RESUMEN

Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4(CRBN) E3 ubiquitin ligase. Here we report the identification of a new cereblon modulator, CC-885, with potent anti-tumour activity. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour cells exhibit high sensitivity to CC-885, indicating the clinical potential of this mechanism. Crystallographic studies of the CRBN-DDB1-CC-885-GSPT1 complex reveal that GSPT1 binds to cereblon through a surface turn containing a glycine residue at a key position, interacting with both CC-885 and a 'hotspot' on the cereblon surface. Although GSPT1 possesses no obvious structural, sequence or functional homology to previously known cereblon substrates, mutational analysis and modelling indicate that the cereblon substrate Ikaros uses a similar structural feature to bind cereblon, suggesting a common motif for substrate recruitment. These findings define a structural degron underlying cereblon 'neosubstrate' selectivity, and identify an anti-tumour target rendered druggable by cereblon modulation.

Asunto(s)

Antineoplásicos/farmacología , Péptido Hidrolasas/metabolismo , Factores de Terminación de Péptidos/metabolismo , Compuestos de Fenilurea/farmacología , Talidomida/análogos & derivados , Proteínas Adaptadoras Transductoras de Señales , Secuencias de Aminoácidos , Antineoplásicos/química , Sitios de Unión , Cristalografía por Rayos X , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , Humanos , Factor de Transcripción Ikaros/química , Factor de Transcripción Ikaros/metabolismo , Modelos Moleculares , Complejos Multiproteicos/química , Complejos Multiproteicos/metabolismo , Péptido Hidrolasas/química , Factores de Terminación de Péptidos/química , Factores de Terminación de Péptidos/deficiencia , Compuestos de Fenilurea/química , Unión Proteica , Proteolisis/efectos de los fármacos , Especificidad por Sustrato , Talidomida/química , Talidomida/farmacología , Ubiquitina-Proteína Ligasas/química , Ubiquitina-Proteína Ligasas/metabolismo

RESUMEN

A series of analogs of the immunomodulary drugs lenalidomide (1) and pomalidomide (2), in which the amino group is replaced with various isosteres, was prepared and assayed for immunomodulatory activity and activity against cancer cell lines. The 4-methyl and 4-chloro analogs 4 and 15, respectively, displayed potent inhibition of tumor necrosis factor-α (TNF-α) in LPS-stimulated hPBMC, potent stimulation of IL-2 in a human T cell co-stimulation assay, and anti-proliferative activity against the Namalwa lymphoma cell line. Both of these analogs displayed oral bioavailability in rat.

Asunto(s)

Talidomida/análogos & derivados , Administración Oral , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Semivida , Humanos , Interleucina-2/metabolismo , Lenalidomida , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Ratas , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Talidomida/química , Talidomida/farmacocinética , Talidomida/toxicidad , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

A series of 1,1-diarylalkene derivatives were prepared to optimize the properties of CC-5079 (1), a dual inhibitor of tubulin polymerization and phosphodiesterase 4 (PDE4). By using the 3-ethoxy-4-methoxyphenyl PDE4 pharmacophore as one of the aromatic rings, a significant improvement in PDE4 inhibition was achieved. Compound 28 was identified as a dual inhibitor with potent PDE4 (IC(50)=54 nM) and antitubulin activity (HCT-116 IC(50)=34 nM and tubulin polymerization IC(50) ∼1 µM). While the nitrile group at the alkene terminus was generally required for potent antiproliferative activity, its replacement was tolerated if there was a hydroxyl or amino group on one of the aryl rings. Conveniently, this group could also serve as a handle for amino acid derivatization to improve the compounds' solubility. The glycinamide analog 45 showed significant efficacy in the HCT-116 xenograft model, with 64% inhibition of tumor growth upon dosing at 20 mg/kg qd.

