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1.
J Org Chem ; 76(2): 583-7, 2011 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-21192653

RESUMEN

A short, asymmetric synthesis of the 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI) analogue of the CC-1065 and duocarmycin DNA alkylation subunits is described. Treatment of iodo-epoxide 5, prepared by late-stage alkylation of 4 with (S)-glycidal-3-nosylate, with EtMgBr at room temperature directly provides the optically pure alcohol 6 in 87% yield (99% ee) derived from selective metal-halogen exchange and subsequent regioselective intramolecular 6-endo-tet cyclization. The use of MeMgBr or i-PrMgBr also provides the product in high yields (82-87%), but requires larger amounts of the Grignard reagent to effect metal-halogen exchange and cyclization. Direct transannular spirocyclization of 7 following O-debenzylation of 6 provides N-Boc-CBI. This approach represents the most efficient (9-steps, 31% overall) and effective (99% ee) route to the optically pure CBI alkylation subunit yet described.


Asunto(s)
Ciclopropanos/química , Ciclopropanos/síntesis química , Halógenos/química , Indicadores y Reactivos/química , Indoles/química , Indoles/síntesis química , Alquilación , Cristalografía por Rayos X , Ciclización , Duocarmicinas , Espectroscopía de Resonancia Magnética , Estructura Molecular
2.
J Am Chem Soc ; 132(39): 13936-40, 2010 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-20839806

RESUMEN

The synthesis of 1,2,10,11-tetrahydro-9H-cyclobuta[c]benzo[e]indol-4-one (17, CbBI), which contains a deep-seated fundamental structural modification in the CC-1065 and duocarmycin alkylation subunit consisting of the incorporation of a ring-expanded fused cyclobutane (vs cyclopropane), its chemical and structural characterization, and its incorporation into a key analogue of the natural products are detailed. The approach to the preparation of CbBI was based on a precedented (Ar-3' and Ar-5') but previously unknown Ar-4' spirocyclization of a phenol onto a tethered alkyl halide to form the desired cyclobutane. The conditions required for the implementation of the Ar-4' spirocyclization indicate that the entropy of activation substantially impacts the rate of reaction relative to that for the much more facile Ar-3' spirocyclization, while the higher enthalpy of activation slows the reaction relative to an Ar-5' spirocyclization. The characterization of the CbBI-based agents revealed their exceptional stability and exquisite reaction regioselectivity, and a single-crystal X-ray structure analysis of N-Boc-CbBI (13) revealed their structural origins. The reaction regioselectivity may be attributed to the stereoelectronic alignment of the two available cyclobutane bonds with the cyclohexadienone π-system, which resides in the bond that extends to the less substituted cyclobutane carbon for 13. The remarkable stability of N-Boc-CbBI (which is stable even at pH 1) relative to N-Boc-CBI containing a cyclopropane (t(1/2) = 133 h at pH 3) may be attributed to a combination of the increased extent of vinylogous amide conjugation, the nonoptimal geometric alignment of the cyclobutane with the activating cyclohexadienone, and the intrinsic but modestly lower strain energy (1.8 kcal/mol) of a cyclobutane versus a cyclopropane.


Asunto(s)
Ciclobutanos/química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Indoles/química , Alquilación , Cristalografía por Rayos X , Ciclización , Duocarmicinas , Entropía , Compuestos Heterocíclicos de 4 o más Anillos/química , Modelos Moleculares , Estructura Molecular , Pirroles/química , Estereoisomerismo
3.
Bioorg Med Chem Lett ; 20(6): 1854-7, 2010 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-20171886

RESUMEN

The design, synthesis and evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]oxazolo[2,3-e]indol-4-one-6-carboxylate (COI) derivatives are detailed representing analogs of duocarmycin SA containing an oxazole replacement for the fused pyrrole found in the alkylation subunit.


Asunto(s)
Alquilantes/síntesis química , Alquilantes/farmacología , Indoles/química , Oxazoles/química , Alquilantes/química , Alquilación , Duocarmicinas , Indoles/síntesis química , Indoles/farmacología , Pirroles/síntesis química , Pirroles/química , Pirroles/farmacología
4.
Bioorg Med Chem Lett ; 19(24): 6962-5, 2009 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-19879753

RESUMEN

The design, synthesis, and preliminary evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]thieno[3,2-e]indol-4-one-6-carboxylate (CTI) derivatives are detailed representing a single atom change (N to S) embedded in the duocarmycin SA alkylation subunit.


