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PubMed1994

Synthesis and evaluation of 9-hydroxy-5-methyl-(and 5,6-dimethyl)-6H-pyrido[4,3-b]carbazole-1-N- [(dialkylamino)alkyl]carboxamides, a new promising series of antitumor olivacine derivatives.

Starting from 2-(2-aminoethyl)-6-methoxy-1-methylcarbazole, ethyl 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole-1-carboxylate was obtained through a three-step sequence. This compound and its 6-methyl derivative react with (dialkylamino)alkylamines to provide various 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole-1-(N-substituted carboxamides) whose boron tribromide demethylation afforded corresponding 9-hydroxy-1-(N-substituted carbamoyl)-olivacines. The same pathway but starting from 2-(2-aminoethyl)-6-methoxy-1,4-dimethylcarbazole led to ethyl 9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxylate which did not normally react with amines. It provided either the recovered starting material at 120 degrees C or 9-methoxyellipticine resulting from an unexpected decarboethylation in a steel vessel at 180 degrees C. Biological testing of the newly obtained 1-carbamoylolivacine derivatives showed that 9-hydroxylated compounds displayed high cytotoxicity for cultured L1210 and colon 38 cells (IC50 range 5-10 nM) and good antitumor activity in vivo in the P388 leukemia and colon 38 models when administered by the iv route. The most active compound in these series is 9-hydroxy-5,6-dimethyl-1-[N-[2-(dimethylamino)ethyl]carbamoyl]-6H- pyrido[4,3-b]carbazole which was selected for further evaluation on murine solid tumors and for toxicological studies.

Adenocarcinoma↗
PubMed1992

New triazine derivatives as potent modulators of multidrug resistance.

A series of 70 triazine derivatives have been synthesized and tested for their capacity to modulate multidrug resistance (MDR) in DC-3F/AD and KB-A1 tumor cells in vitro, in comparison with verapamil (VRP), a calcium channel antagonist currently used in therapy as an antihypertensive drug, which also shows MDR modulating activity. Among the 12 selected compounds, 16 (S9788) showed high MDR reversing properties in vitro (300- and 6-fold VRP at 5 microM in DC-3F/AD and KB-A1 cells, respectively) and induced a strong accumulation of adriamycin. The relationship between the increase of ADR accumulation and the fold reversal induced by these compounds and their lack of effects on the sensitive DC-3F cells suggest that they act mainly by inhibiting the P-glycoprotein (Pgp) catalyzed efflux of cytotoxic agents, as already described for a majority of MDR modulators. In vivo, in association with the antitumor drug vincristine (0.25 mg/kg), 16 (100 mg/kg) increased the T/C by 39% in mice bearing the resistant tumor cell line P388/VCR. According to these interesting properties, 16 was selected for a clinical development because it was more bioavailable than 34, even though it was less active.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Origin of chiral induction in radical reactions with the diastereoisomers (5R)- and (5S)-5-l-menthyloxyfuran-2[5H]-one.

Acetalization of 5-hydroxyfuran-2[5H]-one with l-menthol yields (5R)- (1) and (5S)-5-l-menthyloxyfuran-2[5H]-one (2) in equal amounts. The diastereomer 1 crystallizes preferentially. For the first time, the isolation of pure diastereoisomer 2 is reported. Different diastereoselectivities were observed in the radical tandem reaction of 1 and 2 with N,N-dimethylaniline. The privileged conformations in solution of the substrates and the products of the radical reaction were then determined, and X-ray crystal structure analyses were carried out on the reaction products. The different stereoselectivities in both cases are explained by different orientations of the menthyloxy substituent.

Journal Article↗
PubMed2006

Novel seco-dibenzopyrrocoline alkaloid from Cryptocarya oubatchensis.

[structure: see text] A novel seco-dibenzopyrrocoline alkaloid, named oubatchensine 6, and five phenanthroindolizidines (1-5) were isolated from Cryptocarya oubatchensis, and their structures were elucidated. Displacement centrifugal partition chromatography was used to purify compounds 1 and 6. Structure determination of the latter was carried out by mass spectrometry, NMR spectroscopy, quantum chemistry, and computer-assisted structure determination. Cytotoxic activity against KB cells was then investigated.

Alkaloids↗
PubMed1997

An extract from cultured human keratinocytes that contains the major autoantigens related to autoimmune bullous skin diseases.