Asunto(s)

Alquenos/química , Alquenos/farmacología , Antineoplásicos/química , Derivados del Benceno/química , Derivados del Benceno/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/química , Moduladores de Tubulina/química , Alquenos/síntesis química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Derivados del Benceno/síntesis química , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Células HCT116 , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Ratones , Modelos Moleculares , Simulación de Dinámica Molecular , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacología , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/farmacología

RESUMEN

6-Substituted 8,9-dimethoxy-2,3-methylenedioxy-6H-dibenzo[c,h][2,6]naphthyridin-5-ones were synthesized and evaluated for topoisomerase I-targeting activity and cytotoxicity. Several of these reversed lactam analogues of ARC-111 exhibited exceptional cytotoxicity with IC50 values ranging from 0.5 to 3.0 nM. In contrast to topotecan, no resistance was observed with several of these reversed lactam analogues in tumor cell lines that overexpressed the efflux transporters MDR1 or BCRP.

Asunto(s)

Benceno/química , ADN-Topoisomerasas de Tipo I/metabolismo , Lactamas/química , Naftiridinas/química , Naftiridinas/farmacología , Inhibidores de Topoisomerasa I , Amidas/química , Camptotecina/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , ADN/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/toxicidad , Humanos , Estructura Molecular , Naftiridinas/síntesis química , Naftiridinas/toxicidad , Relación Estructura-Actividad

RESUMEN

The exceptional topoisomerase I-targeting activity and antitumor activity of 5-(2-N,N-dimethylamino)ethyl-8,9-dimethoxy-2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-one (ARC-111, topovale) prompted studies on similarly substituted benzo[i]phenanthridine-12-carboxylic ester and amide derivatives. Among the benzo[i]phenanthridine-12-carboxylic esters evaluated, the 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)-1-methylethyl, and 2-(N,N-dimethylamino)-1,1-dimethylethyl esters possessed similar cytotoxicity, ranging from 30 to 55 nM in RPMI8402 and KB3-1 cells. Several of the carboxamide derivatives possess potent topoisomerase I-targeting activity and cytotoxicity. The 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl, and 2-(pyrrolidin-1-yl)ethyl amides were among the more cytotoxic benzo[i]phenanthridine-12-carboxylic derivatives, with IC50 values ranging from 0.4 to 5.0 nM in RPMI8402 and KB3-1 cells.

Asunto(s)

Amidas/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/toxicidad , Ésteres/química , Inhibidores de Topoisomerasa I , Camptotecina/análogos & derivados , Camptotecina/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , ADN/metabolismo , ADN-Topoisomerasas de Tipo I/metabolismo , Inhibidores Enzimáticos/síntesis química , Humanos , Concentración 50 Inhibidora , Irinotecán , Estructura Molecular , Topotecan/química

RESUMEN

5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one (ARC-111) has potent TOP1-targeting activity and pronounced antitumor activity. Several analogues of ARC-111 were synthesized with NH2, N-alkyl, N,N-dialkyl, pyrrolidinyl, piperidinyl, and piperazinyl substituents at the 2-position of the 5-ethyl group. The relative TOP1-targeting activity and cytotoxicity of these structural analogues were assessed in RPMI8402 and P388 tumor cells and their camptothecin-resistant variants CPT-K5 and P388/CPT45, respectively. Potent TOP1-targeting activity was retained within a series of mono N-alkyl analogues that included NHCH2CH3, NHCH(CH3)2, and NHC(CH3)3. TOP1-targeting activity was diminished by the presence of a N-benzyl moiety. In a comparison of a series of N-alkyl-N-isopropyl analogues, activity decreased in the order CH3 > CH2CH3 > CH(CH3)2. Cytotoxicity in RPMI8402 and P388 did correlate with TOP1-targeting activity. Cytotoxic activity was also determined in KB3-1 cells and its variants KB/V-1 and KBH5.0. As KB/V-1 cells overexpress MDR1 and KBH5.0 cells overexpress BCRP, decreased cytotoxicity in these cell lines relative to the parent cell line is indicative of compounds that are substrates for these efflux transporters. In view of their diminished cytotoxicity in KB/V-1 cells, it appears that the likely demethylated metabolites of ARC-111, i.e., where NH2 or NHCH3 replaces the N(CH3)2 at the 2-position of the 5-ethyl substituent, are substrates for MDR1. In contrast, no significant difference in cytotoxicity among these three cell lines was observed with other N-alkyl analogues, including NHC2H5, NHCH(CH3)2, NHC(CH3)3, N(CH3)2, N(CH2CH3)2, NCH3(CH(CH3)2), and either the pyrrolidinyl or the piperidinyl analogues. The 2-(piperazinyl) analogues were associated with diminished cytotoxicity in KB/V-1 cells, suggesting that the second basic amino substituent is associated with their recognition as substrates by MDR1. Comparative studies on the antitumor activity of ARC-111 and its N-demethylated derivatives (the NHCH3 and NH2 analogues) against SJ-BT45 medulloblastoma xenografts in scid mice revealed that the secondary amine metabolite is at least as active as ARC-111 in vivo, although the primary amine derivative was significantly less potent.

