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1.
Tetrahedron ; 1412023 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-37637188

RESUMEN

An oxidative rearrangement has been established that enables a cucurbitane-to-lanostane type rearrangement that is counter to known biomimetic transformations that proceed in an opposite direction by way of a lanostane-to-cucurbitane transformation. Here, an oxidative dearomatization/Wagner-Meerwein rearrangement with a substrate bearing the characteristic cucurbitane triad of quaternary centers at C9, C13 and C14, and possessing an alkene at C11-C12, proceeds in a manner that selectively shifts the methyl group at C9 to C10 in concert with the establishment of a sterically hindered allylic cation. The major product isolated from this transformation is formed by trapping of the allylic cation by addition of acetate to C12, rather than termination of the cascade by loss of a proton at C8. While proceeding by way of a unique sequence of bond-forming reactions that begins by oxidative dearomatization, this process achieves what we believe is an unprecedented cucurbitane-to-lanostane transformation, generating a product that contains the characteristic lantostane triad of quaternary centers at C10, C13 and C14 while also delivering a functionalized C-ring.

2.
J Am Chem Soc ; 144(19): 8493-8497, 2022 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-35533213

RESUMEN

The asymmetric de novo synthesis of a cucurbitane natural product, octanorcucurbitacin B, has been accomplished. Cucurbitanes are a family of structurally complex triterpenoids that characteristically contain three stereodefined quaternary centers at ring fusion carbons positioned about their tetracyclic skeletons (at positions 9, 13, and 14). Taking a diversion from the biosynthetic hypothesis for cucurbitane synthesis, the approach established here provides direct access to the cucurbitane skeleton without having to proceed by way of a lanostane. Using a simple chiral enyne as starting material, a sequence of annulative cross-coupling and intramolecular Heck reaction provides a stereodefined polyunsaturated tetracycle possessing the C9 and C13 quaternary centers. This intermediate was converted to octanorcucurbitacin B through a 12-step sequence that features hydroxy-directed Simmons-Smith cyclopropanation, regioselective deconjugative alkylation, and allylic oxidation.


Asunto(s)
Triterpenos , Glicósidos , Oxidación-Reducción , Estereoisomerismo
3.
J Org Chem ; 87(21): 14975-14979, 2022 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-36206482

RESUMEN

Efforts to establish an asymmetric entry to hexanorlanostanes has resulted in a concise synthesis of 7,11-dideoxy-Δ5-lucidadone H from epichlorohydrin. By exploiting metallacycle-mediated annulative cross-coupling (to establish a functionalized hydrindane) and stereoselective formation of the steroidal C9-C10 bond to establish a stereodefined 9-alkyl estrane, 14 subsequent steps have been established to generate a hexanorlanostane system. Key transformations include formal inversion of the C13 quaternary center, oxidative dearomatization/group-selective Wagner-Meerwein rearrangement, and Lewis acid mediated semi-Pinacol rearrangement.


Asunto(s)
Epiclorhidrina , Esteroides , Estereoisomerismo , Oxidación-Reducción
4.
J Org Chem ; 87(5): 3352-3362, 2022 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-35175755

RESUMEN

Tetracyclic terpenoid-derived natural products are a broad class of medically relevant agents that include well-known steroid hormones and related structures, as well as more synthetically challenging congeners such as limonoids, cardenolides, lanostanes, and cucurbitanes, among others. These structurally related compound classes present synthetically disparate challenges based, in part, on the position and stereochemistry of the numerous quaternary carbon centers that are common to their tetracyclic skeletons. While de novo syntheses of such targets have been a topic of great interest for over 50 years, semisynthesis is often how synthetic variants of these natural products are explored as biologically relevant materials and how such agents are further matured as therapeutics. Here, focus was directed at establishing an efficient, stereoselective, and molecularly flexible de novo synthetic approach that could offer what semisynthetic approaches do not. In short, a unified strategy to access common molecular features of these natural product families is described that proceeds in four stages: (1) conversion of epichlorohydrin to stereodefined enynes, (2) metallacycle-mediated annulative cross-coupling to generate highly substituted hydrindanes, (3) tetracycle formation by stereoselective forging of the C9-C10 bond, and (4) group-selective oxidative rearrangement that repositions a quaternary center from C9 to C10. These studies have defined the structural features required for highly stereoselective C9-C10 bond formation and document the generality of this four-stage synthetic strategy to access a range of unique stereodefined systems, many of which bear stereochemistry/substitution/functionality not readily accessible from semisynthesis.


