RESUMEN
In an effort to find potent natural inhibitors of RhoA and p115 signaling G-proteins, a systematic in vitro evaluation using enzymatic and plasmonic resonance assays was undertaken on 11â¯317 plant extracts. The screening procedure led to the selection of the New Caledonian endemic species Meiogyne baillonii for a chemical investigation. Using a bioguided isolation procedure, three enediyne-γ-butyrolactones (1-3) and two enediyne-γ-butenolides (4 and 5), named sapranthins H-L, respectively, two enediyne carboxylic acid (6 and 7), two depsidones, stictic acid (8) and baillonic acid (9), aristolactams AIa and AIIa (10 and 11), and two aporphines, dehydroroemerine (12) and noraristolodione (13), were isolated from the ethyl acetate extract of the bark. The structures of the new compounds (1-6, 9, and 11) and their relative configurations were established by NMR spectroscopic analysis and by X-ray diffraction analysis for compound 9. Only stictic acid (8) exhibited a significant inhibiting activity of the RhoA-p115 complex, with an EC50 value of 0.19 ± 0.05 mM. This is the first time that a natural inhibitor of the complex RhoA-p115's activity was discovered from an HTS performed over a collection of higher plant extracts. Thus, stictic acid (8) could be used as the first reference compound inhibiting the interaction between RhoA and p115.
Asunto(s)
Annonaceae/química , Extractos Vegetales/farmacología , Factores de Intercambio de Guanina Nucleótido Rho/antagonistas & inhibidores , Proteína de Unión al GTP rhoA/antagonistas & inhibidores , Espectroscopía de Resonancia Magnética , Estructura Molecular , Corteza de la Planta/química , Extractos Vegetales/químicaRESUMEN
A series of 6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]chromeno[6,5-g][1,8]naphthyridin-7-one (4), 13-aza derivatives of benzo[b]acronycine, the isomeric 5-methoxy-2,2,13-trimethyl-2,13-dihydro-6H-benzo[b]chromeno[7,6-g][1,8]naphthyridin-6-one (5), and related cis-diols mono- and diesters were designed and synthesized. Their in vitro and in vivo biological activities were evaluated. As previously observed in the acronycine series, esters were the most potent derivatives exhibiting submicromolar activities; among them monoesters are particularly active. Racemic diacetate 21 showed a strong activity against KB-3-1 cell lines and was selected for in vivo evaluation and proved to be active, inhibiting tumor growth by more than 80%. After separation of the two enantiomers, compounds 21a and 21b were also evaluated against C38 colon adenocarcinoma; their activities were found to be significantly different.
Asunto(s)
Acronina/química , Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Naftiridinas/síntesis química , Naftiridinas/farmacología , Adenocarcinoma/patología , Animales , Carcinoma de Células Escamosas/patología , Neoplasias del Colon/patología , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Ensayo de Cambio de Movilidad Electroforética , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
AIMS: We have developed biochemical and cell based assays to characterize small therapeutic molecules that inhibit the DNA damage checkpoint enzyme, Chk1 (Checkpoint kinase 1). MAIN METHODS: To prepare a screen of large chemical libraries, we purified the full-length and the catalytic domain versions of human Chk1. We characterized their properties and then selected full-length Chk1 as the variant most suitable for screening. We then identified and characterized structurally different Chk1 inhibitors in cell based-assays by measuring cytotoxicity and checkpoint bypass activity. KEY FINDINGS: We treated human cells with topoisomerase I inhibitors and demonstrated that at the time of Chk1 inhibitor addition, the cells have damaged DNA and activated Chk1. One Chk1 inhibitor, the indolocarbazole S27888, was active in the checkpoint bypass assay. SIGNIFICANCE: Knowing that the protein kinase inhibitory properties are different for each inhibitor, it seems that only a limited range of inhibitory activity is tolerated by cells. Chk1 has an essential role in determining how cancer cells respond to genotoxic treatments, therefore, inhibitors of this protein kinase are of great medical interest.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Carbazoles/farmacología , Neoplasias del Colon/tratamiento farmacológico , Proteínas Quinasas/metabolismo , Inhibidores de Topoisomerasa I/farmacología , Adenocarcinoma/enzimología , Adenocarcinoma/genética , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Neoplasias del Colon/enzimología , Neoplasias del Colon/genética , Daño del ADN , ADN de Neoplasias/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Proteínas Quinasas/genética , Spodoptera/citologíaRESUMEN
The impact of substitutions at position 10 in the A ring of the cytotoxic benzo[a]acronycine and benzo[b]acronycine series has been explored. 10-Bromobenzo[a] and 10-bromobenzo[b]acronycine were prepared in 12% and 15% yield respectively from commercially available chemicals. Their 1,2-dihydro-1,2-dihydroxy diesters were synthesized. The different derivatives were tested against two cell lines KB-3-1 and L1210. Their cytotoxic activities were found in the same range of magnitude as their non-substituted counterparts. These structure-activity relationships permitted to conclude that the introduction of a substituent at position 10 maintains the activity in both the benzo[a] and [b]acronycine series and open the way to further pharmacomodulations.