Asunto(s)
Antineoplásicos Alquilantes/química , Indoles/química , Compuestos de Sulfhidrilo/química , Tiofenos/química , Antineoplásicos Alquilantes/síntesis química , Duocarmicinas , Indoles/síntesis química , Pirroles/síntesis química , Pirroles/química , Compuestos de Sulfhidrilo/síntesis química , Tiofenos/síntesis química
5.
Bioorg Med Chem ; 16(20): 9145-53, 2008 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-18819814

RESUMEN

Imidazole (Im) and Pyrrole (Py)-containing polyamides that can form stacked dimers can be programmed to target specific sequences in the minor groove of DNA and control gene expression. Even though various designs of polyamides have been thoroughly investigated for DNA sequence recognition, the use of H-pin polyamides (covalently cross-linked polyamides) has not received as much attention. Therefore, experiments were designed to systematically investigate the DNA recognition properties of two symmetrical H-pin polyamides composed of PyImPyIm (5) or f-ImPyIm (3e, f=formamido) tethered with an ethylene glycol linker. These compounds were created to recognize the cognate 5'-ACGCGT-3' through an overlapped and staggered binding motif, respectively. Results from DNaseI footprinting, thermal denaturation, circular dichroism, surface plasmon resonance and isothermal titration microcalorimetry studies demonstrated that both H-pin polyamides bound with higher affinity than their respective monomers. The binding affinity of formamido-containing H-pin 3e was more than a hundred times greater than that for the tetraamide H-pin 5, demonstrating the importance of having a formamido group and the staggered motif in enhancing affinity. However, compared to H-pin 3e, tetraamide H-pin 5 demonstrated superior binding preference for the cognate sequence over its non-cognates, ACCGGT and AAATTT. Data from SPR experiments yielded binding constants of 1.6x10(8)M(-1) and 2.0x10(10)M(-1) for PyImPyIm H-pin 5 and f-ImPyIm H-pin 3e, respectively. Both H-pins bound with significantly higher affinity (ca. 100-fold) than their corresponding unlinked PyImPyIm 4 and f-ImPyIm 2 counterparts. ITC analyses revealed modest enthalpies of reactions at 298 K (DeltaH of -3.3 and -1.0 kcal mol(-1) for 5 and 3e, respectively), indicating these were entropic-driven interactions. The heat capacities (DeltaC(p)) were determined to be -116 and -499 cal mol(-1)K(-1), respectively. These results are in general agreement with DeltaC(p) values determined from changes in the solvent accessible surface areas using complexes of the H-pins bound to (5'-CCACGCGTGG)(2). According to the models, the H-pins fit snugly in the minor groove and the linker comfortably holds both polyamide portions in place, with the oxygen atoms pointing into the solvent. In summary, the H-pin polyamide provides an important molecular design motif for the discovery of future generations of programmable small molecules capable of binding to target DNA sequences with high affinity and selectivity.


Asunto(s)
Imidazoles/química , Nylons/síntesis química , Pirroles/química , Secuencia de Bases , Calorimetría , Dicroismo Circular , Simulación por Computador , Modelos Moleculares , Desnaturalización de Ácido Nucleico , Nylons/química , Resonancia por Plasmón de Superficie , Termodinámica , Volumetría
6.
J Med Chem ; 56(17): 6845-57, 2013 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-23944748

RESUMEN

Two systematic series of increasingly hydrophilic derivatives of duocarmycin SA that feature the incorporation of ethylene glycol units (n = 1-5) into the methoxy substituents of the trimethoxyindole subunit are described. These derivatives exhibit progressively increasing water solubility along with progressive decreases in cell growth inhibitory activity and DNA alkylation efficiency with the incremental ethylene glycol unit incorporations. Linear relationships of cLogP with -log IC50 for cell growth inhibition and -log AE (AE = cell-free DNA alkylation efficiency) were observed, with the cLogP values spanning the productive range of 2.5-0.49 and the -log IC50 values spanning the range of 11.2-6.4, representing IC50 values that vary by a factor of 10(5) (0.008 to 370 nM). The results quantify the fundamental role played by the hydrophobic character of the compound in the expression of the biological activity of members in this class (driving the intrinsically reversible DNA alkylation reaction) and define the stunning magnitude of its effect.


