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1.
Clin Ter ; 174(3): 240-244, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37199357

RESUMEN

Abstract: Traumatic rupture of the long head of biceps tendon (LHBT) in the young is rare and it is often related to sports. We describe a technical note of a mini open supra-pectoral tenodesis fixed by the "ToggleLoc™" (Zimmer Biomet, Warsaw, IN, USA) and performed by a two-window approach. The proposed technique guarantees an optimal visualization with low risk of complications and without arthroscopic assistance.


Asunto(s)
Procedimientos de Cirugía Plástica , Deportes , Tenodesis , Humanos , Tenodesis/métodos , Artroscopía/métodos , Tendones
2.
Malays Orthop J ; 17(1): 172-179, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37064623

RESUMEN

Introduction: In this retrospective case-series study we discuss the clinical and radiographic outcomes obtained following the "tibia-first concept" in the treatment of distal tibia fractures, both in patients with fibular comminution and in cases with a simple fibula fracture. Materials and methods: We analysed a consecutive series of 64 patients who presented at our emergency department with a distal articular tibial and fibular fracture from January 2015 to September 2020. A total of 22 patients met the inclusion and exclusion criteria and were included in the study. Clinical and radiographic examination were performed at each follow-up. To quantify pain and functional disability, the Foot and Ankle Outcome Score (FAOS) and the American Orthopaedic Foot and Ankle Society's ankle-hindfoot scale (AOFAS) were applied. Results: The overall mean age was 52.8 years, and the mean follow-up was 13.18 months. Multiple scales data from the FAOS were as follows: pain score 80.70; symptoms score 81.69; activities of daily living score 87.22; quality of life 76.05. The mean AOFAS ankle-hindfoot score was 74.36. Conclusions: Even though the principles of Rüedi and Allgöwer are still valid, in specific circumstances, the tibia-first concept could be considered as a valid option for the treatment of these demanding fractures. If a good reduction is obtained intra-operatively by ligamentotaxis, we recommend fixing the tibia first, avoiding surgical stress on tissues derived from a previous fibular fixation.

3.
Artículo en Inglés | WPRIM (Pacífico Occidental) | ID: wpr-1006161

RESUMEN

@#Introduction: In this retrospective case-series study we discuss the clinical and radiographic outcomes obtained following the “tibia-first concept” in the treatment of distal tibia fractures, both in patients with fibular comminution and in cases with a simple fibula fracture. Materials and methods: We analysed a consecutive series of 64 patients who presented at our emergency department with a distal articular tibial and fibular fracture from January 2015 to September 2020. A total of 22 patients met the inclusion and exclusion criteria and were included in the study. Clinical and radiographic examination were performed at each follow-up. To quantify pain and functional disability, the Foot and Ankle Outcome Score (FAOS) and the American Orthopaedic Foot and Ankle Society’s anklehindfoot scale (AOFAS) were applied. Results: The overall mean age was 52.8 years, and the mean follow-up was 13.18 months. Multiple scales data from the FAOS were as follows: pain score 80.70; symptoms score 81.69; activities of daily living score 87.22; quality of life 76.05. The mean AOFAS ankle-hindfoot score was 74.36. Conclusions: Even though the principles of Rüedi and Allgöwer are still valid, in specific circumstances, the tibiafirst concept could be considered as a valid option for the treatment of these demanding fractures. If a good reduction is obtained intra-operatively by ligamentotaxis, we recommend fixing the tibia first, avoiding surgical stress on tissues derived from a previous fibular fixation.

