RESUMEN
Desoxyepothilone B (dEpoB), currently in clinical trials, is a novel microtubule inhibitor with similar mode-of-action to paclitaxel (Taxol). Intriguingly, it is effective in some cell lines and tumor xenografts refractory to Taxol. The purpose of this study is to compare signaling induced by the two drugs and identify a molecular basis for increased efficacy of dEpoB in resistant lines. The importance of ERK signaling, already established for Taxol, was shown for dEpoB and other G2-blocking agents. However, a role in differential sensitivity was not observed. Affymetrix analysis shows similar gene modulation by either agent, alone or in combination with MEK inhibitor. Differential sensitivity in a set of Taxol-resistant lines correlated to the expression of P-glycoprotein (P-gp), and its importance was demonstrated directly. These results suggest that Taxol and dEpoB elicit similar cell death pathways, and the increased efficacy of dEpoB in resistant tumor lines lies in differential susceptibility to P-gp.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Muerte Celular/efectos de los fármacos , Resistencia a Múltiples Medicamentos , Epotilonas/farmacología , Paclitaxel/farmacología , Transducción de Señal/efectos de los fármacos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/biosíntesis , Adenocarcinoma/patología , Neoplasias de la Mama/patología , Resistencia a Antineoplásicos , Femenino , Humanos , Neoplasias Pulmonares/patología , Células Tumorales CultivadasRESUMEN
Radicicol (1) exhibits potent anticancer properties in vitro, which are likely to be mediated through its high affinity (20 nM) for the molecular chaperone Hsp90. Recently, we reported the results of a synthetic program targeting radicicol (1) and monocillin I (2), highlighted by the application of ring-closing metathesis to macrolide formation. These efforts resulted in a highly convergent synthesis of radicicol dimethyl ether but failed in the removal of the two aryl methyl ethers. Simple exchange of these methyl ethers with more labile functionalities disabled a key esterification in the initial route. Through extended experimentation, a successful route to both natural products was secured, along with some intriguing results that emphasize the implications of this design on a broad range of fused benzoaliphatic targets, including analogues of these natural products.
Asunto(s)
Antifúngicos/síntesis química , Antineoplásicos/síntesis química , Lactonas/síntesis química , Macrólidos , EstereoisomerismoRESUMEN
Phomactin A (1) is a selective antagonist of platelet activating factor (PAF). Herein, we report our progress toward the construction of the oxadecalin core of 1. This route is based on the Diels-Alder cycloaddition of an appropriately functionalized vinyl pyran and a complementary dienophile. A model of this reaction involving 2 and maleic anhydride was conducted. Adduct 3 contains the correct stereochemical arrangements between functional groups necessary for gaining access to phomactin A. Reaction: see text.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Naftalenos/síntesis química , Hongos/química , Compuestos Heterocíclicos de 4 o más Anillos/química , Anhídridos Maleicos/química , Modelos Químicos , Factor de Activación Plaquetaria/antagonistas & inhibidores , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , EstereoisomerismoRESUMEN
[reaction: see text]. In this Letter, we describe an approach to the highly functionalized tetracycle 6, a model compound corresponding to the CDEF ring system contained in the recently discovered antibiotic lactonamycin. Our approach features an unprecedented, highly stereoselective dihydroxylation of quinone 13a, which leads directly to spirocyclic lactone 15, following acid-promoted deprotection/cyclization. The methodology described herein paves the way for a concise, highly diastereo- and enantioselective synthesis of the natural product.