Asunto(s)
Antineoplásicos Alquilantes/farmacología , ADN/efectos de los fármacos , Indoles/farmacología , Animales , Antineoplásicos Alquilantes/química , Sitios de Unión , Línea Celular Tumoral , ADN/química , Duocarmicinas , Interacciones Hidrofóbicas e Hidrofílicas , Indoles/química , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Ratones , Pirroles/química , Pirroles/farmacología , Solubilidad , Espectrometría de Masa por Ionización de Electrospray
7.
Cancer Biol Ther ; 14(6): 527-36, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23760495

RESUMEN

In treating cancer with clinically approved chemotherapies, the high systemic toxicity and lack of selectivity for malignant cells often result in an overall poor response rate. One pharmacological approach to improve patient response is to design targeted therapies that exploit the cancer milieu by reductively activating prodrugs, which results in the selective release of the free drug in the tumor tissue. Previously, we characterized prodrugs of seco-CBI-indole 2 (CBI-indole 2) designed to be activated in hypoxic tumor microenvironments, wherein the tumor maintains higher concentrations of "reducing" nucleophiles capable of preferentially releasing the free drug by nucleophilic attack on a weak N-O bond. Of these prodrugs, BocNHO-CBI-indole 2 (BocNHO) surpassed the efficacy of the free drug, CBI-indole 2, when examined in vivo in the murine L1210 leukemia model and demonstrated reduced toxicity suggesting a targeted or sustained release in vivo. Herein, we further examine the biological activity of the BocNHO prodrug in murine breast cancer, as well as human prostate and lung cancer cell lines, in vitro. Notably, BocNHO manifests potent antiproliferative and cytotoxic activity in all three tumor cell lines. However, in comparison to the activity observed in the murine cancer cell line, the human cancer cell lines were less sensitive, especially at early timepoints for cytotoxicity. Based on these findings, BocNHO was tested in a more clinically relevant orthotopic lung tumor model, revealing significant efficacy and reduced toxicity compared with the free drug. The data suggests that this pharmacological approach to designing targeted therapies is amenable to human solid tumors.


Asunto(s)
Antineoplásicos/farmacología , Carbamatos/farmacología , Indoles/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Profármacos/farmacología , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Carbamatos/uso terapéutico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Indoles/uso terapéutico , Ratones , Ratones Desnudos , Oxidación-Reducción , Profármacos/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Org Lett ; 14(8): 2078-81, 2012 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-22480368

RESUMEN

Divergent total syntheses of (+)-spegazzinine (1) and (-)-aspidospermine (2) and their extensions to the synthesis of C19-epi-aspidospermine and C3-epi-spegazzinine are detailed, confirming the relative stereochemistry and establishing the absolute configuration of (+)-spegazzinine. A powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole provided the pentacyclic skeleton and all the requisite stereochemistry of the natural products in a single reaction that forms three rings, four C-C bonds, and five stereocenters.


Asunto(s)
Alcaloides/síntesis química , Alcaloides Indólicos/síntesis química , Quinolinas/síntesis química , Alcaloides/química , Ciclización , Alcaloides Indólicos/química , Estructura Molecular , Oxadiazoles/química , Quinolinas/química , Estereoisomerismo
9.
J Med Chem ; 53(21): 7731-8, 2010 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-20942408

RESUMEN

A series of N-acyl O-amino derivatives of seco-CBI-indole(2) are reported and examined as prototypical members of a unique class of reductively activated (cleaved) prodrugs of the duocarmycin and CC-1065 family of antitumor agents. These prodrugs were designed to be potentially preferentially activated in hypoxic tumor environments which carry an intrinsically higher concentration of "reducing" nucleophiles (e.g., thiols) capable of activating such derivatives by nucleophilic cleavage of a weak N-O bond. A remarkable range of stabilities and a resulting direct correlation with in vitro/in vivo biological potencies was observed for these prodrugs, even enlisting subtle variations in the electronic and steric environment around the weak N-O bond. An in vivo evaluation of several of the prodrugs demonstrates that some approach the potency and exceed the efficacy of the free drug itself (CBI-indole(2)), suggesting the prodrugs may offer an additional advantage related to a controlled or targeted release.


Asunto(s)
Antineoplásicos Alquilantes/síntesis química , Indoles/síntesis química , Fenoles/síntesis química , Profármacos/síntesis química , Animales , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Duocarmicinas , Indoles/química , Indoles/farmacología , Leucemia L1210 , Ratones , Ratones Endogámicos DBA , Trasplante de Neoplasias , Fenoles/química , Fenoles/farmacología , Profármacos/química , Profármacos/farmacología , Pirroles/síntesis química , Pirroles/química , Pirroles/farmacología , Estereoisomerismo , Relación Estructura-Actividad
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