Asunto(s)

Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismo , Antineoplásicos/síntesis química , ADN-Topoisomerasas de Tipo I/metabolismo , Naftiridinas/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ratones , Ratones SCID , Naftiridinas/química , Naftiridinas/farmacología , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacología , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/farmacología , Relación Estructura-Actividad , Trasplante Heterólogo

RESUMEN

The exceptional TOP1-targeting activity and antitumor activity of ARC-111, 1, prompted studies on similarly substituted benzo[i]phenanthridine-12-carboxylic ester and amide derivatives. These studies were extended to include 6-substituted 8,9-dimethoxy-2,3-methylenedioxy-dibenzo[c,h][2,6]naphthyridin-5-ones, which represent reversed lactam analogues of 1. Several of these analogues retained the potent TOP1-targeting activity and cytotoxicity observed for ARC-111.

Asunto(s)

Antineoplásicos/farmacología , Ácidos Carboxílicos/farmacología , Inhibidores Enzimáticos/farmacología , Naftiridinas/farmacología , Fenantridinas/farmacología , Inhibidores de Topoisomerasa I , Antineoplásicos/síntesis química , Antineoplásicos/química , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Naftiridinas/síntesis química , Naftiridinas/química , Fenantridinas/síntesis química , Fenantridinas/química , Relación Estructura-Actividad

RESUMEN

Recently, 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one, 1, was identified as a TOP1-targeting agent with pronounced antitumor activity. In the present study, the effect on activity of substituting a single nitro or amino group in the A-ring in lieu of the methylenedioxy moiety of 1 was evaluated. The presence of either a nitro or amino substituent at the 4-position had a pronounced adverse affect on both TOP1-targeting activity and cytotoxicity. To a lesser extent, derivatives with a nitro or amino substituent at the 1-position were also less active than 1. Replacement of the methylenedioxy moiety of 1 with either a nitro or amino substituent at either the 2- and 3-position did result in analogues with potent TOP1-targeting activity and cytotoxicity.

Asunto(s)

ADN-Topoisomerasas de Tipo I/metabolismo , Naftiridinas/química , Naftiridinas/farmacología , Nitrógeno/química , Inhibidores de Topoisomerasa I , Aminación , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Línea Celular Tumoral , ADN/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/toxicidad , Humanos , Concentración 50 Inhibidora , Conformación Molecular , Estructura Molecular , Naftiridinas/síntesis química , Naftiridinas/toxicidad , Electricidad Estática

RESUMEN

Recent studies have identified 2,3-dimethoxy-8,9-methylenedioxy-11-[(2-dimethylamino)ethyl]-11H-isoquino[4,3-c]cinnolin-12-one (1a) as a novel topoisomerase I-targeting agent with potent cytotoxic activity. The effect of varied substituents at the 11-position of 2,3-dimethoxy-8,9-methylenedioxy-11H-isoquino[4,3-c]cinnolin-12-ones on topoisomerase I-targeting activity and cytotoxicity was evaluated. Potent TOP1-targeting activity was observed when the 11-position was substituted with either a 2-(N,N-dimethylamino)ethyl, a 2-(N,N-diethylamino)ethyl, a n-butyl, or a 2-(pyrrolidin-1-yl)ethyl group. The addition of a beta-methyl group to 1a provided an analogue with dramatically reduced TOP1-targeting activity and cytotoxicity. Analogues of 1a wherein the 2-(N,N-dimethylamino)ethyl group was replaced with a (2-tetrahydrofuranyl)methyl, a 2-(piperidin-1-yl)ethyl, or a 2-(4-methylpiperazin-1-yl)ethyl substituent exhibited decreased activity as TOP1-targeting agents. Replacement of the dimethoxy groups of 1a with hydrogen atoms resulted in an analogue with significantly decreased TOP1-targeting activity and cytotoxicity. Removal of both the vicinal dimethoxyl groups and the methylenedioxy moiety resulted in a complete loss of TOP1-targeting activity. The presence of a 9-nitro substituent in place of the 8,9-methylenedioxy group of 1a resulted in a decrease in relative TOP1-targeting activity and cytotoxicity. Compounds 1a and the 11-n-butyl analogue 1d were evaluated for antitumor activity in the human tumor xenograft model using athymic nude mice. The non-estrogen responsive breast tumor cell line MDA-MB-435 was used in these assays. At dose levels that approached its maximum tolerated dose, 1a proved to be effective in inhibiting tumor growth in vivo when administered orally or by ip injection.

