RESUMEN
The synthesis of eribulin mesylate from microgram to multi-gram scale is described in this Highlight. Key coupling reactions include formation of the C30a to C1 carbon-carbon bond and macrocyclic ring closure through an intramolecular Nozaki-Hiyama-Kishi reaction.
Asunto(s)
Furanos/síntesis química , Cetonas/síntesis química , Furanos/química , Cetonas/química , Estructura Molecular , EstereoisomerismoRESUMEN
As an anti-inflammatory strategy, MAPK-activated protein kinase-2 (MK2) inhibition can potentially avoid the clinical failures seen for direct p38 inhibitors, especially tachyphylaxis. CC-99677, a selective targeted covalent MK2 inhibitor, employs a rare chloropyrimidine that bonds to the sulfur of cysteine 140 in the ATP binding site via a nucleophilic aromatic substitutions (SNAr) mechanism. This irreversible mechanism translates biochemical potency to cells shown by potent inhibition of heat shock protein 27 (HSP27) phosphorylation in LPS-activated monocytic THP-1 cells. The cytokine inhibitory profile of CC-99677 differentiates it from known p38 inhibitors, potentially suppressing a p38 pathway inflammatory response while avoiding tachyphylaxis. Dosed orally, CC-99677 is efficacious in a rat model of ankylosing spondylitis. Single doses, 3 to 400 mg, in healthy human volunteers show linear pharmacokinetics and apparent sustained tumor necrosis factor-α inhibition, with a favorable safety profile. These results support further development of CC-99677 for autoimmune diseases like ankylosing spondylitis.
Asunto(s)
Enfermedades Autoinmunes , Espondilitis Anquilosante , Adenosina Trifosfato , Animales , Antiinflamatorios , Enfermedades Autoinmunes/tratamiento farmacológico , Cisteína , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Lipopolisacáridos , Proteínas Serina-Treonina Quinasas , Ratas , Azufre , Factor de Necrosis Tumoral alfa , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Eribulin mesylate (Halaven™), a totally synthetic analog of the marine polyether macrolide halichondrin B, has recently been approved in the United States as a treatment for breast cancer. It is also currently under regulatory review in Japan and the European Union. Our continuing medicinal chemistry efforts on this scaffold have focused on oral bioavailability, brain penetration and efficacy against multidrug resistant (MDR) tumors by lowering the susceptibility of these compounds to P-glycoprotein (P-gp)-mediated drug efflux. Replacement of the 1,2-amino alcohol C32 side chain of eribulin with fragments neutral at physiologic pH led to the identification of analogs with significantly lower P-gp susceptibility. The analogs maintained low- to sub-nM potency in vitro against both sensitive and MDR cell lines. Within this series, increasing lipophilicity generally led to decreased P-gp susceptibility. In addition to potency in cell culture, these compounds showed in vivo activity in mouse xenograft models.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/efectos de los fármacos , Antineoplásicos/química , Furanos/química , Cetonas/química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Furanos/farmacocinética , Furanos/farmacología , Humanos , Cetonas/farmacocinética , Cetonas/farmacología , Ratones , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Novel second generation analogs of eribulin mesylate, a tubulin agent recently approved for the treatment of breast cancer, are reported. Our recent efforts have focused on expanding the target indications for this class of compounds to other tumor types. Herein, we describe the design, synthesis and evaluation of eribulin analogs active against brain tumor cell lines in vitro and corresponding brain tumor models in mice. Attenuation of basicity of the amino group(s) in the C32 side-chain region led to compounds with lower susceptibility to P-gp mediated drug efflux, allowing these compounds to permeate through the blood-brain barrier. In preclinical in vivo studies, these compounds showed significantly higher levels in the brain and cerebrospinal fluid as compared to eribulin. In addition, analogs within this series showed antitumor activity in an orthotopic murine model of human glioblastoma.
Asunto(s)
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Furanos/farmacocinética , Furanos/uso terapéutico , Cetonas/farmacocinética , Cetonas/uso terapéutico , Animales , Barrera Hematoencefálica , Línea Celular Tumoral , Modelos Animales de Enfermedad , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos BALB CRESUMEN
Eribulin mesylate is a newly approved treatment for locally advanced and metastatic breast cancer. We targeted oral bioavailability and efficacy against multidrug resistant (MDR) tumors for further work. The design, synthesis and evaluation of novel amine-containing analogs of eribulin mesylate are described in this part. Attenuation of basicity of the amino group(s) in the C32 side-chain region led to compounds with low susceptibility to PgP-mediated drug efflux. These compounds were active against MDR tumor cell lines in vitro and in xenograft models in vivo, in addition to being orally bioavailable.