Autoantibodies characteristic of autoimmune bullous skin diseases (AIBDs) can be detected by immunoblotting on epidermal, dermal, or bovine muzzle extracts. However, none of those substrates contain all the autoantigens involved in AIBDs, and the diagnosis requires the use of various substrates. Human keratinocytes were cultured under such conditions that they expressed the major autoantigens associated with AIBDs. Forty-two sera with antiepidermal antibodies were immunoblotted on the keratinocyte extract. Bands corresponding to desmoglein III, desmoglein I, BPAg2, BPAg1, and type VII collagen were found in 38 sera. Desmoplakins I and II were revealed by specific monoclonal antibodies. A review of the patients' charts showed a perfect correlation between the blots and the diagnoses of pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, cicatricial pemphigoid, and epidermolysis bullosa acquisita. Four sera revealing no band typical of AIBD were from patients with no autoimmune skin disease. Therefore, a single extract of keratinocytes can be used for the differential diagnosis of AIBDs.

Animals↗
PubMed2005

Assessment of antioxidative activity of lipid- and water-soluble vitamins in human whole blood. Comparative analysis between a biological test and chemical methods.

Assessment of the antioxidant activity of vitamins and other compounds is of interest in the understanding of their in vivo effects. In this study, we have investigated the activity of several lipid and water-soluble vitamins in human whole blood. Measurements were carried out using a biological test that enables the evaluation of both red blood cells and plasma resistance against free radical activity induced by 2,2'-azobis (2-amidinopropane)hydrochloride (AAPH). Antioxidant activity of vitamins has been determined by using the biological test versus chemical methods (chemiluminescence, DMPD radical). We have observed strong anti-oxidant potentials for vitamins B6 and B9 with biological tests, but not with chemical methods. At 10 microM, the vitamin B9 efficiency in inhibiting radical-induced red blood cell hemolysis was almost three times higher than vitamin C efficiency and two times higher than alpha-tocopherol efficiency. Antioxidant activity was not observed for vitamins B1 or B2, nor for retinol. The weak activity of beta-carotene still remains to be investigated particularly in relation to oxygen pressure. Our study demonstrated that the biological test is more useful than the chemical methods employed in this instance, for the evaluation of antioxidant capacity of lipophilic and putatively biologically active compounds.

Amidines↗
PubMed1991

Structures in colloidal physical chemistry.

The vast range of technological and industrial application of colloidal systems is largely a direct result of their diversity of structure on microscopic and mesoscopic scales. Recent progress in understanding these structures allows for greater control of the macroscopic properties, as well as providing new avenues of fundamental research in physics, chemistry and materials science.

Animals↗
PubMed1994

Directional motion of brownian particles induced by a periodic asymmetric potential.

Structures possessing spatial asymmetry should act as pumps in the presence of dissipation alone, without the need for macroscopic forces or temperature differences to drive vectorial motion. It has been shown theoretically that particles subjected to an asymmetric periodic potential can display net directional motion even if the space-averaged force is zero. Here we demonstrate such behaviour experimentally. We have studied the behaviour of colloidal particles suspended in solution and exposed to a sawtooth dielectric potential which is turned on and off periodically. The particles exhibit net motion with a velocity that depends on their size, suggesting applications in separation processes for objects in the size range 0.1-5 microns--a range that includes biological structures such as viruses, cells and chromosomes. We furthermore point out the analogy between our device and motor protein assemblies.

Colloids↗
PubMed2000

Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome.

We describe here eleven different mutations in SPINK5, encoding the serine protease inhibitor LEKTI, in 13 families with Netherton syndrome (NS, MIM256500). Most of these mutations predict premature termination codons. These results disclose a critical role of SPINK5 in epidermal barrier function and immunity, and suggest a new pathway for high serum IgE levels and atopic manifestations.

Abnormalities, Multiple↗
PubMed1985

Pentosane polysulfate: the effect on hemostasis of a continuous 3-day infusion.

Pentosane polysulfate (PP) is a sulfated polysaccharide known to exhibit anticoagulant properties that are in part independent of antithrombin III activity. These effects have only been studied in vitro or after single injections in healthy subjects. Our objective was to evaluate the modification of hemostasis induced by a 3-day continuous infusion of PP (4 mg/kg body weight/24 hr) in 10 subjects. No hemorrhagic complication was observed in any patient. Bleeding time was not modified by the infusion, despite a slight decrease in the platelet number. Among the other parameters measured, the automated partial thromboplastin time, prothrombin time, and anti-Xa activity were the most affected by PP. The kinetics of their modifications were quite uniform: clotting times and the anti-Xa effect increased gradually until reaching steady state 24 hours after the start of the infusion. A progressive return to the pretreatment level was then observed during the 6 hours after the end of the infusion. A significant decrease in the factor V concentration was found at day 4. Finally, in contrast with other reported results, no activation of fibrinolysis was induced by PP under the conditions we used, which suggests that discontinuous administration or the route of administration of the drug influences the fibrinolytic effect. In conclusion, we show the excellent tolerance of continuous infusion of PP, detail the modifications in biologic parameters of hemostasis during and after PP infusion, and demonstrate that PP decreases factor V activity.

