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1.
Mol Cell ; 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32220303

RESUMO

To understand the role of the extensive senescence-associated 3D genome reorganization, we generated genome-wide chromatin interaction maps, epigenome, replication-timing, whole-genome bisulfite sequencing, and gene expression profiles from cells entering replicative senescence (RS) or upon oncogene-induced senescence (OIS). We identify senescence-associated heterochromatin domains (SAHDs). Differential intra- versus inter-SAHD interactions lead to the formation of senescence-associated heterochromatin foci (SAHFs) in OIS but not in RS. This OIS-specific configuration brings active genes located in genomic regions adjacent to SAHDs in close spatial proximity and favors their expression. We also identify DNMT1 as a factor that induces SAHFs by promoting HMGA2 expression. Upon DNMT1 depletion, OIS cells transition to a 3D genome conformation akin to that of cells in replicative senescence. These data show how multi-omics and imaging can identify critical features of RS and OIS and discover determinants of acute senescence and SAHF formation.

2.
J Org Chem ; 85(4): 2426-2437, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-31922748

RESUMO

The reaction of C60 with pregnen-20-carboxaldehyde, a biologically active synthetic steroid, by using a 1,3-dipolar cycloaddition reaction (Prato's protocol) results in the formation of pyrrolidine rings bearing a new stereogenic center on the C2 of the five-membered ring. The formation of the fullerene-steroid hybrids proceeds with preference for the Re face of the 1,3-dipole, with formation of a diastereomeric mixture in 73:15 ratio. The investigation of the chiroptical properties of these conjugates allowed determining the absolute configuration of the new fulleropyrrolidines. In addition, a thorough spectroscopical study permitted to determine the structure of the two mono-cycloadducts. The electrochemical properties of the new hybrids were also evaluated by cyclic voltammetry, both systems exhibit three quasi-reversible reduction waves which are cathodically shifted in regard to the parent C60. Theoretical calculations help supporting the experimental data. A conformational study combining semiempirical methods and density functional theory has predicted the most stable diastereomer. On the basis of this agreement, a possible reaction mechanism is presented. Additionally, a molecular docking simulation has been carried out using the HIV-1 protease as receptor, thus paving the way to study the possible application of these stereoisomers in biomedicine.

3.
J Chem Inf Model ; 60(2): 444-448, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-31651166

RESUMO

The growing computational capacity allows the investigation of large biomolecular systems by increasingly extensive molecular dynamics simulations. The resulting huge trajectories demand efficient partition methods to discern relevant structural dissimilarity. Clustering algorithms are available to address this task, but their implementations still need to be improved to gain in computational speed and to reduce the consumption of random access memory. We propose the BitClust code which, based on a combination of Python and C programming languages, performs fast structural clustering of long molecular trajectories. BitClust takes advantage of bitwise operations applied to a bit-encoded pairwise similarity matrix. Our approach allowed us to process a half-million frame trajectory in 6 h using less than 35 GB, a task that is not affordable with any of the similar alternatives.

4.
J Chem Inf Model ; 60(2): 467-472, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-31532987

RESUMO

Clustering Molecular Dynamics trajectories is a common analysis that allows grouping together similar conformations. Several algorithms have been designed and optimized to perform this routine task, and among them, Quality Threshold stands as a very attractive option. This algorithm guarantees that in retrieved clusters no pair of frames will have a similarity value greater than a specified threshold, and hence, a set of strongly correlated frames are obtained for each cluster. In this work, it is shown that various commonly used software implementations are flawed by confusing Quality Threshold with another simplistic well-known clustering algorithm published by Daura et al. (Daura, X.; van Gunsteren, W. F.; Jaun, B.; Mark, A. E.; Gademann, K.; Seebach, D. Peptide Folding: When Simulation Meets Experiment. Angew. Chemie Int. Ed. 1999, 38 (1/2), 236-240). Daura's algorithm does not impose any quality threshold for the frames contained in retrieved clusters, bringing unrelated structural configurations altogether. The advantages of using Quality Threshold whenever possible to explore Molecular Dynamic trajectories is exemplified. An in-house implementation of the original Quality Threshold algorithm has been developed in order to illustrate our comments, and its code is freely available for further use by the scientific community.