Asunto(s)
Acronina/análogos & derivados , Antineoplásicos/farmacología , Acronina/síntesis química , Acronina/química , Acronina/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
The synthesis of new 4-amino-tetrahydroquinazolino[3,2-e]purine derivatives along with their activity in cell-free enzymatic assays on Src is reported. Some compounds emerged as moderately active inhibitors of the enzyme and showed antiproliferative effects on the murine leukemia L1210 cell line. Docking studies have been also performed to analyze the binding mode of compounds under study and to identify the structural determinants of their interaction. Therefore, this study provides a new promising scaffold with moderate enzymatic inhibitory activities for further development of new anticancer drugs targeting Src tyrosine kinase.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Purinas/síntesis química , Purinas/farmacología , Quinazolinas/síntesis química , Quinazolinas/farmacología , Familia-src Quinasas/antagonistas & inhibidores , Animales , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Ratones , Modelos Moleculares , Estructura Molecular , Purinas/química , Quinazolinas/química , Estereoisomerismo , Relación Estructura-Actividad , Familia-src Quinasas/metabolismoRESUMEN
In order to explore the structure-activity relationships in the acronycine and psorospermin series, simplified analogues of the highly cytotoxic (+/-)-(2R*,1'R*)-5-methoxy-11-methyl-2-(2-methyloxiran-2-yl)-1,2-dihydro-11H-furo[2,3-c]acridin-6-one and (+/-)-(2R*,1'R*)-5-methoxy-13-methyl-2-(2-methyloxiran-2-yl)-1,2-dihydro-13H-benzo[b]furo[3,2-h]-acridin-6-one lacking the fused furan ring, including 3-allyloxy-1-methoxy-10-methyl-acridin-9(10H)-one, 3-allyloxy-1-methoxy-5-methyl-benzo[b]acridin-12(5H)-one, the corresponding epoxides, and related dihydrodiol esters and diesters were prepared. Only the simplified oxirane compounds displayed significant antiproliferative activity compared to the parent compounds. The oxirane alkylating unit appears indispensible to observe significant antiproliferative activity in both series, but the presence of the angularly fused furan ring does not appear as a crucial structural requirement to observe significant cytotoxic activity.
Asunto(s)
Acronina/análogos & derivados , Acronina/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Xantonas/química , Acronina/síntesis química , Animales , Antineoplásicos/síntesis química , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Ratones , Relación Estructura-ActividadRESUMEN
The biochemical pathways that lead cells to mitotic catastrophe are not well understood. To identify these pathways, we have taken an approach of treating cells with a novel genotoxic compound and characterizing whether cells enter mitotic catastrophe or not. S23906 is a novel acronycine derivative that forms adducts with the N2 residue of guanine in the minor groove of the DNA helix and destabilizes base pairing to cause helix opening. We observed, in HeLa and HT-29 cells, that S23906 induced gamma-H2AX and activated checkpoint kinase 1, as did bleomycin, camptothecin, and cisplatin, when tested under equi-toxic conditions. S23906 also induced cyclin E1 protein, although this activity was not required for cytotoxicity because knock down of cyclin E1 by RNA interference did not affect the number of dead cells after treatment. Cyclin B1 levels first decreased and then increased after treatment with S23906. Cyclin B1 was associated with Cdk1 kinase activity, which correlated with an increase in the number of mitotic cells. By 32 h after treatment, at least 20% of the cells entered mitotic catastrophe as determined by microscopy. Suppression of the DNA checkpoint response by co-treatment with caffeine increased the number of cells in mitosis. These results suggest that mitotic catastrophe is one of the cellular responses to S23906 and that mitotic catastrophe may be a common cellular response to many different types of DNA damage.
