Generalized perforating granuloma annulare.
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Arm↗
Biomedical subjects
A Afonso
Publications and source records attributed to A Afonso.
Structure elucidation of Sch 20562, a glucosidic cyclic dehydropeptide lactone--the major component of W-10 antifungal antibiotic.
A novel bacterium designated as Aeromonas sp. W-10 produces the antibiotic W-10 complex which comprises of two major and several minor components. The two major components from this complex, Sch 20562 (1) and Sch 20561 (1a), are of biological interest in view of their potent antifungal activity. The chemical degradation studies utilized for the assignment of structure 1 for Sch 20562 are described here. Some of the noteworthy diversity of structural features in this glucosidic cyclic dehydrononapeptide lactone 1 are: an N-terminal (D)-beta-hydroxymyristyl unit, three D-amino acid units, two (E)-alpha-aminocrotonyl units, and an O-alpha-D-glucosyl-N-methyl-L-allo-threonine unit. The structure determination of 1 utilized the selective cleavage of the dehydropeptide units by ozonolysis to form fragments that were sequenced by mass spectrometry. The stereochemistry of the amino acid units were assigned by isolation of the free amino acids from the hydrolysates of the fragments. The stereochemistry of the alpha-aminocrotonyl units and the glucosidic linkage were assigned by nmr spectroscopy and molecular rotation data.
Aeromonas↗
Structure elucidation of Sch 20561, a cyclic dehydropeptide lactone--a major component of W-10 antifungal antibiotic.
Antibiotic W-10 is a fermentation complex produced by the bacterium Aeromonas sp. W-10. The cyclic dehydropeptide lactones Sch 20562 (1) and Sch 20561 (2) are the major components of this fermentation complex and are of biological interest in view of their unique structural features and potent antifungal activity. The chemical degradation studies that were utilized in the assignment of structure 2 for Sch 20561 are described here. The structure determination of 2 made use of the ozonolytic cleavage of the dehydropeptide units to form fragments that were sequenced by mass spectrometry. The cyclic dehydropeptide lactone Sch 20561 (2) was found to be the aglycone of Sch 20562 (1) and these two natural products were correlated by a chemical transformation involving the deglucosidation of 1 to form 2.
Aeromonas↗
Selective chemical modifications of polymyxin B.
Polymyxin B (1) monohydrochloride was converted to the tetra-BOC derivatives 1b and 1c by reaction with di-tert-butyl dicarbonate. The structures of these protected intermediates were established utilizing a degradative sequence that afforded 3 and 5. A method for the deprotection 2,4-dinitrophenylamines to the free amine, utilizing a strongly basic ion-exchange resin, was developed for use in the degradative sequence. The tetra-BOC derivatives 1b and 1c were used to prepare several Polymyxin B derivatives 6-27 at the DAB1 and DAB9-gamma-amine. The antibacterial activity of these selectively functionalized derivatives is reported here.
Anti-Bacterial Agents↗
(+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1,2-b]- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamid e (SCH-66336): a very potent farnesyl protein transferase inhibitor as a novel antitumor agent.
We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories have also established that incorporation of either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in nude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-position of the 3-bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compounds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inhibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human clinical trials.
Alkyl and Aryl Transferases↗
Synthesis and antibacterial activity of 2-alkoxy penems.
The phosphite mediated Oxalimide cyclization reaction was extended to 4-dithiocarbonates of N-oxalyl-2-azetidinones to synthesize 2-alkoxy penems 3. In general, the in vitro antibacterial potency of compounds 3 was weak compared to the highly potent 2-alkylthiopenems 2.
Anti-Bacterial Agents↗
Inhibitors of farnesyl protein transferase. Synthesis and biological activity of amide and cyanoguanidine derivatives containing a 5,11-dihydro[1]benzthiepin, benzoxepin, and benzazepin [4,3-b]pyridine ring system.
Bioisosteric replacement of the C-6 carbon atom in piperidine I and piperazine II with S, O, and N heteroatoms is described. Amide and cyanoguanidine derivatives of these compounds were evaluated in vitro and found to be good inhibitors of farnesyl-protein transferase. An improved method of preparing the 5,11-dihydro-[1]-benzthiepin nucleus 6 was accomplished in high yield and with excellent regioselectivity using an AlCl3 melt protocol.
Alkyl and Aryl Transferases↗
Neutrophil and macrophage responses to inflammation in the peritoneal cavity of rainbow trout Oncorhynchus mykiss. A light and electron microscopic cytochemical study.