5.
J Am Acad Dermatol ; 81(5): 1037-1057, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31610857

RESUMO

Obesity is a worldwide major public health problem with an alarmingly increasing prevalence over the past 2 decades. The consequences of obesity in the skin are underestimated. In this paper, we review the effect of obesity on the skin, including how increased body mass index affects skin physiology, skin barrier, collagen structure, and wound healing. Obesity also affects sebaceous and sweat glands and causes circulatory and lymphatic changes. Common skin manifestations related to obesity include acanthosis nigricans, acrochordons, keratosis pilaris, striae distensae, cellulite, and plantar hyperkeratosis. Obesity has metabolic effects, such as causing hyperandrogenism and gout, which in turn are associated with cutaneous manifestations. Furthermore, obesity is associated with an increased incidence of bacterial and Candida skin infections, as well as onychomycosis, inflammatory skin diseases, and chronic dermatoses like hidradenitis suppurativa, psoriasis, and rosacea. The association between atopic dermatitis and obesity and the increased risk of skin cancer among obese patients is debatable. Obesity is also related to rare skin conditions and to premature hair graying. As physicians, understanding these clinical signs and the underlying systemic disorders will facilitate earlier diagnoses for better treatment and avoidance of sequelae.

6.
J Dermatolog Treat ; : 1-3, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31566077

RESUMO

Introduction: Non-melanoma skin cancers (NMSCs) are the most common malignancies in humans. When treating NMSC, quality-of-life (QOL) is an important consideration. The purpose of this study was to measure and compare QOL outcomes of two common therapies for NMSC: Mohs micrographic surgery and excision, using a disease-specific QOL instrument, the Skin Cancer Index (SCI). Methods: The University of Miami Institutional Review Board approved this retrospective chart review of patients diagnosed with NMSC from 2016 through 2019 at a private dermatology clinic (Deerfield Beach, FL, USA). Disease-specific QOL before and after surgery was measured with the SCI. Results: Pre- and post-surgery surveys were completed by 208 patients undergoing Mohs surgery and 30 patients undergoing excisional surgery. All patients were similar in age, gender, and race, and most patients undergoing either procedure had a history of additional prior skin cancers. For the Mohs cohort, the total SCI scores and each of the subscales were significantly higher post-surgery when compared with the baseline scores. In contrast, in the excision cohort, the social subscale was significantly lower post-surgery when compared with the baseline scores. Conclusion: There is limited data in the literature describing the specific effects of Mohs or excision for NMSC on QOL using a disease-specific QOL instrument. Our data supports increased QOL at 2-week follow up for patients with NMSC treated with Mohs, but no improvement in QOL was noted for patients treated with excision. This data is limited by the fact there were far more patients that underwent Mohs as opposed to excision, which gave the Mohs cohort greater statistical power when analyzing the difference in SCI.

7.
Neuroimage ; 203: 116181, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31521824

RESUMO

When humans make decisions, objective rewards are mainly discounted by delay, risk and effort. Whereas recent research has demonstrated that several brain areas process costs and code subjective value in effort-based decision making, it remains obscure how neural activity patterns change when effort costs are reduced due to the acquisition of healthy habits, such as moving from sedentary to active lifestyles. Here, a sample of sedentary volunteers was behaviorally assessed and fMRI-scanned before and after completing a 3-month fitness plan. The impact of effort cost on decisions, measured as the constant defining a hyperbolic decaying function, was reduced after the plan. A logistic mixed model demonstrated that the explanatory power of effort decreased with time. At a neural level, there was a marginally significant disruption of effort-cost related functional activity in the anterior cingulate after the plan. Functional connectivity between the amygdala and anterior cingulate cortex was strengthened after habit acquisition. In turn, this interaction was stronger in those participants with lower effort discounting. Thus, we show for the first time changes in value-based decision making after moving from a sedentary to an active lifestyle, which points to the relevance of the amygdala-cingulate interplay when the impact of effort on decisions fades away.