Asunto(s)
Antibacterianos/síntesis química , Indoles/síntesis química , Naftoquinonas/química , Naftoquinonas/síntesis química , Antibacterianos/química , Hidroxilación , Indoles/química , Conformación MolecularRESUMEN
We have evaluated two synthetic epothilone analogues lacking the 12,13-epoxide functionality, 12,13-desoxyepothilone B (dEpoB), and 12,13-desoxyepothilone F (dEpoF). The concentrations required for 50% growth inhibition (IC(50)) for a variety of anticancer agents were measured in CCRF-CEM/VBL1000 cells (2,048-fold resistance to vinblastine). By using dEpoB, dEpoF, aza-EpoB, and paclitaxel, the IC(50) values were 0.029, 0.092, 2.99, and 5.17 microM, respectively. These values represent 4-, 33.5-, 1,423- and 3,133-fold resistance, respectively, when compared with the corresponding IC(50) in the parent [nonmultiple drug-resistant (MDR)] CCRF-CEM cells. We then produced MDR human lung carcinoma A549 cells by continuous exposure of the tumor cells to sublethal concentrations of dEpoB (1.8 yr), vinblastine (1.2 yr), and paclitaxel (1.8 yr). This continued exposure led to the development of 2.1-, 4,848-, and 2,553-fold resistance to each drug, respectively. The therapeutic effect of dEpoB and paclitaxel was also compared in vivo in a mouse model by using various tumor xenografts. dEpoB is much more effective in reducing tumor sizes in all MDR tumors tested. Analysis of dEpoF, an analog possessing greater aqueous solubility than dEpoB, showed curative effects similar to dEpoB against K562, CCRF-CEM, and MX-1 xenografts. These results indicate that dEpoB and dEpoF are efficacious antitumor agents with both a broad chemotherapeutic spectrum and wide safety margins.
Asunto(s)
Antineoplásicos/farmacología , Epotilonas , Lactonas/farmacología , Microtúbulos/efectos de los fármacos , Neoplasias Experimentales/tratamiento farmacológico , Tiazoles/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Humanos , Lactonas/síntesis química , Lactonas/química , Lactonas/uso terapéutico , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias Experimentales/patología , Tiazoles/síntesis química , Tiazoles/química , Tiazoles/uso terapéutico , Trasplante HeterólogoRESUMEN
Two concise syntheses of (+/-)-frondosin B (1), an interleukin-8 receptor antagonist, have been achieved from commercially available 5-methoxysalicylaldehyde. The seven-membered ring in ketone 33, the common intermediate for both syntheses, was built by a classical Friedel-Crafts reaction. The key step of the first route was facile cationic cyclization of the vinylogous benzofuran to the trisubstituted olefin (30 --> 16 + 38) to construct a six-membered carbocycle. Although this route demonstrated the efficacy of the stepwise approach to the frondosin ring-system, it also resulted in olefinic isomers that were easily isomerized in acidic conditions. In the second route, we utilized a Diels-Alder reaction between sterically demanding diene 42 and nitroethylene to fix the double bond in its required position in the resultant dimethylcyclohexane ring. A third total synthesis was devised for the purpose of determining the absolute configuration of frondosin B. It reached diene 42, this time in the enantiomerically defined form. From this point, naturally configured frondosin B was obtained in the enantiomerically enriched form. These studies establish the absolute configuration of the secondary methyl center in frondosin B to be R.
Asunto(s)
Aldehídos/síntesis química , Benzofuranos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Conformación Molecular , Receptores de Interleucina-8A/antagonistas & inhibidores , EstereoisomerismoRESUMEN
A novel preparation of nonnatural glycoamino acids starting from n-pentenyl glycosides is described. The approach involves a Horner-Emmons olefination with a suitably protected glycine-derived phosphonate, followed by catalytic asymmetric hydrogenation, which proceeds with excellent diastereomeric selectivity. The synthetic methodology was useful for the preparation of glycoamino acids containing the Tn antigen, the MBr1 antigen (Globo-H), the Le(y) antigen, and lactose. These glycoamino acids can also serve as units for peptide synthesis. The synthesis of polyvalent glycopeptides containing three different antitumor antigens is described (28 and 29), and these have been prepared for conjugation to carrier protein in order to access the immunogenicity for tumor immunotherapy applications.
