RESUMEN
A variety of substituted pentadiynols, -diynals, and -diynones have been prepared en route to precursors to dialkynyl carbenes (R(1)-C≡C-C-C≡C-R(2)). In light of the marginal stability associated with these simple systems, several strategies were required to assemble the carbon backbones. The requisite five-carbon skeletons were prepared using 4 + 1, 3 + 2, 2 + 2 + 1, and 2 + 1 + 1 + 1 coupling methodologies. The Dess-Martin periodinane serves as an excellent method for the oxidation of pentadiynols to diynals and diynones, although many of the oxidized products are sufficiently reactive that they were not isolated; rather, they were generated in situ and intercepted with nucleophiles such as tosylhydrazide or trisylhydrazide. The hydrazone derivatives are generally reliable precursors to diazo compounds and carbenes, although cyclization of the hydrazone to afford a pyrazole can be a complicating factor in certain instances.
Asunto(s)
Alcoholes/síntesis química , Alquinos/química , Compuestos Azo/síntesis química , Hidrazonas/síntesis química , Cetonas/síntesis química , Metano/análogos & derivados , Alcoholes/química , Compuestos Azo/química , Hidrazonas/química , Cetonas/química , Metano/química , Estructura Molecular , EstereoisomerismoRESUMEN
The phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascade is an important component of the insulin signaling in normal tissues leading to glucose uptake and homeostasis and for cell survival signaling in cancer cells. Hyperglycemia is an on-target side effect of many inhibitors of PI3K/Akt signaling including the specific PI3K inhibitor PX-866. The peroxisome proliferator-activated receptor gamma agonist pioglitazone, used to treat type 2 diabetes, prevents a decrease in glucose tolerance caused by acute administration of PX-866. Our studies have shown that pioglitazone does not inhibit the antitumor activity of PX-866 in A-549 non-small cell lung cancer and HT-29 colon cancer xenografts. In vitro studies also showed that pioglitazone increases 2-[1-(14)C]deoxy-D-glucose uptake in L-6 muscle cells and prevents inhibition of 2-deoxyglucose uptake by PX-866. Neither pioglitazone nor PX-866 had an effect on 2-deoxyglucose uptake in A-549 lung cancer cells. In vivo imaging studies using [18F]2-deoxyglucose (FDG) positron emission tomography showed that pioglitazone increases FDG accumulation by normal tissue but does not significantly alter FDG uptake by A-549 xenografts. Thus, peroxisome proliferator-activated receptor gamma agonists may be useful in overcoming the increase in blood glucose caused by inhibitors of PI3K signaling by preventing the inhibition of normal tissue insulin-mediated glucose uptake without affecting antitumor activity.
Asunto(s)
Gonanos/farmacología , Hiperglucemia/enzimología , Hiperglucemia/prevención & control , PPAR gamma/agonistas , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Tiazolidinedionas/farmacología , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Progresión de la Enfermedad , Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Glucosa-6-Fosfato/análogos & derivados , Glucosa-6-Fosfato/metabolismo , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/patología , PPAR gamma/metabolismo , Pioglitazona , Tiazolidinedionas/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The synthesis of a thiophene-containing analogue of halenaquinone was realized. Key steps include an alkynyl ketone-benzocyclobutane Diels-Alder reaction to construct the C,D-ring naphthalene subunit, a Heck cyclization to form the quaternary carbon, and a ring closing metathesis to add the A-ring.