4.
Clin Ter ; 173(6): 520-523, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36373447

RESUMEN

Introduction: Femur fractures represent a major public health issue and are commonly treated by intramedullary nailing. Among the possible complications of this technique, the injury of the superior gluteal artery (SGA) is quite rare, but it must be promptly recognized and treated. Case report: A 35-year-old male was admitted with a right femur diaphyseal fracture. After an early damage control surgery, he under-went a close reduction and long intramedullary nail fixation. During the post-operative rehabilitation, a sudden hip pain and hemoglobin drop occurred. A CT-scan showed an extensive hematoma; angiography confirmed a superior gluteal artery bleeding which was subsequently treated with selective embolization. Discussion and Conclusion: Whenever a patient presents with postoperative suspect of active bleeding, it is important to consider even the rarest complications. Sharing our experience in the management of a SGA lesion case, we want to stress the importance of its early diagnosis and correction, since it can represent a life-threatening condition.


Asunto(s)
Fracturas del Fémur , Fijación Intramedular de Fracturas , Masculino , Humanos , Adulto , Fracturas del Fémur/diagnóstico por imagen , Fracturas del Fémur/etiología , Fracturas del Fémur/cirugía , Fijación Intramedular de Fracturas/efectos adversos , Fijación Intramedular de Fracturas/métodos , Fémur , Arteria Ilíaca , Complicaciones Posoperatorias/etiología , Clavos Ortopédicos/efectos adversos
5.
Clin Ter ; 172(6): 542-546, 2021 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-34821349

RESUMEN

BACKGROUND: Tibial plateau fractures pose multiple challenges to the surgeon given their frequent intra-articular involvement and the tendency to displace under axial load. The aim of this study is to de-scribe the clinical outcomes of a retrospective case series in which tibial plateau fractures were not treated with PL fragment osteosynthesis. METHODS: In the present retrospective study, we included patients treated for tibial plateau fracture with PL fragment in our department from January 2016 to January 2020. All patients were seen at the outpa-tient clinic 2 and 5 weeks after surgery, and at 3, 6 and 12 months, and thereafter at regular intervals, depending on the overall clinical status. Every patient included in this study was then contacted by phone to assess self-reported clinical outcomes. The Oxford Knee Score (OKS) questionnaire was used to assess functional outcomes. Patients were divided in six groups depending on the three-column classification by Lou (groups A1-A6). Patients were also divided in four groups based on the whole area of the PL column and on the depression of the PL fragment (group B1-B4). One-way ANOVA was used to compare groups of patients. RESULTS: OKS scores, extension and step-off of the PL fragment were analyzed in groups A1 - A6. No significant differences between OKS scores and step-off were found, while statistical difference was found between surfaces of PL fragment. No significant difference was found between OKS scores in groups B1-B4. CONCLUSION: Our findings suggest that the treatment outcome is influenced not only by the superficial involvement or collapse of PL fragments, but also by other variables, including BMI, pre-injury physi-cal health, and age.


Asunto(s)
Articulación de la Rodilla , Fracturas de la Tibia , Fijación Interna de Fracturas , Humanos , Rango del Movimiento Articular , Estudios Retrospectivos , Fracturas de la Tibia/diagnóstico por imagen , Fracturas de la Tibia/cirugía
6.
Clin Ter ; 172(6): 552-558, 2021 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-34821351

RESUMEN

BACKGROUND: Distal metaphyseal-diaphyseal fractures of the hume-rus can be challenging. The success lies in achieving a stable fixation that could allow early functional recovery. Our aim is to combine dif-ferent approaches already reported, to obtain an ideal surgical strategy for treating these fracture patterns. METHODS: In this retrospective study, we present the clinical outco-me of a 12-patient cohort in which we used a combined paratricipital and triceps-splitting approach to the distal humerus. The mean age of the group was 50 years (range 17 - 88). Clinical and radiographic evaluation was performed at 1, 3, 6, and 12 months after surgery and thereafter, depending on the necessity of a further control. Patients' range of motion (ROM) of the elbow was reported, and functional outcome was assessed using the Mayo Elbow Performance Index (MEPI).The minimum follow-up was fixed at 12 months. RESULTS: Union was achieved in all fractures. After a median follow-up of 15.7 months (range 12-21), none of the patients complained of any limitation in daily activities. The ROM at the last follow-up was complete in eight patients. Instead, three patients had ROM limitations, but none of them mentioned limitations in the activities of daily living. We observed a single iatrogenic radial nerve palsy undergoing a full functional recovery at the final follow-up. No further complications occurred. CONCLUSION: We believe that the here presented modified approach could represent a solution that meets the modern demands for both ro-bust fixation and early mobilization, with minimal soft tissues damage around distal humeral fractures.