9.
Acta Crystallogr E Crystallogr Commun ; 75(Pt 6): 717-720, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31391952

RESUMO

Two crystallographically independent mol-ecules (A and B) are present in the asymmetric unit of the title compound, C11H9IN2OS, which differ mainly in the dihedral angle between the phenyl and thia-zole rings [38.94 (16) and 32.12 (15)°, respectively]. In the crystal, the mol-ecules form ⋯A⋯B⋯A⋯B⋯ chains along the [001] and [010] directions through moderate N-H⋯O hydrogen bonds and C-H⋯π inter-actions, respectively. The overall three-dimensional network is formed by I⋯I and I⋯S inter-actions. Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H⋯C/C⋯H (26.2%), H⋯H (20.9%), H⋯I/I⋯H (19.4%) and H⋯O/O⋯H (6.8%) inter-actions.

10.
Front Psychiatry ; 10: 421, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31258496

RESUMO

Previous research has suggested the prevalence of certain personality traits, some of which are related to a disorganized attachment, in substance abuse disorders. Further, frustration tolerance (FT) has been proposed as an important factor in addiction, both at the inception-following the "self-medication" hypothesis-and regarding treatment compliance. In turn, an inadequate response to frustrating events has been also associated with a disrupted attachment. Our goal is to explore the mediational role of FT in the relationship between personality traits and two different treatments for substance addiction: therapeutic community (TC) and ambulatory treatment (AT). Eighty-four subjects with substance abuse disorder were recruited in total (22 female), including 46 volunteers (13 female) in TC and 38 (9 female) in AT. They were assessed with Rosenzweig's test for FT and the Millon Clinical Multiaxial Inventory-III (MCMI-III) test to evaluate personality factors. By comparing with a control sample (335 volunteers, 268 female), we found that FT was lower in patients. Between therapeutic groups, FT was significantly lower in TC. Depressive, antisocial, sadistic, negativistic, schizotypal, borderline, paranoid, anxiety, dysthymia, alcohol use, drug use, posttraumatic stress disorder (PTSD), thought disorder, and delusional disorder traits were suggestive of pathology in the clinical samples and were significantly different between control, AT, and TC groups. Further, anxiety and PTSD traits were higher in TC than in AT. A mediational analysis revealed that the effect of anxiety and PTSD scales on therapeutic group was partially mediated by FT. In conclusion, FT and its interplay with personality traits commonly related to disorganized attachment (anxiety and PTSD) might be important factors to consider within therapeutic programs for persons with substance addiction.

11.
Food Chem Toxicol ; 131: 110529, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31150784

RESUMO

The health promoting effects of extra virgin olive oil (EVOO) relate to its unique repertoire of phenolic compounds. Here, we used a chemoinformatics approach to computationally identify endogenous ligands and assign putative biomolecular targets to oleacein, one of the most abundant secoiridoids in EVOO. Using a structure-based virtual profiling software tool and reference databases containing more than 9000 binding sites protein cavities, we identified 996 putative oleacein targets involving more than 700 proteins. We subsequently identified the high-level functions of oleacein in terms of biomolecular interactions, signaling pathways, and protein-protein interaction (PPI) networks. Delineation of the oleacein target landscape revealed that the most significant modules affected by oleacein were associated with metabolic processes (e.g., glucose and lipid metabolism) and chromatin-modifying enzymatic activities (i.e., histone post-translational modifications). We experimentally confirmed that, in a low-micromolar physiological range (<20 µmol/l), oleacein was capable of inhibiting the catalytic activities of predicted metabolic and epigenetic targets including nicotinamide N-methyltransferase, ATP-citrate lyase, lysine-specific demethylase 6A, and N-methyltransferase 4. Our computational de-orphanization of oleacein provides new mechanisms through which EVOO biophenols might operate as chemical prototypes capable of modulating the biologic machinery of healthy aging.


Assuntos
Aldeídos/metabolismo , Fenóis/metabolismo , Proteômica/métodos , ATP Citrato (pro-S)-Liase/química , ATP Citrato (pro-S)-Liase/metabolismo , Aldeídos/química , Domínio Catalítico , Ensaios Enzimáticos , Epigenômica/métodos , Ontologia Genética/estatística & dados numéricos , Histona Desmetilases/química , Histona Desmetilases/metabolismo , Humanos , Informática/métodos , Metiltransferases/química , Metiltransferases/metabolismo , Simulação de Acoplamento Molecular , Nicotinamida N-Metiltransferase/química , Nicotinamida N-Metiltransferase/metabolismo , Olea/química , Azeite de Oliva/química , Fenóis/química , Ligação Proteica , Mapeamento de Interação de Proteínas , Software
12.
Skin Appendage Disord ; 5(3): 169-171, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31049341