Adult↗
PubMed1986

Reduction of beta-adrenergic receptors by tertatolol: an additional mechanism for beta-adrenergic blockade.

Tertatolol is a potent new beta-blocker with no intrinsic sympathomimetic activity or beta 1/beta 2-receptor subtype selectivity. When given at therapeutic doses (5 mg/day) to human subjects it induced a reduction in the beta-adrenergic receptor number measured by 3H-CGP 12177 specific binding, without any change in the affinity on intact lymphocytes. This reduction was seen 7 hours (54%), 24 hours (35%), and 48 hours (30%) after a single drug dose. A similar receptor reduction was observed 7 hours (42%), 24 hours (37%), and 48 hours (15%) after 14 doses of the drug. In parallel, the pharmacologic efficacy of the drug was evident from the reduction in supine and upright heart rates and after submaximal exercise; heart rate was reduced to the same extent after single or repeated drug doses. The reduction of receptor number correlated well with the reduction in heart rate in the supine (P less than 0.001) and upright (P less than 0.01) positions and after exercise (P less than 0.02). In in vitro competitive binding experiments tertatolol was found to be a competitive inhibitor of beta-adrenergic receptors. However, on intact human lymphocytes preincubated with this drug, tertatolol reduced the density of beta-adrenergic receptors. We conclude that tertatolol, besides competitively inhibiting beta-adrenergic receptors, induced a marked and lasting decrease in the beta-adrenergic receptor number. This effect may be important for its beta-blocking effects.

Adrenergic beta-Antagonists↗
PubMed2001

Impaired homocysteine metabolism and atherothrombotic disease.

Based on recent retrospective, prospective, and experimental studies, mild to moderate elevation of fasting or postmethionine-load plasma homocysteine is accepted as an independent risk factor for cardiovascular disease and thrombosis in both men and women. Hyperhomocysteinemia results from an inhibition of the remethylation pathway or from an inhibition or a saturation of the transsulfuration pathway of homocysteine metabolism. The involvement of a high dietary intake of methionine-rich animal proteins has not yet been investigated and cannot be ruled out. However, folate deficiency, either associated or not associated with the thermolabile mutation of the N(5,10)-methylenetetrahydrofolate reductase, and vitamin B(6) deficiency, perhaps associated with cystathionine beta-synthase defects or with methionine excess, are believed to be major determinants of the increased risk of cardiovascular disease related to hyperhomocysteinemia. Recent experimental studies have suggested that moderately elevated homocysteine levels are a causal risk factor for atherothrombotic disease because they affect both the vascular wall structure and the blood coagulation system. The oxidant stress that results from impaired homocysteine metabolism, which modifies the intracellular redox status, might play a central role in the molecular mechanisms underlying moderate hyperhomocysteinemia-mediated vascular disorders. Because folate supplementation can efficiently reduce plasma homocysteine levels, both in the fasting state and after methionine loading, results from further prospective cohort studies and from on-going interventional trials will determine whether homocysteine-lowering therapies can contribute to the prevention and reduction of cardiovascular risk. Additionally, these studies will provide unequivocal arguments for the independent and causal relationship between hyperhomocysteinemia and atherothrombotic disease.

Age Factors↗
PubMed1993

A missense mutation in the rod domain of keratin 14 associated with recessive epidermolysis bullosa simplex.

Epidermolysis bullosa simplex (EBS) is a group of epidermal blistering diseases almost invariably transmitted as a dominant trait, which has recently been shown to arise from mutations in keratins 14 and 5 (K14 and K5). We describe a family with recessive EBS in which the disease is tightly linked to the substitution of the highly conserved glutamic acid-144 to alanine in the first helical segment of the rod domain of keratin 14. In contrast, linkage with keratin 5 was excluded. The loss of an ionic interaction with keratin 5 is likely to affect K14-K5 heterodimer formation. Our data suggest that this mutation underlies EBS in our family, and that mutations in keratin genes may impair the mechanical integrity of basal keratinocytes in a recessive as well as dominant fashion.