Asunto(s)

Antineoplásicos/química , Antineoplásicos/toxicidad , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/toxicidad , Inhibidores de Topoisomerasa I , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular , ADN/genética , ADN/metabolismo , ADN-Topoisomerasas de Tipo I/metabolismo , Femenino , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Desnudos , Estructura Molecular , Trasplante de Neoplasias , Topotecan/farmacología

RESUMEN

8,9-Dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxy-5H-dibenzo[c,h][1,6] naphthyridin-6-one (ARC-111, topovale) is a new synthetic antitumor agent. In the current study, we show that ARC-111 is highly potent in scid mice carrying human tumor xenografts. ARC-111 was shown to be as active as camptothecin (CPT)-11 in the HCT-8 colon tumor model, and compared favorably with CPT-11 and topotecan in the SKNEP anaplastic Wilms' tumor model. In tissue culture models, ARC-111 exhibited low nM cytotoxicity against a panel of cancer cells. ARC-111 cytotoxicity as well as ARC-111-induced apoptosis was reduced >100-fold in CPT-resistant topoisomerase I (TOP1)-deficient P388/CPT45 cells as compared with P388 cells. Similarly, ARC-111 cytotoxicity was greatly reduced in CPT-resistant CPT-K5 and U937/CR cells, which express CPT-resistant mutant TOP1, suggesting that the cytotoxic target of ARC-111 is TOP1. Indeed, ARC-111, like CPT, was shown to induce reversible TOP1 cleavage complexes in tumor cells as evidenced by specific reduction of the TOP1 immunoreactive band in a band depletion assay, as well as elevation of small ubiquitin modifier-TOP1 conjugate levels and activation of 26S proteasome-mediated degradation of TOP1. Unlike CPT, ARC-111 is not a substrate for the ATP-binding cassette transporter breast cancer resistance protein. In addition, ARC-111 cytotoxicity was not significantly reduced in the presence of human serum albumin. These results suggest that ARC-111 is a promising new TOP1-targeting antitumor drug with a different drug resistance profile than CPT.

Asunto(s)

Antineoplásicos/farmacología , Neoplasias del Colon/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Naftiridinas/farmacología , Inhibidores de Topoisomerasa I , Tumor de Wilms/tratamiento farmacológico , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Apoptosis/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular Tumoral , Neoplasias del Colon/enzimología , Neoplasias del Colon/patología , Ensayo Cometa , ADN-Topoisomerasas de Tipo I/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Inhibidores Enzimáticos/metabolismo , Femenino , Humanos , Ratones , Ratones SCID , Naftiridinas/metabolismo , Proteínas de Neoplasias/metabolismo , Unión Proteica , Albúmina Sérica/farmacología , Tumor de Wilms/enzimología , Tumor de Wilms/patología , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

In this paper, we present our results from a docking study of the title compounds with the DNA/topoisomerase I complex based on the recently published X-ray crystal structure of the topotecan/DNA/topoisomerase I ternary cleavable complex (Staker, B.L., et al. PNAS 2002, 99, 15387) using the Autodock program. Simple intermolecular docking energies (E(dock)) correlate well with in vitro DNA cleavage data suggesting that the binding mode from the crystal structure is a reasonable binding mode for these compounds.