RESUMO

Retronychia is a frequently misdiagnosed nail disorder characterized by proximal ingrowth of the nail into the proximal nail plate. Often presenting with chronic paronychia, retronychia is commonly misdiagnosed and treated ineffectively with antimicrobials. The main cause is repeated micro-trauma to the affected nail, therefore a thorough history of exposures and insults to the toenail is crucial in identifying the cause of this nail abnormality. Herein, we describe a case of a UPS employee who presented with a painful nail after dropping a package on her foot that was unresponsive to medical treatment for 2 years. This case highlights the importance of taking a thorough history and physical examination for diagnosing retronychia.

13.
Nat Commun ; 10(1): 1938, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31028255

RESUMO

Chromosome conformation capture techniques, such as Hi-C, are fundamental in characterizing genome organization. These methods have revealed several genomic features, such as chromatin loops, whose disruption can have dramatic effects in gene regulation. Unfortunately, their detection is difficult; current methods require that the users choose the resolution of interaction maps based on dataset quality and sequencing depth. Here, we introduce Binless, a resolution-agnostic method that adapts to the quality and quantity of available data, to detect both interactions and differences. Binless relies on an alternate representation of Hi-C data, which leads to a more detailed classification of paired-end reads. Using a large-scale benchmark, we demonstrate that Binless is able to call interactions with higher reproducibility than other existing methods. Binless, which is freely available, can thus reliably be used to identify chromatin loops as well as for differential analysis of chromatin interaction maps.


Assuntos
Caulobacter crescentus/genética , Cromatina/química , Mapeamento Cromossômico/métodos , Biologia Computacional/métodos , DNA/química , Genoma , Benchmarking , Mapeamento Cromossômico/estatística & dados numéricos , DNA/genética , Conjuntos de Dados como Assunto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Conformação de Ácido Nucleico
14.
J Clin Med ; 8(4)2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30987403

RESUMO

For the cancer genomics era, there is a need for clinically annotated close-to-patient cell lines suitable to investigate altered pathways and serve as high-throughput drug-screening platforms. This is particularly important for drug-resistant tumors like chondrosarcoma which has few models available. Here we established and characterized new cell lines derived from two secondary (CDS06 and CDS11) and one dedifferentiated (CDS-17) chondrosarcomas as well as another line derived from a CDS-17-generated xenograft (T-CDS17). These lines displayed cancer stem cell-related and invasive features and were able to initiate subcutaneous and/or orthotopic animal models. Different mutations in Isocitrate Dehydrogenase-1 (IDH1), Isocitrate Dehydrogenase-2 (IDH2), and Tumor Supressor P53 (TP53) and deletion of Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) were detected both in cell lines and tumor samples. In addition, other mutations in TP53 and the amplification of Mouse Double Minute 2 homolog (MDM2) arose during cell culture in CDS17 cells. Whole exome sequencing analysis of CDS17, T-CDS17, and matched patient samples confirmed that cell lines kept the most relevant mutations of the tumor, uncovered new mutations and revealed structural variants that emerged during in vitro/in vivo growth. Altogether, this work expanded the panel of clinically and genetically-annotated chondrosarcoma lines amenable for in vivo studies and cancer stem cell (CSC) characterization. Moreover, it provided clues of the genetic drift of chondrosarcoma cells during the adaptation to grow conditions.