The neutrophil and macrophage responses that accompany inflammation were studied in the peritoneal cavity of rainbow trout Oncorhynchus mykiss using light and electron microscopic cytochemistry. Neutrophils of inflammatory peritoneal exudates were alpha-naphthyl butyrate esterase-negative, peroxidase-positive and rich in cytoplasmic glycogen granules. Macrophages were poor in glycogen, esterase-positive and usually peroxidase-negative. Some peroxidase-positive macrophages were due to the transfer to macrophages of neutrophilic peroxidase. The ultrastructural double labelling for glycogen-peroxidase or esterase/peroxidase was most useful for precisely characterising neutrophils and macrophages in the inflamed peritoneal cavities and for correctly labelling peroxidase-positive macrophages. Intraperitoneal injection of casein, Incomplete Freund's Adjuvant (IFA) and live or formol-killed Yersinia ruckeri resulted in a rapid influx of neutrophils, peaking at 24 to 48 h post-injection and reaching values, in the case of live bacteria, 500 x those in the resting, unstimulated peritoneal cavity. Peritoneal macrophages also increased, but the response was slower (peak at 5 d) and with more modest increases in number (7.5 x). Neutrophil and mononuclear cells returned to normal values after 15 d in the case of casein and bacteria, but continued above base values 30 d after the injection of IFA. Conversely, after the injection of phosphate buffered saline, India ink or with sham-injections, very moderate neutrophil and and macrophage responses subsided in a few hours. Phagocytosis of bacteria was studied by light microscopy of preparations stained for peroxidase by a new method which allows for the simultaneous observation of intracellular bacteria and peroxidase staining. When Y. ruckeri was injected into resting peritoneal cavities, bacteria were ingested by the resident macrophages. When the bacteria were injected into cavities with high numbers of neutrophils (due to the previous injection of casein), more neutrophils than macrophages contained bacteria. Results show that the macrophages are the resident phagocytes of the peritoneal cavity of trout, while neutrophils are present in that body cavity in significant numbers only in situations of inflammation and only as long as the inflammation persists.
Animals↗
Novel H3 receptor antagonists. Sulfonamide homologs of histamine.
Sulfonamides derived from 4(5)-(omega-aminoalkyl)-1H-imidazoles containing chain lengths of three- to five-carbons were synthesized. Good to moderate H3 receptor binding affinities were observed for several butyl and pentyl homologs, whereas binding affinities were considerably weaker in the propyl series. Separation of the imidazole ring and the sulfonamide unit by a four- or five-carbon tether afforded potent H3 receptor antagonists.
Animals↗
Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4 -hydroxyphenyl)-2-azetidinone (SCH 58235): a designed, potent, orally active inhibitor of cholesterol absorption.
(3R)-(3-Phenylpropyl)-1,(4S)-bis(4-methoxyphenyl)-2-azetidinone (2, SCH 48461), a novel inhibitor of intestinal cholesterol absorption, has recently been described by Burnett et al. and has been demonstrated to lower total plasma cholesterol in man. The potential sites of metabolism of 2 were considered, and the most probable metabolites were prepared. The oral cholesterol-lowering efficacy of the putative metabolites was evaluated in a 7-day cholesterol-fed hamster model for the reduction of serum total cholesterol and liver cholesteryl esters versus control. On the basis of our analysis of the putative metabolite structure-activity relationship (SAR), SCH 58235 (1, 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)- (4-hydroxyphenyl)-2-azetidinone) was designed to exploit activity enhancing oxidation and to block sites of potential detrimental metabolic oxidation. Additionally, a series of congeners of 2 were prepared incorporating strategically placed hydroxyl groups and fluorine atoms to further probe the SAR of 2-azetidinone cholesterol absorption inhibitors. Through the SAR analysis of a series of putative metabolites of 2, compound 1 was targeted and found to exhibit remarkable efficacy with an ED50 of 0.04 mg/kg/day for the reduction of liver cholesteryl esters in a 7-day cholesterol-fed hamster model.
Animals↗
Transient hyperandrogenemia and its relation to ovulation.