Asunto(s)
Productos Biológicos , Terpenos , Productos Biológicos/química , Carbono/química , Humanos , Oxidación-Reducción , Estereoisomerismo , Esteroides
5.
J Am Chem Soc ; 142(30): 12937-12941, 2020 07 29.
Artículo en Inglés | MEDLINE | ID: mdl-32609506

RESUMEN

A stereoselective entry to ryanoids is described that culminates in the synthesis of anhydroryanodol and thus the formal total synthesis of ryanodol. The pathway described features an annulation reaction conceived to address the uniquely complex and highly oxygenated polycyclic skeleton common to members of this natural product class. It is demonstrated that metallacycle-mediated intramolecular coupling of an alkyne and a 1,3-diketone can proceed with a highly functionalized enyne and with outstanding levels of stereoselection. Furthermore, the first application of this technology in natural product synthesis is demonstrated here. More broadly, the advances described demonstrate the value that programs in natural product total synthesis have in advancing organic chemistry, here through the design and realization of an annulation reaction that accomplishes what previously established reactions do not.


Asunto(s)
Productos Biológicos/síntesis química , Rianodina/análogos & derivados , Productos Biológicos/química , Ciclización , Estructura Molecular , Rianodina/síntesis química , Rianodina/química , Estereoisomerismo
6.
J Am Chem Soc ; 139(36): 12374-12377, 2017 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-28844136

RESUMEN

Densely substituted and highly oxygenated carbocycles are challenging targets for synthesis. In particular, those possessing numerous contiguous, fully substituted carbon atoms (i.e., tertiary alcohols and quaternary centers) are often not accessible in a direct fashion, necessitating the strategic decoupling of ring-formation from the establishment of functionality about the system. Here, we describe an approach to the construction of highly oxygenated mono-, di-, and polycyclic carbocycles from the reaction of disubstituted alkynes with ß- or γ-dicarbonyl systems. These processes embrace a variant of metallacycle-mediated annulation chemistry where initial alkyne-carbonyl coupling is followed by a second, now intramolecular, stereoselective C-C bond-forming event. In addition to revealing the basic reactivity pattern in intermolecular settings, we demonstrate that this class of reactivity is quite powerful in a fully intramolecular context and, when terminated by a stereoselective oxidation process, can be used to generate polycyclic systems containing a fully substituted and highly oxygenated five-membered ring.


Asunto(s)
Alquinos/química , Cetonas/química , Oxígeno/química , Carbono/química , Ciclización , Estereoisomerismo
7.
Isr J Chem ; 57(3-4): 228-238, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28652644

RESUMEN

Alkoxide-directed metallacycle-mediated cross-coupling is a rapidly growing area of reaction methodology in organic chemistry. Over the last decade, developments have resulted in > thirty new and highly selective intermolecular (or "convergent") C-C bond-forming reactions that have established powerful retrosynthetic relationships in stereoselective synthesis. While early studies were focused on developing transformations that forge a single C-C bond by way of a functionalized and unsaturated metallacyclopentane intermediate, recent advances mark the ability to employ this organometallic intermediate in additional stereoselective transformations. Among these more advanced coupling processes, those that embrace the metallacycle in subsequent [4+2] chemistry have resulted in the realization of a number of highly selective annulative cross-coupling reactions that deliver densely functionalized and angularly substituted carbocycles. This review discusses the early development of this chemistry, recent advances in reaction methodology, and shares a glimpse of the power of these processes in natural product synthesis.