Asunto(s)
Amino Azúcares/síntesis química , Antígenos de Carbohidratos Asociados a Tumores/química , Vacunas contra el Cáncer/química , Vacunas contra el Cáncer/síntesis química , Glicoconjugados/síntesis química , Glicopéptidos/síntesis química , Antígenos del Grupo Sanguíneo de Lewis/química , Polisacáridos/síntesis química , Vacunas Conjugadas/química , Conformación de Carbohidratos , Secuencia de Carbohidratos , Inmunoterapia/métodosRESUMEN
A processable total synthesis of a potent antitumor agent, desoxyepothilone F (dEpoF, 21-hydroxy-12,13-desoxyepothilone B, 21-hydroxyepothilone D), has been accomplished. The route is highly convergent. The new technology has also been applied to a total synthesis of 12,13-desoxyepothilone (dEpoB). The crucial point of departure from previous syntheses of dEpoB and dEpoF involves presentation of the C1-C11 sector for Suzuki coupling with C3 in reduced form. Hitherto, the required S stereochemistry at C3 had been implemented via reduction of a keto function after Suzuki coupling. Whereas that chemistry worked quite well in a synthesis of dEpoB, it was not transferable to a high-yielding synthesis of dEpoF. The reduction of the keto group at C3 via a Noyori protocol after Suzuki coupling had proved to be very difficult. In our current approach, two consecutive aldol reactions are used to fashion the acyl sector. In the first aldol condensation, C6 becomes attached to C7. Following protection at C7, a two-carbon acetate equivalent is used to join C2 and C3 with very high asymmetric induction at C3. Only after this center has been implemented is the Suzuki reaction conducted. This major advance allowed us to synthesize dEpoF in a straightforward fashion. These findings found ready application in the total synthesis of dEpoB. Another part of the study involved analysis of the factors associated with aldol condensations joining C6 to C7. In the work described herein, the consequences of the status of C3 in promoting the C6-C7 aldol coupling are probed in detail. Dramatic stereochemical long-range effects uncovered during the study are described, and a working model to explain these effects has emerged.
Asunto(s)
Antineoplásicos/síntesis química , Epotilonas , Lactonas/síntesis química , Tiazoles/síntesis química , EstereoisomerismoRESUMEN
Taxol is currently one of the most effective anticancer agents available. However, limitations due to multidrug-resistance (MDR) susceptibility and lack of aqueous solubility render it less than an ideal drug. These limitations, coupled with taxol's unique mechanism of tumor inhibition, involving the stabilization of microtubule assembly, have spurred the search for more effective chemotherapeutic agents. This review will discuss the chemistry and biology of some of the most promising new molecules with "taxol-like" activity. The extended family of microtubule-stabilizing agents now includes the epothilones, eleutherobins, discodermolide, laulimalide and WS9885B. The epothilones have emerged as one of the most exciting new candidates for detailed structure-activity-related studies. A review of our efforts in the synthetic and biological aspects of this research is presented, as are the latest developments reported from other laboratories in academia and the pharmaceutical industry. The synthesis and structure-activity studies of eleutherobins, as well as recent progress with discodermolide, laulimalide and WS9885B are also reviewed. An abundance of exciting advances in chemistry and biology have emerged from these studies, and it is hoped that it will ultimately result in the development of new and more effective chemotherapeutic agents in the fight against cancer.
Asunto(s)
Alcaloides/síntesis química , Antineoplásicos/síntesis química , Diterpenos , Epotilonas , Compuestos Epoxi/síntesis química , Tiazoles/síntesis química , Alcaloides/farmacología , Animales , Antineoplásicos/farmacología , Compuestos Epoxi/farmacología , Humanos , Relación Estructura-Actividad , Tiazoles/farmacologíaRESUMEN
[reaction: see text] A concise, four-step conversion of 2-methylcyclopentenone to hydroazulene 2 is described. An alternative approach that led to an unexpected [5,5]-bicyclic carbon framework is also discussed.
Asunto(s)
Antibacterianos/síntesis química , Cicloheptanos/síntesis química , Diterpenos/síntesis química , Azulenos , Ciclopentanos/químicaRESUMEN
The total syntheses of 12,13,15-desoxy-15(S)-aza-epothilone B (aza-dEpoB; dEpoB-lactam) and 12,13,15-desoxy-15(R)-aza-epothilone B (15-epi-aza-dEpoB; 15-epi-dEpoB-lactam) have been accomplished via a highly convergent strategy. We have also successfully oxidized 12,13,15-desoxy-15(S)-aza-epothilone B to aza-epothilone B (aza-EpoB; EpoB-lactam). Aza-epothilone B has been advanced to phase I clinical trials by the Bristol-Myers Squibb group. Our synthesis is efficient and was amenable to the production of significant quantities of these lactams. Using our fully synthetically derived lactams, in vitro and in vivo studies were conducted in comparison with advanced clinical candidates, 12,13-desoxyepothilone B and 12,13-desoxyepothilone F, also derived by total synthesis.