Alanine↗
PubMed2002

Age-related changes in fatty acids in obese offspring of streptozotocin-induced diabetic rats.

OBJECTIVE: The long-term effects of fetal hyperinsulinemia, time course of changes in liver and very-low-density lipoprotein (VLDL) lipid levels and fatty acid compositions were investigated in obese offspring of streptozotocin-induced mildly diabetic rats. RESEARCH METHODS AND PROCEDURES: Mild hyperglycemia in pregnant rats was induced by intraperitoneal injection of streptozotocin on day 5 of gestation. Control pregnant rats were injected with citrate buffer. Liver and VLDL lipids and fatty acids were analyzed in offspring at different ages. RESULTS: At birth, obese pups had higher VLDL triglyceride levels, saturated fatty acids, and C20:4n-6. They also had lower C18:2n-6 proportions in VLDL triglycerides, phospholipids, and cholesteryl esters than controls pups. In 1-month-old male and female obese rats, VLDL and liver lipid amounts were similar to those in their respective controls; however, high levels of C18:2n-6 and C20:4n-6 were noted in liver and VLDL lipids. At the age of 2 months, liver and VLDL triglyceride levels were higher in obese females than in control females. Fatty acid abnormalities seen in obese rats included low C18:3n-3 and high C22:6n-3 proportions in liver triglycerides and phospholipids. At the age of 3 months, obese rats, both males and females, compared with control animals, had higher VLDL and hepatic lipids with reduced C20:4n-6 levels and polyunsaturated/saturated fatty acids ratios in hepatic and VLDL triglycerides and phospholipids. DISCUSSION: Fetal obesity, associated with alterations in VLDL lipid fatty acid composition, represents an important risk factor for adult obesity and diabetes.

Aging↗
PubMed2000

Linkage of Marie-Unna hypotrichosis locus to chromosome 8p21 and exclusion of 10 genes including the hairless gene by mutation analysis.

Marie-Unna hypotrichosis (MU) is a rare autosomal dominant congenital alopecia characterised by progressive hair loss starting in early childhood, often aggravated at puberty and leading to scarring alopecia of variable severity. We have studied three multigeneration families of Belgian, British and French descent. The human genome was screened with microsatellite markers spaced at 10-cM intervals and significant evidence for linkage to the disease was observed on chromosome 8p21, with a maximum two-point lod score of 8.26 for D8S1786 at a recombination fraction of 0. Recombinants narrowed the region of interest to a genetic interval of about 12 cM flanked by markers D8S280 and D8S1839. This interval contains the hairless gene which is mutated in autosomal recessive congenital atrichia. Sequencing of the entire coding region and intronic splice sites of the hairless gene in these three families and in two unrelated familial cases revealed several polymorphic changes but failed to identify causative mutations. Nine other genes located within this region and expressed in skin were also excluded by mutation analysis. Together with a recent linkage study performed in a Dutch and a British family by van Steensel et al these results provide evidence for the presence of a gene distinct from hairless in chromosomal region 8p21 playing an important role in hair follicle biology.

Alopecia↗
PubMed2005

Exclusion of the dymeclin and PAPSS2 genes in a novel form of spondyloepimetaphyseal dysplasia and mental retardation.

Spondyloepimetaphyseal dysplasias (SEMD) represent a heterogeneous group of conditions composed of at least 15 well-defined entities. The classification is based on clinical, radiological and molecular findings. Among them, several conditions also include a mental retardation (MR) syndrome, namely Wolcott-Rallison syndrome, Dyggve-Melchior-Clausen syndrome (DMC) and lysosomal storage disorders. Here, we report on a novel form of SEMD with MR in two Pakistani sisters born to first-cousin parents. SEMD, MR, microcephaly, ataxia, facial dysmorphism and hirsutism of back and legs were noted in the two children. Skeletal findings included flat vertebral bodies with irregular vertebral plates, irregular and flared metaphyses with vertical striations, small and irregular epiphyses, small carpal bones and narrow iliac wings without lacy pelvis iliac crest. Similarities with DMC prompted us to test and eventually exclude the DMC gene, dymeclin, by direct sequencing. Similarly, we excluded the PAPSS2 gene (3'-alpha phosphoadenosine 5'-phosphosulphate synthase 2) responsible for SEMD Pakistani type. The combination of features observed in the two sisters does not fit with any previously reported SEMD and represents therefore a novel form of autosomal recessive SEMD with MR.

Abnormalities, Multiple↗