8.
J Am Chem Soc ; 138(4): 1150-3, 2016 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-26785051

RESUMEN

An asymmetric approach to the synthesis of neurotrophic seco-prezizaane sesquiterpenes is described that is based on the strategic application of a hydroxyl-directed metallacycle-mediated [2 + 2 + 2] annulation and an intramolecular radical cyclization cascade. Targets prepared are among the most potent members of the natural product class and include (1R,10S)-2-oxo-3,4-dehydroneomajucin, (2S)-hydroxy-3,4-dehydroneomajucin, and (-)-jiadifenin. In addition to representing the first application of the alkoxide-directed metallacycle-mediated hydrindane-forming annulation reaction in natural product synthesis and the first total synthesis of (2S)-hydroxy-3,4-dehydroneomajucin, these pursuits have resulted in the elucidation of a complex radical cascade process for installation of the C5 quaternary center common to the natural product class.


Asunto(s)
Sesquiterpenos/síntesis química , Estructura Molecular , Sesquiterpenos/química
9.
Acc Chem Res ; 48(3): 663-73, 2015 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-25668752

RESUMEN

Convergent C-C bond-forming reactions define the fabric of organic synthesis and, when applied in complex molecule synthesis, can have a profound impact on efficiency by decreasing the longest linear sequence of transformations required to convert simple starting materials to complex targets. Despite their well-appreciated strategic significance, campaigns in natural product synthesis typically embrace only a small suite of reactivity to achieve such bond construction (i.e., nucleophilic addition to polarized π-bonds, nucleophilic substitution, cycloaddition, and metal-catalyzed "cross-coupling"), therefore limiting the sites at which convergent coupling chemistry can be strategically employed. In our opinion, it is far too often that triumphs in the field are defined by chemical sequences that do not address the challenges associated with discovery, development, and production of natural product-inspired agents. We speculated that advancing an area of chemical reactivity not represented in the few well-established strategies for convergent C-C bond formation may lead to powerful new retrosynthetic relationships that could simplify approaches to the syntheses of a variety of different classes of natural products. Our studies ultimately embraced the pursuit of strategies to control the course of metallacycle-mediated "cross-coupling" between substrates containing sites of simple π-unsaturation (ubiquitous functionality in organic chemistry including alkenes, alkynes, allenes, aldehydes, and imines, among others). In just eight years since our initial publication in this area, we have defined over 20 stereoselective intermolecular C-C bond-forming reactions that provide access to structural motifs of relevance for the synthesis of polyketides, fatty acids, alkaloids, and terpenes, while doing so in a direct and stereoselective fashion. These achievements continue to serve as the foundation of my group's activity in natural product and function-oriented synthesis, where our achievements in reaction development are challenged in the context of complex targets. Among our early efforts, we achieved the most concise synthesis of a benzoquinone ansamycin ever described (macbecin I), and moved beyond this achievement to explore the role of our chemistry in function-oriented synthesis targeting the discovery of natural product-inspired Hsp90 inhibitors. These later efforts have led to the discovery of a uniquely selective benzoquinone ansamycin-inspired Hsp90 inhibitor that lacks the problematic quinone present in the natural series. This achievement was made possible by a concise chemical synthesis pathway that had at its core the application of metallacycle-mediated cross-coupling chemistry.


Asunto(s)
Alcaloides/síntesis química , Productos Biológicos/síntesis química , Ácidos Grasos/síntesis química , Policétidos/síntesis química , Terpenos/síntesis química , Alcaloides/química , Productos Biológicos/química , Ácidos Grasos/química , Conformación Molecular , Policétidos/química , Terpenos/química
10.
Tetrahedron Lett ; 57(34): 3848-3850, 2016 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-27713588