Asunto(s)
Antineoplásicos/síntesis química , Epotilonas , Compuestos Epoxi/síntesis química , Tiazoles/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Epoxi/química , Compuestos Epoxi/farmacología , Humanos , Células K562 , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Análisis Espectral , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
Glycoproteins contain carbohydrate and peptide sectors. As a model for studying whether there exists stereochemical "communication" between the two domains, we prepared two glycopeptides differing only in the absolute stereochemistry of the peptide domain (L-peptide vs D-peptide). High-field NMR spectroscopy revealed that there are distinct and measurable differences, indicating that the two domains are at some level interactive.
Asunto(s)
Glicoconjugados/química , Glicopéptidos/química , Glicoproteínas/química , Conformación de Carbohidratos , Secuencia de Carbohidratos , Glicoconjugados/síntesis química , Glicopéptidos/síntesis química , Modelos Moleculares , Datos de Secuencia Molecular , Péptidos/químicaRESUMEN
The feasibility of using carbohydrate-based vaccines for the immunotherapy of cancer is being actively explored at the present time. Although a number of clinical trials have already been conducted with glycoconjugate vaccines, the optimal design and composition of the vaccines has yet to be determined. Among the candidate antigens being examined is Lewis(y) (Le(y)), a blood group-related antigen that is overexpressed on the majority of human carcinomas. Using Le(y) as a model for specificity, we have examined the role of epitope clustering, carrier structure, and adjuvant on the immunogenicity of Le(y) conjugates in mice. A glycolipopeptide containing a cluster of three contiguous Le(y)-serine epitopes and the Pam(3)Cys immunostimulating moiety was found to be superior to a similar construct containing only one Le(y)-serine epitope in eliciting antitumor cell antibodies. Because only IgM antibodies were produced by this vaccine, the effect on immunogenicity of coupling the glycopeptide to keyhole limpet hemocyanin was examined; although both IgM and IgG antibodies were formed, the antibodies reacted only with the immunizing structure. Reexamination of the clustered Le(y)-serine Pam(3)Cys conjugate with the adjuvant QS-21 resulted in the identification of both IgG and IgM antibodies reacting with tumor cells, thus demonstrating the feasibility of an entirely synthetic carbohydrate-based anticancer vaccine in an animal model.
Asunto(s)
Anticuerpos Antineoplásicos/inmunología , Vacunas contra el Cáncer/inmunología , Carbohidratos/inmunología , Antígenos del Grupo Sanguíneo de Lewis/inmunología , Vacunas Conjugadas/inmunología , Adyuvantes Inmunológicos , Animales , Anticuerpos Antineoplásicos/biosíntesis , Secuencia de Carbohidratos , Epítopos de Linfocito B/inmunología , Lipoproteínas/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Datos de Secuencia MolecularRESUMEN
The carbohydrate antigen globo H commonly found on breast cancer cells is a potential target for vaccine therapy. The objectives of this trial were to determine the toxicity and immunogenicity of three synthetic globo H-keyhole limpet hemocyanin conjugates plus the immunologic adjuvant QS-21. Twenty-seven metastatic breast cancer patients received five vaccinations each. The vaccine was well tolerated, and no definite differences were observed among the three formulations. Serologic analyses demonstrated the generation of IgM antibody titers in most patients, with minimal IgG antibody stimulation. There was significant binding of IgM antibodies to MCF-7 tumor cells in 16 patients, whereas IgG antibody reactivity was observed in a few patients. There was evidence of complement-dependent cytotoxicity in several patients. Affinity column purification supported the specificity of IgM antibodies for globo H. On the basis of these data, globo H will constitute one component of a polyvalent vaccine for evaluation in high-risk breast cancer patients.
