained from growth fraction analysis.

Evaluation Studies as Topic↗
PubMed1979

[Heatstroke among psychiatric patients under neuroleptic therapy. Apropos of 2 fatal cases].

Heat stroke is uncommon in temperate climates but may be favourised by drug treatment. A report of two cases of fatal hyperthermia occuring in patients treated with neuroleptic drugs and during a heat wave is followed by a discussion of the characteristics which may be used to differentiate heat stroke from the hyperthermia of malignant twenty cases. It indicated that high degree of severity of this type of heat stroke, in great part related to the high prevalence of massive inhalation. The action of neuroleptics is very probably central by an effect upon the thermostat and also by changes in behaviour. The role of associated anti-parkinsonian agents is discussed. A review of treatment emphasises its difficulties.

Adult↗
PubMedDate not supplied

[Stereomorphological relationship between colonic adenomas and peri-adenomatous mucosa in scanning electron microscopy. Histogenetic correlations].

Using scanning electron microscopy (SEM), then light microscopy, the authors have studied 25 colonic adenomas, 5 specimens of peri-adenomatous mucosa and 9 specimens of normal colonic mucosa. Comparison between SEM features and histological characteristics has shown that each of the three histological entities had an specific surface architecture. Comparative analysis of the different aspects observed at SEM has shown a close architectural relationship between the adenomas and the adjacent mucosa, and suggests the hypothesis that adenomatous polyps are formed by invagination of the surface epithelium which has a well-known capacity of proliferation.

Adenoma↗