RESUMEN

Investigation of titanium-centered metallacycle-mediated cross-coupling between unsymmetrical internal alkynes has led to the discovery that TMSCl significantly accelerates the C-C bond forming event. We report a collection of results that compare the efficiency of this reaction employing Ti(Oi-Pr)4/2n-BuLi in PhMe with and without TMSCl, demonstrating in every case that the presence of TMSCl has a profound impact on efficiency. While relevant in the context of developing this fundamental bond-forming process as an entry to more complex organometallic transformations, these modified reaction conditions allow coupling processes to be run at > 10 times the concentrations previously possible [in 2.4M n-BuLi (hexanes)], without the requirement of additional solvent. Finally, we demonstrate the effectiveness of these modified reaction conditions for the annulative cross-coupling between TMS-alkynes and 1,6-enynes leading to the formation of angularly substituted hydrindanes with, now well appreciated, high levels of regio- and stereoselection.

11.
Angew Chem Int Ed Engl ; 55(42): 13099-13103, 2016 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-27634059

RESUMEN

A convergent coupling reaction is described that enables the stereoselective construction of angularly substituted trans-fused decalins from acyclic precursors. The process builds on our alkoxide-directed titanium-mediated alkyne-alkyne coupling and employs a 1,7-enyne coupling partner. Overall, the reaction is thought to proceed through initial formation of a tetrasusbstituted metallacyclopentadiene, stereoselective intramolecular [4+2] cycloaddition, elimination, isomerization, and regio- and stereoselective protonation. Distinct from our early studies directed at the synthesis of trans-fused hydrindanes, the current annulative coupling reveals an important effect of TMSCl in controlling the final protonation-the event that establishes the stereochemistry of the ring fusion.


Asunto(s)
Ciclopentanos/química , Naftalenos/síntesis química , Compuestos Organometálicos/química , Titanio/química , Ciclización , Reacción de Cicloadición , Estructura Molecular , Naftalenos/química , Estereoisomerismo
12.
J Am Chem Soc ; 137(20): 6624-8, 2015 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-25930967

RESUMEN

Bridged bicyclic metallacyclopentenes generated from the [4 + 2] cycloaddition of metallacyclopentadienes with alkenes have been proposed as reactive intermediates in the course of [2 + 2 + 2] annulation reactions. Recently a collection of alkoxide-directed Ti-mediated [2 + 2 + 2] annulation reactions have been discovered for the synthesis of densely functionalized hydrindanes, where the bridged bicyclic metallacyclopentenes from intramolecular [4 + 2] were treated as fleeting intermediates en route to cyclohexadiene products formed by formal cheletropic extrusion of Ti(Oi-Pr)2. In studies aimed at understanding the course of these organometallic cascade reactions it was later discovered that these bridged bicyclic intermediates can be trapped by various elimination processes. Here, we have realized metallacycle-mediated annulation reactions for the assembly of angularly substituted decalins--structural motifs that are ubiquitous in natural products and molecules of pharmaceutical relevance. In addition to defining the basic annulation reaction we have discovered a surprising stability associated with the complex organometallic intermediates generated in the course of this coupling process and document here the ability to control the fate of such species. Ligand-induced cheletropic extrusion of the titanium center delivers cyclohexadiene-containing products, while several distinct protonation events have been identified to realize polycyclic products that contain three new stereocenters (one of which is the angular quaternary center that is a hallmark of alkoxide-directed titanium-mediated [2 + 2 + 2] annulation reactions). Examples of this metallacycle-mediated annulation reaction are provided to demonstrate that a range of stereodefined fused bicyclo[4.4.0]decanes are accessible, including those that contain aromatic and aliphatic substituents, and an empirical model is presented to accompany the observations made.


Asunto(s)
Compuestos Bicíclicos con Puentes/química , Ciclopentanos/química , Naftalenos/química , Naftalenos/síntesis química , Compuestos Organometálicos/química , Titanio/química , Compuestos Bicíclicos con Puentes/síntesis química , Ciclización , Estructura Molecular , Compuestos Organometálicos/síntesis química
13.
Tetrahedron Lett ; 56(23): 3357-3359, 2015 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-26097265

RESUMEN

LiOOt-Bu is an effective oxidant for converting the penultimate organometallic intermediate generated in a titanium alkoxide-mediated [2+2+2] reaction cascade to an allylic alcohol. Oxidation of the presumed allylic titanium species is highly regioselective, providing direct access to substituted hydroindanes containing a primary allylic alcohol. In addition to demonstrating the feasibility of this oxidation process, we document the ability to convert the primary allylic alcohol products to angularly substituted cis-fused hydroindanes.

