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 , EstereoisomerismoRESUMEN
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/químicaRESUMEN
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 TándemAsunto(s)
Benzoquinonas/química , Lactamas Macrocíclicas/síntesis química , Rifabutina/química , Ácido Shikímico/química , Sitios de Unión , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Proteínas HSP90 de Choque Térmico/química , Proteínas HSP90 de Choque Térmico/metabolismo , Células HeLa , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/toxicidad , Células MCF-7 , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/metabolismo , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Rifabutina/síntesis química , Rifabutina/toxicidad , EstereoisomerismoRESUMEN
We report a concise and convergent laboratory synthesis of the rare marine natural product lehualide B that has led to the discovery that (1) this compound has low nanomolar activity against human multiple myeloma cells and (2) the anticancer effects of lehualide B and its analogues are selective (i.e., they are approximately 2-3 orders of magnitude less toxic to human breast cancer cells). Synthetic lehualide B is shown to be an effective inhibitor of complex I of the mitochondrial electron transport chain, with potency similar to that observed for the terrestrial natural products piericidin A1 and rotenone, an observation that led to the discovery that piericidin A1 is also selectively cytotoxic toward human multiple myeloma cells. Interestingly, synthetic derivatives of lehualide B that resemble verticipyrone (an established complex I inhibitor composed of a γ-pyrone and a simple monounsaturated hydrophobic chain) lack the potent antimyeloma activity of the natural product. Finally, the synthesis and evaluation of a collection of lehualide-inspired analogues led to the elucidation of structure-activity relationships for this rare natural product that established important roles for the substituted γ-pyrone headgroup and the skipped polyene side chain.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Productos Biológicos/química , Productos Biológicos/farmacología , Mieloma Múltiple/tratamiento farmacológico , Pironas/química , Pironas/farmacología , Antineoplásicos/síntesis química , Productos Biológicos/síntesis química , Línea Celular Tumoral , Humanos , Pironas/síntesis químicaRESUMEN
A convergent synthesis of benzoquinone ansamycin analogs is described that proceeds by a sequence of metallacycle-mediated alkyne-alkyne coupling, followed by site- and stereoselective dihydroxylation and global carbamate formation. These studies have led to (1) validation of alkyne-alkyne coupling to produce geldanamycin analogs that lack the problematic quinone, (2) the discovery that C6-C7 bis-carbamate functionality is compatible with Hsp90 inhibition, and (3) the identification of 1 as a nonquinone geldanamycin-inspired paralog-selective Hsp90 inhibitor.
Asunto(s)
Benzoquinonas/química , Productos Biológicos/síntesis química , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Lactamas Macrocíclicas/síntesis química , Productos Biológicos/farmacología , Lactamas Macrocíclicas/farmacología , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The total synthesis of anticancer marine natural product lehualide B is described. Overall, the synthesis proceeds in just eight steps from a simple gamma-pyrone, does not require the use of protecting groups, and delivers each nonconjugated trisubstituted alkene with high levels of stereoselection. The challenging C12-C16 bis-trisubstituted 1,4-diene was installed with a complex reductive cross-coupling reaction between a preformed Ti-alkyne complex and a pyrone-containing allylic alcohol.
Asunto(s)
Alquinos/química , Propanoles/química , Pironas/síntesis química , Estructura Molecular , Oxidación-Reducción , Pironas/química , EstereoisomerismoRESUMEN
The first total synthesis of tovophyllin B (2), an antimicrobial xanthone derived from mangosteen, has been accomplished through a convergent strategy from building blocks 6 and 7 involving lithium-mediated coupling, dehydrative cyclization, and 6π electrocyclization as key steps.