Asunto(s)
Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/uso terapéutico , Vacunas Conjugadas/uso terapéutico , Adulto , Neoplasias Óseas/secundario , Neoplasias Óseas/terapia , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Secuencia de Carbohidratos , Femenino , Humanos , Inmunización , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Metástasis Linfática , Persona de Mediana Edad , Datos de Secuencia Molecular , Metástasis de la Neoplasia , Resultado del Tratamiento , Vacunas Conjugadas/efectos adversos , Vacunas Conjugadas/inmunologíaRESUMEN
The total syntheses of two octasaccharide antigens isolated from human milk, 1 and 2, and their corresponding allyl glycosides, 3 and 4, have been achieved by utilizing the glycal method. Convergent assembly of the core hexasaccharides and concurrent introduction of two alpha-L-fucosyl moieties at the late stage of the syntheses provided these complex carbohydrates in a concise manner. With synthetic material obtained, biological evaluations of these antigens as potential gastrointestinal cancer immunotherapeutic agents have been initiated.
Asunto(s)
Antígenos de Carbohidratos Asociados a Tumores/química , Oligosacáridos/química , Anticuerpos Monoclonales , Secuencia de Carbohidratos , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Leche Humana/química , Datos de Secuencia MolecularRESUMEN
A total synthesis of a structure proposed for himastatin was accomplished. The non-identity of the fully synthetic material with himastatin necessitated a revision of the assigned structure. Confirmation of the revised stereostructure was subsequently confirmed through total synthesis. Among the achievements during this effort were i) stereospecific routes to both anti-cis and syn-cis pyrrolindoline substructures; ii) a practical synthesis to 5-hydroxypiperazic acid in enantiomerically pure form; iii) a Stille coupling leading to a complex bi-indole moiety, and iv) efficient protecting group management throughout the evolving depsipeptide domain. The outlines for a biological pharmacophore have been delineated. The alternating D- and L-substituents in the 6-mer as well as the biaryl linkage connecting the two identical subunits are critical for maintaining biological activity. This pattern is simulated in another antibiotic, and suggests a possible structural trend for future SAR investigations.
Asunto(s)
Actinomycetales/química , Antibióticos Antineoplásicos/síntesis química , Péptidos Cíclicos/síntesis química , Actinomycetales/metabolismo , Alcaloides/química , Antibióticos Antineoplásicos/química , Dimerización , Humanos , Conformación Molecular , Estructura Molecular , Péptidos Cíclicos/química , Pirroles/química , Estereoisomerismo , Triptófano/químicaRESUMEN
[reaction: see text] We report in this Letter a synthesis of the densely oxygenated CDEF ring system (27) corresponding to that found in the recently discovered antibiotic lactonamycin. The key steps in the synthesis consist of an intramolecular Wessely oxidative lactonization of acid 18, followed by a hydroxyl-directed epoxidation of enol ether 21.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/química , Diseño de Fármacos , Indicadores y Reactivos , Indoles/síntesis química , Indoles/química , Conformación Molecular , Naftoquinonas/síntesis química , Naftoquinonas/química , Relación Estructura-ActividadAsunto(s)
Adyuvantes Inmunológicos/síntesis química , Productos Biológicos/síntesis química , Alcaloides/síntesis química , Animales , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Biología Marina , Métodos , Receptores de Interleucina-8A/antagonistas & inhibidores , Compuestos de Espiro/síntesis química , Molécula 1 de Adhesión Celular Vascular/efectos de los fármacosRESUMEN
A new epothilone analogue, 12,13-desoxyepothilone F (dEpoF, 21-hydroxy-12,13-desoxyepothilone B, 21-hydroxyepothilone D), was synthesized and evaluated for antitumor potential. A convergent strategy employed for the semipractical synthesis of 12,13-desoxyepothilone B (dEpoB) has been utilized to yield an amount of dEpoF sufficient for relevant biological studies. The results from an in vitro assay reveal that this new analogue is highly active against various tumor cell lines with a potency comparable to that of dEpoB. In particular, the growth of resistant tumor cells is inhibited by dEpoF at concentrations where paclitaxel (Taxol) is basically ineffective. A preliminary assessment of its in vivo activity is also promising. The new analogue, containing an additional hydroxyl group at C21, exhibits advantages over other epothilones in terms of water solubility, and can serve as a readily functionalizable handle to produce other useful compounds for pertinent biological studies.