14.
J Am Chem Soc ; 136(23): 8209-12, 2014 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-24856045

RESUMEN

Angularly substituted trans-fused hydroindanes are now accessible by the direct and convergent union of trimethylsilyl (TMS)-alkynes with 4-hydroxy-1,6-enynes by a process that forges three C-C bonds, one C-H bond, and two new stereocenters. The annulation is proposed to proceed by initial formation of a Ti-alkyne complex (with a TMS-alkyne) followed by regioselective alkoxide-directed coupling with the enyne, stereoselective intramolecular cycloaddition, elimination of phenoxide, 1,3-metallotropic shift, and stereoselective protonation of the penultimate allylic organometallic intermediate. Several examples are given to demonstrate the compatibility of this reaction with substrates bearing aromatic and aliphatic substituents, and an empirical model is presented to accompany the stereochemical observations.


Asunto(s)
Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/síntesis química , Hidrocarburos Acíclicos/química , Alquinos/química , Ciclización , Reacción de Cicloadición , Estructura Molecular , Estereoisomerismo , Compuestos de Trimetilsililo/química
15.
Drug Metab Dispos ; 42(3): 334-42, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24335391

RESUMEN

Almost half of prescription medications are metabolized by cytochrome P450 3A4 and 3A5. CYP3A4 and 3A5 have significant substrate overlap, and there is currently no way to selectively monitor the activity of these two enzymes, which has led to the erroneous habit of attributing the cumulative activity to CYP3A4. While CYP3A4 expression is ubiquitous, CYP3A5 expression is polymorphic, with large individual differences in CYP3A5 expression level. The CYP3A5 genotype has been shown to alter the pharmacokinetics of drugs in clinical trials. We report the first tool compound capable of determining CYP3A5 activity in biologic samples containing both enzymes. Oxidation of T-5 by CYP3A5 yields an N-oxide metabolite that is over 100-fold selective over CYP3A4. Formation of T-5 N-oxide highly correlates with the CYP3A5 genotype and CYP3A5 expression levels in human liver microsomes and human hepatocytes.


Asunto(s)
Óxidos N-Cíclicos/metabolismo , Citocromo P-450 CYP3A/metabolismo , Isoquinolinas/farmacología , Piridinas/farmacología , Biotransformación , Catálisis , Células Cultivadas , Cromatografía Líquida de Alta Presión , Citocromo P-450 CYP3A/genética , Inhibidores del Citocromo P-450 CYP3A , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Femenino , Genotipo , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Humanos , Isoquinolinas/metabolismo , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Oxidación-Reducción , Piridinas/metabolismo , Proteínas Recombinantes , Especificidad por Sustrato , Espectrometría de Masas en Tándem
17.
Org Lett ; 26(5): 1073-1077, 2024 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-38277646

RESUMEN

Asymmetric de novo construction of limonoids remains a challenging problem in stereoselective synthesis due to the diverse and complex structures associated with this class of natural products. Here, a unique synthetic pathway to an "intact" limonoid system is described. The synthetic route is based on exploiting an oxidative rearrangement reaction of a densely functionalized late-stage intermediate to simultaneously establish the stereodefined C10 quaternary center and an allylic acetate at C12. This is a unique example of a complex rearrangement reaction that proceeds on a system whose presumed intermediate allyl cation is highly hindered and lacks neighboring protons that are otherwise required for cation termination.