Asunto(s)
Actividades Cotidianas , Fracturas del Húmero , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Placas Óseas , Fijación Interna de Fracturas , Humanos , Fracturas del Húmero/diagnóstico por imagen , Fracturas del Húmero/cirugía , Húmero , Persona de Mediana Edad , Rango del Movimiento Articular , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
7.
Malays Orthop J ; 14(3): 124-128, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33403072

RESUMEN

INTRODUCTION: The aim of our retrospective study was to investigate the role of the medial side involvement in the treatment choice of radial head fractures. MATERIALS AND METHODS: We searched the databases of our institutions for the surgical procedures diagnosed as "fracture of the radial head" and for the procedures related to "prosthesis of the radial head" and "osteosynthesis of the radial head" in the period from May 2014 to October 2017. The fractures were first classified according to the Mason classification . We then allocated the patients into three study groups according to the site of the fracture, either the medial or lateral side of the radial head : Group A, with an isolated lateral fracture of the radius head; Group B1, with a medial fracture of the radius head with two medial fragments; and Group B2, with a medial fracture of the radius head with multiple medial fragments. We performed a multivariate analysis to identify statistically significant correlation between the pre-operative classifications of Mason and our study, the type of surgical procedure, and the clinical outcome. RESULTS: Mayo Elbow Performance (MEP) scores determined at the final follow-up of the study (mean 16.6 months, range 12-26 months) was excellent in 17 patients (4 in Group A, 6 in Group B1 and 7 in Group B2), and good in 12 patients (3 in Group A, 7 in Group B1, and 2 in Group B2). One patient showed a poor result in MEP score probably because of an infection and implant removal. CONCLUSION: Regarding medial fractures of the radial head, our study showed satisfactory results with a radial head prosthesis for comminuted or multifragmentary radial head fractures. For surgeons with advanced elbow fracture expertise, osteosynthesis could be attempted in a fracture pattern that involved only two medial fragments.

8.
Artículo en Inglés | WPRIM (Pacífico Occidental) | ID: wpr-837606

RESUMEN

@#Introduction: The aim of our retrospective study was to investigate the role of the medial side involvement in the treatment choice of radial head fractures. Materials and Methods: We searched the databases of our institutions for the surgical procedures diagnosed as "fracture of the radial head" and for the procedures related to "prosthesis of the radial head" and "osteosynthesis of the radial head" in the period from May 2014 to October 2017. The fractures were first classified according to the Mason classification . We then allocated the patients into three study groups according to the site of the fracture, either the medial or lateral side of the radial head : Group A, with an isolated lateral fracture of the radius head; Group B1, with a medial fracture of the radius head with two medial fragments; and Group B2, with a medial fracture of the radius head with multiple medial fragments. We performed a multivariate analysis to identify statistically significant correlation between the pre-operative classifications of Mason and our study, the type of surgical procedure, and the clinical outcome. Results: Mayo Elbow Performance (MEP) scores determined at the final follow-up of the study (mean 16.6 months, range 12-26 months) was excellent in 17 patients (4 in Group A, 6 in Group B1 and 7 in Group B2), and good in 12 patients (3 in Group A, 7 in Group B1, and 2 in Group B2). One patient showed a poor result in MEP score probably because of an infection and implant removal. Conclusion: Regarding medial fractures of the radial head, our study showed satisfactory results with a radial head prosthesis for comminuted or multifragmentary radial head fractures. For surgeons with advanced elbow fracture expertise, osteosynthesis could be attempted in a fracture pattern that involved only two medial fragments.