15.
Am J Dermatopathol ; 41(7): 492-497, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30624243

RESUMO

BACKGROUND: Frontal fibrosing alopecia (FFA) is an irreversible scarring alopecia, and its incidence has reached epidemic size. Immune privilege collapse of the bulge and epithelial mesenchymal transition play a role in the pathogenesis. We have noted adipose tissue in the dermis in several specimens from FFA. OBJECTIVE: Our primary objective was to verify the presence of adipose tissue at the isthmus level in biopsies from FFA. Additional objectives included the presence of deep inflammation and position of the sweat coils. METHODS: Eighty-three histologic specimens of FFA diagnosed at the Dermatopathology Laboratory at the Department of Dermatology, University of Miami, within 3 years were evaluated retrospectively. All biopsies were bisected horizontally and assessed at several levels. Sixty biopsies from androgenetic alopecia served as controls. Statistical analysis was performed using the χ test. A P value of 0.05 or less was considered significant. RESULTS: Sixty specimens met the inclusion criteria for optimal quality and classic diagnostic features. Seventy percent demonstrated fat tissue infiltration at the isthmus level as clusters of cells or small globules versus 23% of the controls. The fat infiltration in the arrector pili muscle (APM) was present in 55% versus 15% of the controls, and the sweat coils were positioned in the reticular dermis in 43% versus 1.7% of the controls. All results were statistically significant (P < 0.0001). When accounting for the simultaneous presence of any of these 3 variables, 30% of the FFA cases had triple positivity, 61.7% had double positivity, and 75% had at least 1 positive variable versus 0%, 15%, and 10%, respectively, of the controls. CONCLUSION: New histologic findings in FFA involve the presence of adipose tissue in the dermis. We believe that the close interaction of the hair follicles and the APM with the adipose tissue may play a role in APM degeneration and in epithelial mesenchymal transition.


Assuntos
Tecido Adiposo/patologia , Alopecia/patologia , Derme/patologia , Glândulas Écrinas/patologia , Folículo Piloso/patologia , Músculo Liso/patologia , Biópsia , Fibrose , Testa , Humanos , Estudos Retrospectivos , Couro Cabeludo/patologia
16.
Cortex ; 113: 96-110, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30634107

RESUMO

According to the theory of value-based decision making, subjects tend to choose the most valuable among a set of options. However, agents may not be consistent when facing the same decision several times. In this paper, Shannon's entropy (H) is employed as a measure of behavioral inconsistency: it is a central measure of information theory that, applied to decision making, allows the estimation of behavioral preferences among a set of options. We scanned (functional magnetic resonance imaging, fMRI) 24 young (18-25 year) subjects (14 female) while performing a decision-making task, where monetary rewards were devalued by physical effort (minutes running in the treadmill) and risk. Twenty different pairs of options were presented nine times each, and H was calculated for each pair and subject. Behavioral analyses showed that subjective value (SV) significantly explained agents' preferences only in pairs with a low inconsistent response. Averaged response time positively correlated with H, confirming entropy as an indicator of choice difficulty. Group analyses on fMRI data revealed a cluster in the paracingulate cortex as the neural correlate of H. Besides, BOLD signal in the posterior cingulate correlated with the SV of the pair only in consistent decisions, confirming that SV loses its explanatory power on highly inconsistent decisions. Finally, the anterior and central cingulate were especially recruited when predicting a secured effortless reward, compared with a secured reward that involved a maximum effort. Our study shows that different regions of the cingulate cortex are involved in choice inconsistency, SV and processing effort costs.

17.
Dermatol Ther ; 32(4): e12622, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30152568

RESUMO

Trichotillomania (hair pulling disorder) is a fairly common but underreported disorder characterized by recurrent episodes of pulling hair from different parts of the body. Currently classified in Diagnostic and Statistical Manual of Psychiatric Disorders (DSM-5) under the heading of the "Obsessive-compulsive spectrum and related disorders." The estimated prevalence data suggest that 0.5-2% of the general population suffers from this disorder. Stress and anxiety are directly correlated to the production of trichotillomania symptoms. The psychosocial aspects of trichotillomania are greatly underestimated, but recent literature suggests an increased interest in this neglected area. Although no FDA approved medications are available for the treatment of trichotillomania, a variety of medications including N-acetylcysteine have shown benefit in case reports. Combined liaison clinics, with an interdisciplinary approach, are highly advisable in the treatment of these cases.