OBJECTIVE: To study serum androgen levels in relation to ovulation. DESIGN: Prospective, controlled clinical study. SETTING: Outpatient endocrine department of a public central hospital. PATIENT(S): Forty-eight consecutive young, nonobese, hirsute women. INTERVENTION(S): Endocrine evaluation between days 2 and 5 and between days 22 and 25 of a spontaneous menstrual cycle. MAIN OUTCOME MEASURE(S): Levels of FSH, LH, E2, P, androstenedione (A), total testosterone (T), DHEAS, and 17alpha-hydroxyprogesterone (17-OHP). RESULT(S): Hyperandrogenemia occurred equally in a persistent (56%) or a transient form (44%). Transient hyperandrogenemia was more common in the early follicular phase in ovulatory cycles and in the second phase in delayed or anovulatory cycles (63% and 37% versus 10% and 90%, respectively). In delayed or anovulatory cycles, A, total T, and DHEAS increased significantly during the delayed follicular phase. CONCLUSION(S): In delayed or anovulatory cycles, transient hyperandrogenemia occurs late in the follicular phase because of previous ineffective steroidogenesis. In contrast, in ovulatory cycles, transient hyperandrogenemia occurs mainly in the early follicular phase. After ovulation, effective aromatization attenuates the condition. During evaluation and medical treatment of hirsutism, physicians should consider the common occurrence of transient hyperandrogenemia and its relation to ovulation.
Adult↗
Synthesis of isomeric 3-piperidinyl and 3-pyrrolidinyl benzo[5,6]cyclohepta[1,2-b]pyridines: sulfonamido derivatives as inhibitors of Ras prenylation.
Blocking farnesylation of oncogenic Ras proteins is a mechanism based therapeutic approach that is of current interest for the development of antitumor agents to treat ras associated tumors. As part of a SAR study on the lead farnesyl protein transferase (FPT) inhibitor I, we report here the synthesis of novel geometric isomers II and III and the FPT inhibition activity of their N-acyl and N-sulfonamido derivatives 15-65. The N-acyl derivatives are markedly less active than the lead inhibitor I thereby demonstrating that the spatial location of the N-acyl group in I is critical for binding of the compound to FPT. In contrast to I, the N-sulfonamido-II series is a novel lead of non-sulfhydryl, nonpeptidic compounds that are dual FPT/GGPT inhibitors. In light of recent reports on the alternative prenylation of N- and K-Ras, dual FPT/GGPT inhibitors may be required to control cell proliferation in tumors containing activated Ras.
Alkyl and Aryl Transferases↗
Dyslipidaemia in female overweight and obese patients. Relation to anthropometric and endocrine factors.
OBJECTIVE: To characterize serum lipid abnormalities in overweight and obese female patients and to quantify the relative importance of associated factors. METHODS: Cross sectional study at the first visit to the out-patient department. 237 consecutive overweight and obese female patients (age 31 +/- 14 y, body mass index (BMI) 34.2 +/- 6.0 kg/m2) were studied. Evaluation included a questionnaire-based assessment of dietary and physical activity habits, determination of anthropometric indexes (BMI, abdominal/thigh ratio (A/T) and conicity index (CI)) and endocrine evaluation. Statistical analysis by factorial ANOVA and multiple regression. RESULTS: Dyslipidaemia was present in 46% of the patients, with hypercholesterolaemia (35%) being more frequent than hypertriglyceridaemia (10%). Age but not dietary habits or physical activity patterns was significantly related to serum lipid concentrations, independently accounting for 6-10% of their variability. Pharmacological drug use resulted in increased serum triglyceride concentrations, explaining less than 5% of their variability. Serum cholesterol concentrations were not significantly related either to anthropometric or to endocrine indexes. For serum triglyceride concentrations, anthropometric indexes accounted for 6% of their variability and endocrine indexes-postprandial insulin, serum cortisol, testosterone and androstenedione together accounted for 32%. CONCLUSION: In mild to moderate female obesity of the peripheral type, dyslipidaemia is common. However the most common abnormality, hypercholesterolaemia is not significantly related to anthropometric or endocrine indexes, while these together account for more than one third of variability in serum triglyceride concentrations.
Adolescent↗
SCH 43478 and analogs: in vitro activity and in vivo efficacy of novel agents for herpesvirus type 2.
SCH 43478 and analogs are a class of non-nucleoside antiviral agents that have potent and selective activity against herpes simplex virus type 2 (HSV-2). The IC50 for these compounds in plaque reduction analysis using Vero cells ranges from 0.8 to 2.0 microg/ml. All compounds have a LC50 > 100 microg/ml in cytotoxicity analysis. Mechanism of action studies suggest that these molecules have an effect on the transactivation of viral immediate early (alpha) gene expression. Time of addition studies indicate that antiviral activity of these analogs is limited to the initial 2-3 h after infection and is not due to inhibition of viral adsorption or penetration. Analysis of HSV protein expression demonstrates that SCH 49286 inhibits the accumulation of viral immediate early (alpha) gene products. SCH 43478 demonstrates statistically significant efficacy (P < 0.05) in the guinea pig genital model of HSV infection. Following subcutaneous administration in a therapeutic treatment regimen, SCH 43478 (90 mg/kg/day) is efficacious in reducing the number and severity of lesions and the neurological complications of acute HSV infection. Thus, SCH 43478 and analogs are anti-herpesvirus agents with a unique mechanism of action.