9.
Clin Ter ; 164(2): e133-6, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23698215

RESUMEN

We present a 42-years-old male who developed a radial shaft pseudoartrosis and a chronic DRUJ dislocation/instability, following a Galeazzi fracture. He presented to our Office with a severe inability of wrist and forearm motion. A Sauve'-Kapandji procedure was adopted, performing a lateral approach to the ulna and grafting the excised ulnar block to retrieve radial length at the pseudoarthrosis level. Cancellous bone grafts from the iliac crest were also applied and mixed with autologous platelet rich plasma to promote callus formation. The goal was to create an intentional pseudoarthrosis of the distal ulna combined with a DRUJ arthrodesis, in order to resolve instability and regain forearm pronation/supination. We obtained bone healing, an excellent clinical recovery, and the patient returned to all his previous activities six months after surgery. To our knowledge, this is the first reported case of a radial shaft psudoarthrosis treated with the Sauve'-Kapandji technique.


Asunto(s)
Luxaciones Articulares/cirugía , Procedimientos Ortopédicos/métodos , Seudoartrosis/cirugía , Fracturas del Radio/cirugía , Articulación de la Muñeca , Adulto , Placas Óseas , Trasplante Óseo , Enfermedad Crónica , Humanos , Luxaciones Articulares/complicaciones , Masculino , Seudoartrosis/complicaciones , Fracturas del Radio/complicaciones
10.
Bioorg Chem ; 33(6): 415-25, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16182338

RESUMEN

Fluorescent molecular rotors belong to a group of twisted intramolecular charge transfer complexes (TICT) whose photophysical characteristics depend on their environment. In this study, the influence of solvent polarity and viscosity on several representative TICT compounds (three Coumarin derivatives, 4,4-dimethylaminobenzonitrile DMABN, 9-(dicyanovinyl)-julolidine DCVJ), was examined. While solvent polarity caused a bathochromic shift of peak emission in all compounds, this shift was lowest in the case of molecular rotors. Peak intensity was influenced strongly by solvent viscosity in DMABN and the molecular rotors, but polarity and viscosity influences cannot be separated with DMABN. Coumarins, on the other hand, did not show viscosity sensitivity. This study shows the unique suitability of molecular rotors as fluorescent viscosity sensors.


Asunto(s)
Colorantes Fluorescentes/química , Sondas Moleculares/química , Solventes/química , Estructura Molecular , Espectrometría de Fluorescencia , Viscosidad
11.
J Org Chem ; 66(26): 8843-53, 2001 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-11749614

RESUMEN

An enantioselective synthesis of the potent antiinflammatory agent (-)-acanthoic acid (1) is described. The successful strategy departs from (-)-Wieland-Miescher ketone (10), which is readily available in both enantiomeric forms and constitutes the starting point toward a fully functionalized AB ring system of 1. Conditions were developed for a regioselective double alkylation at the C4 center of the A ring, which produced compound 32 as a single stereoisomer. Construction of the C ring of 1 was accomplished via a Diels-Alder reaction between sulfur-containing diene 43 and methacrolein (36), which after desulfurization and further functionalization yielded synthetic acanthoic acid. The described synthesis confirms the proposed stereochemistry of the natural product and represents a fully stereocontrolled entry into an underexplored class of biologically active diterpenes.


Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Diterpenos/síntesis química , Antiinflamatorios no Esteroideos/química , Cristalografía por Rayos X , Diterpenos/química , Indicadores y Reactivos , Modelos Moleculares , Estereoisomerismo
12.
Bioorg Med Chem ; 9(6): 1365-70, 2001 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-11408157

RESUMEN

Clerocidin, a diterpenoid natural product, has been shown in vitro to inhibit DNA religation following cleavage by topoisomerase II. Herein, we characterize the efficacy and specificity of clerocidin in HeLa cells. Our results suggest that clerocidin recognizes topoisomerase II as its main intracellular target and binds to this enzyme prior to formation of the 'cleavable complex' with DNA. These pharmacological features attest to the promising chemotherapeutic potential of this natural product.


