RESUMEN
We report that Ru(bpz)32+ is an excellent sensitizer for the photooxygenation of aryl cyclopropanes upon irradiation with visible light. The effectiveness of this photocatalyst enables the synthesis of a range of five-membered endoperoxides in excellent yield with quite low (0.5 mol%) catalyst loadings even when standard household light sources are utilized.
RESUMEN
The C(5)-hydroperoxyenals (C(5)-HPALDs) are a newly-recognized class of multi-functional hydrocarbons produced during the hydroxyl radical (OH)-initiated oxidation of isoprene. Recent theoretical calculations suggest that fast photolysis of these compounds may be an important OH source in high-isoprene, low-NO regions. We report experimental constraints for key parameters of photolysis, OH reaction and ozone reaction of these compounds as derived from a closely-related, custom-synthesized C(6)-HPALD. The photolysis quantum yield is 1.0 ± 0.4 over the range 300-400 nm, assuming an absorption cross section equal to the average of those measured for several analogous enals. The yield of OH from photolysis was determined as 1.0 ± 0.8. The OH reaction rate constant is (5.1 ± 1.8) × 10(-11) cm(3) molecule(-1) s(-1) at 296 K. The ozone reaction rate constant is (1.2 ± 0.2) × 10(-18) cm(3) molecule(-1) s(-1) at 296 K. These results are consistent with previous first-principles estimates, though the nature and fate of secondary oxidation products remains uncertain. Incorporation of C(5)-HPALD chemistry with the above parameters in a 0-D box model, along with experimentally-constrained rates for C(5)-HPALD production from isomerization of first-generation isoprene hydroxyperoxy radicals, is found to enhance modeled OH concentrations by 5-16% relative to the traditional isoprene oxidation mechanism for the chemical regimes of recent observational studies in rural and remote regions. This enhancement in OH will increase if C(5)-HPALD photo-oxidation products also photolyze to yield additional OH or if the C(5)-HPALD production rate is faster than has been observed.
RESUMEN
The synthesis and biological evaluation of potent and selective anaplastic lymphoma kinase (ALK) inhibitors from a novel class of 2,4-diaminopyrimidines, incorporating 2,3,4,5-tetrahydro-benzo[d]azepine fragments, is described. An orally bioavailable analogue (18) that displayed antitumor efficacy in ALCL xenograft models in mice was identified and extensively profiled.
Asunto(s)
Benzazepinas/química , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/química , Administración Oral , Quinasa de Linfoma Anaplásico , Animales , Benzazepinas/farmacocinética , Benzazepinas/uso terapéutico , Ratones , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Proteínas Tirosina Quinasas Receptoras , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Brevetoxin A is a decacyclic ladder toxin that possesses 5-, 6-, 7-, 8-, and 9-membered oxacycles, as well as 22 tetrahedral stereocenters. Herein, we describe a unified approach to the B, E, G, and J rings based upon a ring-closing metathesis strategy from the corresponding dienes. The enolate technologies developed in our laboratory allowed access to the precursor acyclic dienes for the B, E, and G medium-ring ethers. The strategies developed for the syntheses of these four monocycles ultimately provided multigram quantities of each of the rings, supporting our efforts toward the completion of a convergent synthesis of brevetoxin A.
Asunto(s)
Éteres/síntesis química , Toxinas Marinas/síntesis química , Oxocinas/síntesis química , Alquilación , Ciclización , Éteres/química , Toxinas Marinas/química , Estructura Molecular , Oxocinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
[reaction: see text] A stereoselective synthesis of the GHIJ fragment of brevetoxin A utilizing a convergent assembly strategy is described. Glycolate alkylation, ring-closing metathesis, and Hosomi-Sakurai reactions were central operations in the construction of the G ring and J ring subunits, which were united through a Horner-Wadsworth-Emmons coupling. Subsequent dehydrative cyclization produced an endocyclic enol ether that was further elaborated to the tetracyclic GHIJ fragment of brevetoxin A.
Asunto(s)
Toxinas Marinas/síntesis química , Oxocinas/síntesis química , Toxinas Marinas/química , Estructura Molecular , Oxocinas/química , EstereoisomerismoRESUMEN
Structurally novel endoperoxides can be sythesized by the photocatalytic cyclotrimerization of bis(styrene) substrates with molecular oxygen. The optimal catalyst for this process is Ru(bpz)(3)(2+), which is a markedly more efficient catalyst for these photooxygention reactions than conventional organic photosensitizers. The 1,2-dioxolane products are amenable to synthetic manipulation and can be easily processed to 1,4-diols and γ-hydroxyketones. An initial screen of the biological activity of these compounds reveals promising inhibition of cancer cell growth.
Asunto(s)
Alcoholes/síntesis química , Antineoplásicos/síntesis química , Peróxidos/síntesis química , Alcoholes/química , Antineoplásicos/química , Antineoplásicos/farmacología , Catálisis , Ciclización , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Oxígeno/química , Peróxidos/química , Peróxidos/farmacología , Procesos FotoquímicosRESUMEN
A total synthesis of brevetoxin A is reported. Two tetracyclic coupling partners, prepared from previously reported advanced fragments, were effectively united via a Horner-Wittig olefination. The resulting octacycle was progressed to substrates that were explored for reductive etherification, the success of which led to a penultimate tetraol intermediate. The tetraol was converted to the natural product through an expeditious selective oxidative process followed by methylenation.