Asunto(s)
Antineoplásicos/farmacología , Furanos/farmacología , Cetonas/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Resistencia a Antineoplásicos , Furanos/administración & dosificación , Furanos/farmacocinética , Humanos , Cetonas/administración & dosificación , Cetonas/farmacocinética , Ratones , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Eribulin (E7389), a mechanistically unique microtubule inhibitor in phase III clinical trials for cancer, exhibits superior efficacy in vivo relative to the more potent compound ER-076349, a fact not explained by different pharmacokinetic properties. A cell-based pharmacodynamic explanation was suggested by observations that mitotic blockade induced by eribulin, but not ER-076349, is irreversible as measured by a flow cytometric mitotic block reversibility assay employing full dose/response treatment. Cell viability 5 days after drug washout established relationships between mitotic block reversibility and long-term cell survival. Similar results occurred in U937, Jurkat, HL-60, and HeLa cells, ruling out cell type-specific effects. Studies with other tubulin agents suggest that mitotic block reversibility is a quantifiable, compound-specific characteristic of antimitotic agents in general. Bcl-2 phosphorylation patterns parallel eribulin and ER-076349 mitotic block reversibility patterns, suggesting persistent Bcl-2 phosphorylation contributes to long-term cell-viability loss after eribulin's irreversible blockade. Drug uptake and washout/retention studies show that [3H]eribulin accumulates to lower intracellular levels than [3H]ER-076349, yet is retained longer and at higher levels. Similar findings occurred with irreversible vincristine and reversible vinblastine, pointing to persistent cellular retention as a component of irreversibility. Our results suggest that eribulin's in vivo superiority derives from its ability to induce irreversible mitotic blockade, which appears related to persistent drug retention and sustained Bcl-2 phosphorylation. More broadly, our results suggest that compound-specific reversibility characteristics of antimitotic agents contribute to interactions between cell-based pharmacodynamics and in vivo pharmacokinetics that define antitumor efficacy under intermittent dosing conditions.
Asunto(s)
Antimitóticos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Furanos/farmacología , Cetonas/farmacología , Mitosis/efectos de los fármacos , Antimitóticos/administración & dosificación , Esquema de Medicación , Interacciones Farmacológicas , Furanos/administración & dosificación , Furanos/farmacocinética , Células HL-60 , Células HeLa , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Células Jurkat , Cetonas/administración & dosificación , Cetonas/farmacocinética , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Tritio , Células U937RESUMEN
E7974 is a synthetic analogue of the marine sponge natural product hemiasterlin. Here, we show that E7974, such as parental hemiasterlin, acts via a tubulin-based antimitotic mechanism. E7974 inhibits polymerization of purified tubulin in vitro with IC(50) values similar to those of vinblastine. In cultured human cancer cells, E7974 induces G(2)-M arrest and marked disruption of mitotic spindle formation characteristic of tubulin-targeted anticancer drugs. Extensive hypodiploid cell populations are seen in E7974-treated cells, indicating initiation of apoptosis after prolonged G(2)-M blockage. Consistent with this observation, E7974 induces caspase-3 activation and poly ADP ribose polymerase cleavage, typical biochemical markers of apoptosis. Only a short cellular exposure to E7974 is sufficient to induce maximum mitotic arrest, suggesting that E7974's antitumor effects in vivo may persist even after blood levels of the drug decrease after drug administration. Interactions of E7974 with purified tubulin were investigated using two synthetic tritiated photoaffinity analogues incorporating a benzophenone photoaffinity moiety at two different positions of the E7974 scaffold. Both analogues preferentially photolabeled alpha-tubulin, although minor binding to beta-tubulin was also detected. E7974 thus seems to share a unique, predominantly alpha-tubulin-targeted mechanism with other hemiasterlin-based compounds, suggesting that, unlike many tubulin-targeted natural products and related drugs, the hemiasterlins evolved to mainly target alpha-tubulin, not beta-tubulin subunits.
Asunto(s)
Antimitóticos/farmacología , Antineoplásicos/farmacología , Productos Biológicos/química , Oligopéptidos/química , Oligopéptidos/farmacología , Piperidinas/farmacología , Poríferos/química , Agua de Mar , Tubulina (Proteína)/metabolismo , Animales , Antimitóticos/química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Productos Biológicos/farmacología , Bovinos , Línea Celular Tumoral , Fase G2/efectos de los fármacos , Humanos , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Mitosis/efectos de los fármacos , Etiquetas de Fotoafinidad , Piperidinas/química , Huso Acromático/efectos de los fármacos , Huso Acromático/metabolismo , Vinblastina/farmacologíaRESUMEN
A structurally simplified macrolactone analogue of halichondrin B was identified that retains the potent cell growth inhibitory activity of the natural product in vitro.
Asunto(s)
Éteres Cíclicos/química , Éteres Cíclicos/farmacología , Lactonas/química , Lactonas/farmacología , Animales , División Celular/efectos de los fármacos , Línea Celular Tumoral , Éteres Cíclicos/síntesis química , Humanos , Lactonas/síntesis química , Macrólidos , Conformación Molecular , Relación Estructura-ActividadRESUMEN
Structurally simplified macrocyclic ketone analogues of halichondrin B were prepared by total synthesis and found to retain the potent cell growth inhibitory activity in vitro, stability in mouse serum, and in vivo efficacy of the natural product.