Asunto(s)
Antibacterianos/farmacología , ADN-Topoisomerasas de Tipo II/efectos de los fármacos , Diterpenos/farmacología , Glicoproteínas de Membrana , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , ADN-Topoisomerasas de Tipo II/metabolismo , Células HeLa/efectos de los fármacos , Células HeLa/virología , Humanos , Biosíntesis de Proteínas , Transporte de Proteínas/efectos de los fármacos , Transcripción Genética , Proteínas del Envoltorio Viral/efectos de los fármacos , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/metabolismo
13.
Chem Biol ; 8(2): 123-31, 2001 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11251287

RESUMEN

BACKGROUND: Molecular rotors are fluorescent molecules that exhibit viscosity-dependent fluorescence quantum yield, potentially allowing direct measurements of cell membrane viscosity in cultured cells. Commercially available rotors, however, stain not only the cell membrane, but also bind to tubulin and migrate into the cytoplasm. We synthesized molecules related to 9-(dicyanovinyl)-julolidine (DCVJ), which featured hydrocarbon chains of different length to increase membrane compatibility. RESULTS: Longer hydrocarbon chains attached to the fluorescent rotor reduce the migration of the dye into the cytoplasm and internal compartments of the cell. The amplitude of the fluorescence response to fluid shear stress, known to decrease membrane viscosity, is significantly higher than the response obtained from DCVJ. Notably a farnesyl chain showed a more than 20-fold amplitude over DCVJ and allowed detection of membrane viscosity changes at markedly lower shear stresses. CONCLUSIONS: The modification of molecular rotors towards increased cell membrane association provides a new research tool for membrane viscosity measurements. The use of these rotors complements established methods such as fluorescence recovery after photobleaching with its limited spatial and temporal resolution and fluorescence anisotropy, which has low sensitivity and may be subject to other effects such as deformation.


Asunto(s)
Membrana Celular , Colorantes Fluorescentes/química , Células Cultivadas , Espectrometría de Masas , Resonancia Magnética Nuclear Biomolecular , Viscosidad
14.
Org Lett ; 2(14): 2073-6, 2000 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-10891233

RESUMEN

[reaction: see text] The first stereoselective synthesis of (-)-acanthoic acid (1) has been designed and accomplished. Our synthetic plan departs from (-) Wieland-Miesher ketone (7) and calls upon a Diels-Alder cycloaddition reaction for the construction of the C ring of 1. The described synthesis confirms the proposed stereochemistry of 1 and represents an efficient entry into an unexplored class of biologically active diterpenes.


Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Diterpenos/síntesis química , Antiinflamatorios no Esteroideos/química , Cristalografía por Rayos X , Ciclización , Diterpenos/química , Indicadores y Reactivos , Corea (Geográfico) , Conformación Molecular , Raíces de Plantas/química , Plantas Medicinales/química , Estereoisomerismo
15.
Chemistry ; 6(11): 1987-2001, 2000 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-10894398

RESUMEN

Our studies toward the total synthesis of the reveromycin family of natural products are described herein. Our synthetic approach is efficient, stereocontrolled, and convergent and has resulted in the first synthesis of reveromycin B (4) and C19-epi-reveromycin B (55). Key steps of this successful strategy include: a modified Negishi coupling (construction of C7-C8 bond) and a Kishi-Nozaki reaction (construction of C19-C20 bond), which were employed in the attachment of the target side chains. The key building blocks for the total synthesis were thus defined as vinyl iodide 6, alkyne 7, and alkyne 8. Our synthesis illustrates the utility of the modified Negishi coupling for the construction of complex dienes, confirms the proposed stereochemistry of reveromycins and paves the way for the preparation of designed analogues for biological study.