Assuntos
Tricotilomania/tratamento farmacológico , Adolescente , Criança , Ética Médica , Humanos , Uso Off-Label , Tricotilomania/etiologia , Tricotilomania/psicologia
18.
Dermatol Ther (Heidelb) ; 9(1): 19-31, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30539425

RESUMO

Acne vulgaris is the most common dermatological disorder worldwide. It is a multifactorial disease that involves increased sebum production, hyperkeratinization of the pilosebaceous unit, Propionibacterium acnes (Cutibacterium acnes) colonization, and inflammation. The human skin microbiome hosts a wide variety of microorganisms, including bacteria, viruses, and fungi. A delicate balance of these microorganisms is essential for the barrier function of the skin. Propionibacterium acnes represents nearly 90% of the human skin microbiome of healthy adults. Acne is a chronic recurrent disease that requires long-lasting treatment, which has led to the emergence of antibiotic resistance. New alternatives to traditional therapy are emerging, including antimicrobial peptides, natural engineered antibodies, and bacteriophages. Bacteriophages have been shown to play a role in human skin health and disease. There is evidence supporting phage therapy in many types of skin infections. P. acnes bacteriophages have been isolated and characterized. However, only a few in vitro studies have tested the ability of bacteriophages to kill P. acnes. Furthermore, there is no evidence on bacteriophage therapy in the treatment of acne in humans. In this review, we summarize the most recent evidence regarding P. acnes bacteriophages and the potential role of these bacteriophages in the treatment of acne. Further research on this field will provide the evidence to use phage therapy to decrease rates of antibiotic resistance and restore antibiotic susceptibility of P. acnes.

19.
Drug Dev Res ; 80(1): 155-161, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30570769

RESUMO

Trichomoniasis, caused by the protozoan parasite Trichomonas vaginalis, is the most common nonviral sexually transmitted infection worldwide. Although drug treatment is available, unpleasant side effects and increased resistance to the nitroimidazole family have been documented. Hence, there is a need for the identification of new and safe therapeutic agents against T. vaginalis. Antimicrobial activity of anthraquinone compounds has been reported by a number of authors. The genus Morinda is well known for the diversity of anthraquinones with numerous biological activities. A new anthraquinone, lucidin-ω-isopropyl ether, was isolated from the roots of Morinda panamensis Seem. The structure of the compound was determined by 1 H and 13 C Nuclear Magnetic Resonance (NMR) analyses, in addition to comparison with literature reports. Using in vitro susceptibility assay, the half inhibitory concentration (IC50 ) of lucidin-ω-isopropyl ether for T. vaginalis (1.32 µg/mL) was found similar to that of metronidazole concentration tested (6 µM = 1.03 µg/mL). In addition, this anthraquinone was capable of inhibiting the parasite's ability to kill HeLa cells and decreased proteolytic activity of the proteinase TvMP50 from T. vaginalis. This was associated with the decreased expression of the mp50 gene. These results demonstrate the trichomonicidal potential by lucidin-ω-isopropyl ether. Further action-mode studies are necessary to elucidate the antiparasitic mechanism of this new anthraquinone to develop a more potent antitrichomonal agent.


Assuntos
Antraquinonas/farmacologia , Antitricômonas/farmacologia , Morinda , Extratos Vegetais/farmacologia , Raízes de Plantas , Trichomonas vaginalis/efeitos dos fármacos , Antraquinonas/isolamento & purificação , Antitricômonas/isolamento & purificação , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Extratos Vegetais/isolamento & purificação , Trichomonas vaginalis/metabolismo
20.
Molecules ; 23(10)2018 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-30274324

RESUMO

Mechanistic theoretical studies about the feasibility of the traditional proposed mechanism of formation for icetexane diterpene dimer grandione were assessed using density functional method at the M06-2X/6-31G(d,p) level of theory. Bulk water solvent effects were taken into account implicitly using the polarizable continuum model (SCI-PCM). The results were compared with the selectivity found in the biomimetic synthesis performed by experimental research groups. The relative free energy calculation shows that the one-step H-DA formation mechanism nominated in the literature is not a viable mechanism. We found that an alternative competing Tandem pathway is consistent with the experimental trends. Thus, our results suggested that the compound grandione is formed via a H-DA/retro-Claisen rearrangement and not by the traditional H-DA mechanism proposed early in the experimental studies. The H-DA initial step produce a biecyclic adduct followed by a domino retro-Claisen rearrangement that releases the energy strain of the bicyclic intermediary. Steric issues and hyperconjugation interactions are the mainly factors driving the reaction nature and the selectivity in the formation reaction. Finally, the enzymatic assistance for dimer formation was analyzed in terms of the calculated transition state energy barrier.


Assuntos
Diterpenos/química , Diterpenos/síntese química , Modelos Químicos
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