Asunto(s)
Limoninas , Cationes , Limoninas/síntesis química , Estereoisomerismo
18.
Org Lett ; 26(15): 3054-3059, 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38557107

RESUMEN

While pentacyclic triterpenoids have a rich history in chemistry and biology, the challenges associated with their asymmetric synthesis contribute to the current reality that medicinal exploration in the area is largely constrained to natural product derivatization. To address this deficiency, a function-oriented synthesis of pentacyclic triterpenoids was pursued. Overall, we report a divergent synthesis of 26-norgermanicol and 26-norlupeol and we have identified a new class of androgen receptor antagonist that is ∼6× more potent than lupeol.


Asunto(s)
Productos Biológicos , Triterpenos , Triterpenos Pentacíclicos , Triterpenos/farmacología , Antagonistas de Receptores Androgénicos/farmacología , Productos Biológicos/farmacología
19.
ACS Cent Sci ; 10(2): 477-486, 2024 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-38435518

RESUMEN

Fatty acids play important signaling roles in biology, albeit typically lacking potency or selectivity, due to their substantial conformational flexibility. While being recognized as having properties of potentially great value as therapeutics, it is often the case that the functionally relevant conformation of the natural fatty acid is not known, thereby complicating efforts to develop natural-product-inspired ligands that have similar functional properties along with enhanced potency and selectivity profiles. In other words, without structural information associated with a particular functional relationship and the hopelessly unbiased conformational preferences of the endogenous ligand, one is molecularly ill-informed regarding the precise ligand-receptor interactions that play a role in driving the biological activity of interest. To address this problem, a molecular strategy to query the relevance of distinct subpopulations of fatty acid conformers has been established through "conformational profiling", a process whereby a unique collection of chiral and conformationally constrained fatty acids is employed to deconvolute beneficial structural features that impart natural-product-inspired function. Using oleic acid as an example because it is known to engage a variety of receptors, including GPR40, GPR120, and TLX, a 24-membered collection of mimetics was designed and synthesized. It was then demonstrated that this collection contained members that have enhanced potency and selectivity profiles, with some being clearly biased for engagement of the GPCRs GPR40 and GPR120 while others were identified as potent and selective modulators of the nuclear receptor TLX. A chemical synthesis strategy that exploited the power of modern technology for stereoselective synthesis was critical to achieving success, establishing a common sequence of bond-forming reactions to access a disparate collection of chiral mimetics, whose conformational preferences are impacted by the nature of stereodefined moieties differentially positioned about the C18 skeleton of the parent fatty acid. Overall, this study establishes a foundation to fuel future programs aimed at developing natural-product-inspired fatty acid mimetics as valuable tools in chemical biology and potential therapeutic leads.

20.
J Med Chem ; 67(18): 16185-16194, 2024 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-39240657

RESUMEN

Natural products are widely recognized as valuable starting points for the development of therapeutics, with synthetic tetracyclic triterpenoids (e.g., steroids) being the most well represented among the drugs approved by the Food and Drug Administration. Here, recently developed synthetic tools for concise, asymmetric, and convergent construction of steroidal systems are leveraged to drive a program aimed at identifying novel glucocorticoid receptor (GR) modulators. While glucocorticoids have been extensively used as anti-inflammatory agents, they are plagued by severe side effects that include bone loss, muscle wasting, and metabolic disease. Ultimately, a program targeting the unnatural enantiomers of estranes (ent-estranes) that are practically inaccessible from natural product derivatization (semisynthesis) has resulted in the identification of a new class of potent dissociated GR modulators. We identify several leads with >99% efficacy as antagonists of GR trans-activation (potency within 10-fold of that of mifepristone) and further characterize examples that also inhibit release of pro-inflammatory cytokines IL-6 and TNF-α.


Asunto(s)
Productos Biológicos , Interleucina-6 , Receptores de Glucocorticoides , Factor de Necrosis Tumoral alfa , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/antagonistas & inhibidores , Productos Biológicos/química , Productos Biológicos/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Interleucina-6/metabolismo , Interleucina-6/antagonistas & inhibidores , Estereoisomerismo , Humanos , Animales , Relación Estructura-Actividad , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/química
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