Adsorption↗
Guided bone regeneration using osteopatite granules and polytetrafluoroethylene membranes.
Granules of a modified hydroxyapatite, Osteopatite, were implanted in the right posterior tibiae of adult rabbits. We studied the extent of bone regeneration in bone holes. In the right tibiae, that were filled with granules of this biomaterial covered with a polytetrafluoro-ethylene (PTFE) membrane using, as a control, uncovered granules. In the left tibia, an empty hole was covered with PTFE membrane and a second hole was left empty to be used as a control. A histomorphometric study was carried out using light microscopy, four and eight weeks after the surgery. The covered granules presented a higher percentage of bone contact than the uncovered ones, and it was also possible to observe a better bone tissue organization, mainly produced by the immobilization action of the PTFE membrane. Empty bone defects covered with PTFE membranes, two months after implantation, presented large areas of Haversian bone and direct bone contact to the PTFE membrane.
Journal Article↗
Pityriasis rotunda.
Pityriasis rotunda is an uncommon cutaneous disorder consisting of asymptomatic, strikingly circular, scaly lesions on the trunk and extremities, with the histologic appearance of ichthyosis vulgaris. Previous cases have been described in Japanese, South African, and West Indian persons, usually in association with an underlying serious systemic disease. A case of pityriasis rotunda in a 32-year-old black man in whom no diagnosable disorder could be demonstrated is presented.
Adult↗
SCH 51344 inhibits ras transformation by a novel mechanism.
A pyrazolo-quinoline compound, 6-methoxy-4-[2-[(2-hydroxyethoxyl)-ethyl]amino]-3-methyl-1M-pyrazo lo [3,4-b]quinoline (SCH 51344), was identified based on its ability to derepress human smooth muscle alpha-actin promoter activity in ras-transformed cells. In this study, we show that SCH 51344 reverts several key aspects of ras transformation, such as morphological changes, actin filament organization, and anchorage-independent growth, and also inhibits Val-12 Ras-induced maturation of Xenopus oocytes. SCH 51344 is also a potent inhibitor of the anchorage-independent growth of human tumor lines known to contain multiple genetic alterations in addition to activated ras genes. We have sought to determine whether SCH 51344 disrupts the signaling pathway that activates mitogen-activated protein (MAP) kinase or extracellular signal-regulated kinase (ERK) in normal and ras-transformed fibroblast cells. NIH 3T3 cells transformed by different oncogenes, which have products that participate at different steps of the Ras signaling pathway, were tested in a soft-agar colony formation assay to determine which step of the pathway is inhibited by SCH 51344. Our results indicate that SCH 51344 inhibits the ability of v-abl, v-mos, H-ras, v-raf, and mutant active MAP kinase kinase-transformed NIH 3T3 cells to grow in soft agar. Only v-fos-transformed cells were found to be resistant to the treatment of SCH 51344. SCH 51344 treatment had very little effect, if any, on the activation of MAP kinase kinase, MAP kinase, and p90RSK activity in response to growth factor stimulation. Treatment of ras-transformed cells with SCH 51344 led to stimulation of serum response factor DNA binding activity and activation of serum response element-dependent gene transcription, accounting for its ability to activate alpha-actin promoter activity in ras-transformed cells. Our results indicate that SCH 51344 inhibits ras transformation by a novel mechanism and acts at a point either downstream or parallel to extracellular signal-regulated kinase-dependent Ras signaling pathway.
3T3 Cells↗
Acrokeratosis paraneoplastica (Bazex syndrome) with oropharyngeal squamous cell carcinoma.
A 65-year-old white man presented with all the clinical features of acrokeratosis paraneoplastica of Bazex, characterized by violaceous erythema and scaling of the nose, aural helices, fingers, and toes, with keratoderma and severe nail dystrophy. Examination of the patient for possible associated malignancy disclosed an asymptomatic squamous cell carcinoma at the oropharyngeal region. The skin lesions resolved almost completely following radiation therapy of the neoplasm, but the onychodystrophy persisted. This case report illustrates the importance of early recognition of Bazex syndrome.
Acrodermatitis↗