Asunto(s)

ADN-Topoisomerasas de Tipo I/efectos de los fármacos , Naftiridinas/química , Cristalografía por Rayos X , Modelos Moleculares , Estructura Molecular , Naftiridinas/farmacología

RESUMEN

5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one exhibits potent TOP1-targeting activity and pronounced antitumor activity. It was hypothesized that replacement of the two methoxyl groups with a nitro substituent would allow for retention of similar activity. In this study 8-, 9-, and 10-nitro-5H-2,3-methylenedioxy-5-(2-N,N-dimethylaminoethyl)dibenzo[c,h][1,6]naphthyridin-6-one and their amino derivatives were synthesized and assessed for their relative TOP1-targeting activity and cytotoxicity. In the case of both the 8- and 9-nitro analogues, their TOP1-targeting activity and cytotoxicity are greater than that of camptothecin and comparable to that of 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one.

Asunto(s)

Antineoplásicos/síntesis química , ADN-Topoisomerasas de Tipo I/metabolismo , Naftiridinas/síntesis química , Aminas/síntesis química , Aminas/química , Aminas/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Naftiridinas/química , Naftiridinas/farmacología , Nitrocompuestos/síntesis química , Nitrocompuestos/química , Nitrocompuestos/farmacología , Relación Estructura-Actividad , Células Tumorales Cultivadas

RESUMEN

5H-Dibenzo[c,h]1,6-naphthyridine-6-ones can exhibit potent antitumor activity. The effect of varied substituents at the 5-position of 5H-8,9-dimethoxy-2,3-methylenedioxydibenzo[c,h]1,6-naphthyridine on relative cytotoxicity and topoisomerase I-targeting activity was evaluated. Potent TOP-1-targeting activity is observed when the 5-position is substituted with either a 2-(N,N-dimethylamino)ethyl group, as in 3a, or a 2-(pyrrolidin-1-yl)ethyl substituent, 3c. In contrast, the addition of a beta-methyl group or a beta-hydroxymethyl group to compound 3a, as in 3b and 3j, results in a loss of significant TOP1-targeting activity. While the presence of a 3-(N,N-dimethylamino)propyl substituent at the 5-position or a methyl(2-tetrahydrofuranyl) group allows for retention of TOP1-targeting activity, the 2-(4-methyl-1-piperazinyl)ethyl analogue, 3d, did not exhibit significant activity. Replacement of the N,N-dimethylamino group of 3a with either C(2)H(5) or OH, as in 3f and 3h, respectively, also had a negative impact on both cytotoxicity and TOP1-targeting activity. Treatment of 3a with LAH gave the 5,6-dihydrodibenzo[c,h]naphthyridine, 4a. This dihydro derivative has approximately 2/3 the potency of 3a as a TOP1-targeting agent. Compounds 3a, 3b, 3h, 3i, and 4a were evaluated for antitumor activity in the human tumor xenograft model using athymic nude mice. The non-estrogen responsive breast tumor cell line, MDA-MB-435, was used in these assays. Compound 3a proved to be effective in regressing tumor growth in vivo when administered either by ip injection or orally 3x week at a dose of 2.0mg/kg. Compound 4a when administered orally 5x weekly at a dose of 40 mg/kg also suppressed tumor growth.

Asunto(s)

Antineoplásicos/toxicidad , Sistemas de Liberación de Medicamentos/métodos , Naftiridinas/toxicidad , Inhibidores de Topoisomerasa I , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Femenino , Humanos , Masculino , Ratones , Ratones Desnudos , Naftiridinas/administración & dosificación , Naftiridinas/química , Ensayos Antitumor por Modelo de Xenoinjerto/métodos

RESUMEN

Several 5,12-diazachrysen-6-ones and 5,6,11-triazachrysen-12-ones were synthesized with varied substituents at the 5- or 11-position, respectively. Each compound was evaluated for its potential to stabilize the cleavable complex formed with TOP1 and DNA. Two analogues with very potent TOP1-targeting activity, 3a and 4a, exhibited cytotoxic activity with IC(50) values at or below 2nM against RPMI8402. Compound 3a was active in vivo by either ip or po administration in the human tumor xenograft athymic nude mice model.

Asunto(s)

Antineoplásicos/síntesis química , Crisenos/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Inhibidores de Topoisomerasa I , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Compuestos Aza/administración & dosificación , Compuestos Aza/síntesis química , Compuestos Aza/farmacología , División Celular/efectos de los fármacos , Crisenos/administración & dosificación , Crisenos/síntesis química , ADN/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Trasplante Heterólogo , Resultado del Tratamiento , Células Tumorales Cultivadas