Asunto(s)
Antibióticos Antineoplásicos/síntesis química , Piranos/síntesis química , Compuestos de Espiro/síntesis química , Antibióticos Antineoplásicos/química , Piranos/química , Análisis Espectral , Compuestos de Espiro/química , Estereoisomerismo
16.
Org Lett ; 2(2): 207-10, 2000 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-10814283

RESUMEN

[structure: see text] Reveromycin A (1) belongs to a family of microbial polyketides with unusual structural features and biological activities. The structure of 1 is composed of a [6,6] spiroketal core decorated with highly unsaturated side chains. As a prelude to the synthesis of 1, we present herein a short, efficient, and enantioselective synthesis of the C9-C21 fragment 5 (spiroketal core) of reveromycin A.


Asunto(s)
Piranos/química , Compuestos de Espiro/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Factor de Crecimiento Epidérmico/antagonistas & inhibidores , Resonancia Magnética Nuclear Biomolecular , Inhibidores de la Síntesis de la Proteína/síntesis química , Inhibidores de la Síntesis de la Proteína/química , Piranos/síntesis química , Compuestos de Espiro/síntesis química , Estereoisomerismo , Streptomyces/química
17.
Bioorg Med Chem ; 7(5): 727-36, 1999 May.
Artículo en Inglés | MEDLINE | ID: mdl-10400326

RESUMEN

N-Benzoyloxy-2-thiopyridone (12) was shown to induce single-strand nicks in duplex DNA upon irradiation with visible light (lambda&350 nm). This finding led to the design of a series of compounds, in which an acridinyl nucleus was covalently linked to the N-benzoyloxy-2-thiopyridone unit. These conjugates (15, 16, 17 and 18) were synthesized and evaluated as novel DNA photocleaving reagents. Optimal photocleaving activity was observed for conjugate 16, in which a flexible polymethylene spacer of 4 carbons was used to connect the aminoacridine entity to the thiopyridone. This compound was shown to cleave DNA at low microM concentrations and was approximately two-orders of magnitude more efficient than the parent N-benzoyloxy-2-thiopyridone (12). Furthermore, the DNA cleavage ladders induced by 16 and 12 were found to be identical and of no significant sequence selectivity. These data suggest that the N-aroyloxy-2-thiopyridones can be used for the design of new DNA photocleaving reagents with potential use as 'photofootprinting agents' or as 'site-directed photonucleases'.


Asunto(s)
ADN/efectos de los fármacos , Piridinas/síntesis química , Autorradiografía , Bacteriófago phi X 174/efectos de los fármacos , Enzimas de Restricción del ADN/metabolismo , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Electroforesis en Gel de Poliacrilamida , Concentración de Iones de Hidrógeno , Luz , Modelos Químicos , Temperatura
18.
Proc Natl Acad Sci U S A ; 93(2): 940-4, 1996 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-8570664

RESUMEN

The synthetic oligosaccharide moiety of the antibiotic calicheamicin and the head-to-head dimer of this oligosaccharide are known to bind to the minor groove of DNA in a sequence-selective manner preferring distinct target sequences. We tested these carbohydrates for their ability to interfere with transcription factor function. The oligosaccharides inhibit binding of transcription factors to DNA in a sequence-selective manner, probably by inducing a conformational change in DNA structure. They also interfere with transcription by polymerase II in vitro. The effective concentrations of the oligosaccharides for inhibition of transcription factor binding and for transcriptional inhibition are in the micromolar range. The dimer is a significantly more active inhibitor than is the monomer.


Asunto(s)
Aminoglicósidos , Antibacterianos/química , ADN/metabolismo , Oligosacáridos/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética/efectos de los fármacos , Secuencia de Bases , Secuencia de Carbohidratos , ADN Polimerasa II/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Enediinos , Conformación Molecular , Datos de Secuencia Molecular , Oligodesoxirribonucleótidos/metabolismo , Oligosacáridos/farmacología , Unión Proteica/efectos de los fármacos , Factor de Transcripción STAT3 , Transactivadores/metabolismo
19.
Chem Biol ; 2(8): 533-41, 1995 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-9383457