Asunto(s)
Quinonas/química , Quinonas/síntesis química , Tiofenos/química , Animales , Ciclización , Estructura Molecular , Poríferos/química , EstereoisomerismoRESUMEN
We have developed biologically stable semisynthetic viridins as inhibitors of phosphoinositide (PtdIns)-3-kinases. The most active compound was PX-866 (acetic acid (1S,4E,10R,11R,13S,14R)-[4-diallylaminomethylene-6-hydroxy-1-methoxymethyl-10,13-dimethyl-3,7,17-trioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester), which inhibited purified PtdIns-3-kinase with an IC50 of 0.1 nmol/L and PtdIns-3-kinase signaling measured by phospho-Ser473-Akt levels in HT-29 colon cancer cells with an IC50 of 20 nmol/L. PX-866 administered to mice at 10 mg/kg inhibited phospho-Ser473-Akt in HT-29 colon tumor xenografts up to 80% with recovery taking >48 hours after p.o. administration but more rapidly after i.v. or i.p. administration. PX-866 was eliminated from mouse plasma with a half-life of 18 minutes and a clearance of 360 mL/min/kg following i.v. administration and, when administered i.p. or p.o., showed first-pass metabolism with sequential N-deallylation. Synthetic standards of the N-deallylated metabolites of PX-866 inhibited PtdIns-3-kinase at low nanomolar per liter concentrations. PX-866 exhibited in vivo antitumor activity against s.c. OvCar-3 human ovarian cancer and A-549 human lung cancer xenografts in immunodeficient mice with log cell kills up to 1.2. PX-866 also increased the antitumor activity of cisplatin against A-549 xenografts and radiation treatment against OvCar-3 xenografts. The results show that PX-866 is a biologically stable broad-spectrum PtdIns-3-kinase inhibitor with good pharmacokinetics that causes prolonged inhibition of PtdIns-3-kinase signaling in human tumor xenografts. PX-866 exhibits single agent in vivo antitumor activity and increases the antitumor effects of cisplatin and radiation treatment.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Gonanos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Androstadienos/sangre , Androstadienos/farmacología , Androstadienos/toxicidad , Androstenos/sangre , Androstenos/farmacología , Androstenos/toxicidad , Animales , Anticuerpos Fosfo-Específicos/inmunología , Antineoplásicos/química , Bacteriocinas/sangre , Bacteriocinas/farmacología , Bacteriocinas/toxicidad , Línea Celular Tumoral , Cisplatino/farmacología , Neoplasias del Colon/enzimología , Inhibidores Enzimáticos/química , Femenino , Gonanos/química , Humanos , Neoplasias Pulmonares/enzimología , Ratones , Ratones SCID , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/radioterapia , Proteínas Serina-Treonina Quinasas/análisis , Proteínas Serina-Treonina Quinasas/inmunología , Proteínas Proto-Oncogénicas/análisis , Proteínas Proto-Oncogénicas/inmunología , Proteínas Proto-Oncogénicas c-akt , Wortmanina , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
1-Diazo-2,4-pentadiyne (6a), along with both monodeuterio isotopomers 6b and 6c, has been synthesized via a route that proceeds through diacetylene, 2,4-pentadiynal, and 2,4-pentadiynal tosylhydrazone. Photolysis of diazo compounds 6a-c (lambda > 444 nm; Ar or N2, 10 K) generates triplet carbenes HC5H (1) and HC5D (1-d), which have been characterized by IR, EPR, and UV/vis spectroscopy. Although many resonance structures contribute to the resonance hybrid for this highly unsaturated carbon-chain molecule, experiment and theory reveal that the structure is best depicted in terms of the dominant resonance contributor of penta-1,4-diyn-3-ylidene (diethynylcarbene, H-C[triple bond]C-:C-C[triple bond]C-H). Theory predicts an axially symmetric (D(infinity h)) structure and a triplet electronic ground state for 1 (CCSD(T)/ANO). Experimental IR frequencies and isotope shifts are in good agreement with computed values. The triplet EPR spectrum of 1 (absolute value(D/hc) = 0.6157 cm(-1), absolute value(E/hc) = 0.0006 cm(-1)) is consistent with an axially symmetric structure, and the Curie law behavior confirms that the triplet state is the ground state. The electronic absorption spectrum of 1 exhibits a weak transition near 400 nm with extensive vibronic coupling. Chemical trapping of triplet HC5H (1) in an O2-doped matrix affords the carbonyl oxide 16 derived exclusively from attack at the central carbon.
RESUMEN
Recent synthetic and biological studies of the viridin class of steroidal furans have revealed multiple opportunities for fundamental discoveries as well as advanced drug design. Wortmannin is a potent enzyme inhibitor that binds to the ATP site of important regulatory kinases such as PI-3 kinase and Polo-like kinase. The natural product shares a unique mechanism-based biological activation pathway with other viridins. Furthermore, while there have been several encouraging approaches toward the total synthesis of these compounds, there is still ample room for improvements in synthetic strategies and tactics, and the development of structurally simplified analogs that exert more specific biological effects and are devoid of toxicity issues that have thwarted the clinical development of the parent compounds.
Asunto(s)
Androstadienos/química , Androstadienos/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Adenosina Trifosfato/metabolismo , Modelos Moleculares , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , WortmaninaRESUMEN
A series of viridin analogs was prepared from wortmannin by nucleophilic ring opening at C(20) and evaluated against the signaling kinases PI-3-kinase and mTOR. Several subnanomolar enzyme inhibitors with orders of magnitude selectivity for PI-3-kinase and strong cytotoxic activity against four cancer cell lines were identified. Among the ten most promising derivatives, six demonstrated lower liver toxicity and greater promise for inhibition of tumor cell growth than the lead structure wortmannin.