RESUMEN

BACKGROUND: Brevetoxins are polyether ladder toxins that are ichthyotoxic at nanomolar concentrations. They bind to voltage-gated sodium channels, causing four distinct electrophysiological effects: (i) a shift of activation potential; (ii) occurrence of subconductance states; (iii) induction of longer mean open times of the channel; and (iv) inhibition of channel inactivation. We set out to determine whether these functions all require the same structural elements within the brevetoxin molecules. RESULTS: Several synthetically prepared structural analogs of brevetoxin B were examined in synaptosome receptor binding assays and by functional electrophysiological measurements. A truncated analog is not ichthyotoxic at micromolar concentrations, shows decreased receptor-binding affinity, and causes only a shift of activation potential without affecting mean open times or channel inactivation. An analog with the A-ring carbonyl removed binds to the receptor with nanomolar affinity, produces a shift of activation potential and inhibits inactivation, but does not induce longer mean open times. An analog in which the A-ring diol is reduced shows low binding affinity, yet populates five subconductance states. CONCLUSIONS: Our data are consistent with the hypothesis that binding to sodium channels requires an elongated cigar-shaped molecule, approximately 30 A long. The four electrophysiological effects of the brevetoxins are not produced by a single structural feature, however, since they can be decoupled by using modified ligands, which are shown here to be partial sodium channel agonists. We propose a detailed model for the binding of brevetoxins to the channel which explains the differences in the effects of the brevetoxin analogs. These studies also offer the potential for developing brevetoxin antagonists.


Asunto(s)
Toxinas Marinas/farmacología , Neuronas/metabolismo , Neurotoxinas/farmacología , Oxocinas , Bloqueadores de los Canales de Sodio , Animales , Electrofisiología , Técnicas In Vitro , Masculino , Toxinas Marinas/química , Potenciales de la Membrana/efectos de los fármacos , Modelos Moleculares , Neuronas/efectos de los fármacos , Neurotoxinas/química , Ganglio Nudoso/citología , Ganglio Nudoso/efectos de los fármacos , Ganglio Nudoso/metabolismo , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Canales de Sodio/metabolismo , Relación Estructura-Actividad , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo
20.
Chem Biol ; 1(1): 57-66, 1994 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-9383371

RESUMEN

BACKGROUND: Calicheamicin gamma 1I is a bacterial product that is a prominent member of the enediyne class of antitumor antibiotics, and has been extensively studied. Calicheamicin gamma 1I binds to DNA, causing double-stranded breaks, and cells exposed to it eventually become apoptotic. It can now be made synthetically, and highly potent biological mimics have been designed. Such molecules have many potential clinical applications, but are complex to make. We therefore investigated whether simplified versions of these molecules are biologically active. RESULTS: We designed and synthesized a number of simple calicheamicin mimics and evaluated their biological activity. We also constructed mimics that are particularly suitable for conjugation to proteins, oligonucleotides, and other delivery systems. Several active mimics were found, and two in particular, which lack the trisulfide and oligosaccharide moieties of calicheamicin, had potent DNA-cleaving and cytotoxic activities. They caused chiefly single-stranded cuts in DNA, however, unlike the natural molecule, which causes double-stranded DNA cuts. Although they were able to induce apoptosis, they were less potent than the natural compound in this assay. CONCLUSIONS: The simple enediyne mimics were less potent than calicheamicin gamma 1I, presumably because they lack the oligosaccharide DNA-binding domain. Nevertheless, considering their relatively primitive structures, they have remarkable biological properties. They may be useful biological tools and are potential leads for the development of chemotherapeutic agents. We propose that the ability of the enediynes to induce apoptosis is related to their ability to make double-stranded cuts in DNA.


Asunto(s)
Aminoglicósidos , Antibacterianos/farmacología , Antibióticos Antineoplásicos/farmacología , ADN/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Enediinos , Humanos , Iniciación de la Cadena Peptídica Traduccional/efectos de los fármacos
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