Asunto(s)
Acronina/análogos & derivados , ADN/metabolismo , Mitosis/efectos de los fármacos , Acronina/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Northern Blotting , Proteína Quinasa CDC2/metabolismo , Cafeína/farmacología , Ciclina B1/metabolismo , Ciclina E/antagonistas & inhibidores , Ciclina E/genética , Ciclina E/metabolismo , Técnica del Anticuerpo Fluorescente , Células HT29 , Células HeLa , Humanos , Proteínas Oncogénicas/antagonistas & inhibidores , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , ARN Interferente Pequeño/farmacologíaRESUMEN
S23906-1 is a benzo[b]acronycine derivative acting as a DNA-alkylating agent through covalent bonding to the exocyclic amino group of guanines and subsequent local opening of the DNA helix. This compound was selected for phase I clinical trials based on its efficient antitumor activity in experimental models and its unique mode of action. S23906-1 is the racemate of cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one. Here, we evaluated the cytotoxic and antitumor activities of the two pure cis-enantiomers and investigated the mechanism of action of both cis- and trans-racemates and their enantiomers in terms of DNA alkylation potency and locally drug-induced DNA helix opening process. Reaction with glutathione, as a detoxification process, was also studied. The trans-compounds, both as racemate or separated enantiomers, were found less potent than the corresponding cis-derivatives. Among the cis-enantiomers, the most efficient one regarding DNA alkylation bears the acetate on the reactive C1 position in the R configuration, both on purified DNA and genomic DNA extracted from cell cultures. By contrast, the most cytotoxic and tumor-active enantiomer bears the C1-acetate in the S configuration. Distinct cellular DNA-alkylation levels or covalent bonding to glutathione could not explain the differences. However, we showed that the S and R orientations of the acetate on C1 asymmetric carbon lead to different local opening of the DNA, as visualized using nuclease S1 mapping. These different interactions could lead to modulated DNA-repair, protein/DNA interaction, and apoptosis processes.
Asunto(s)
Acronina/análogos & derivados , Antineoplásicos Alquilantes/farmacología , Citotoxinas/farmacología , Sustancias Intercalantes/farmacología , Acronina/química , Acronina/farmacología , Animales , Antineoplásicos Alquilantes/química , Dominio Catalítico , División Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citotoxinas/química , Aductos de ADN/metabolismo , Humanos , Sustancias Intercalantes/química , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Neoplasias Experimentales/tratamiento farmacológico , EstereoisomerismoRESUMEN
In an effort to discover potent inhibitors of the antiapoptotic protein Bcl-xL, a systematic in vitro evaluation was undertaken on extracts prepared from various parts of Vietnamese plants. The ethyl acetate extracts obtained from the leaves and flowers of Combretum sundaicum and the leaves of Lantana camara were selected for their interaction with the Bcl-xL/Bak association. Bioassay-guided purification of these species led to the isolation of 15 pentacyclic triterpenoids (1-15) possessing olean-12-en-28-oic acid and olean-12-en-29-oic acid aglycons, of which compounds 1-6 and 8-10 are new. Five compounds exhibited binding activity with K(i) values between 5.3 and 17.8 microM. The cytotoxic activity of 1-15 was also evaluated on various cancer cell lines.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Combretum/química , Lantana/química , Plantas Medicinales/química , Triterpenos/aislamiento & purificación , Triterpenos/farmacología , Proteína Destructora del Antagonista Homólogo bcl-2/efectos de los fármacos , Proteína bcl-X/efectos de los fármacos , Antineoplásicos Fitogénicos/química , Apoptosis/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Flores/química , Humanos , Estructura Molecular , Hojas de la Planta/efectos de los fármacos , Triterpenos/química , VietnamRESUMEN
Based on the definition of a 5-HT(4) receptor antagonist pharmacophore, a series of pyrrolo[1,2-a]thieno[3,2-e] and pyrrolo[1,2-a]thieno[2,3-e] pyrazine derivatives were designed, prepared, and evaluated to determine the properties necessary for high-affinity binding to 5-HT(4) receptors. The compounds were synthesized by substituting the chlorine atom of the pyrazine ring with various N-alkyl-4-piperidinylmethanolates. They were evaluated in binding assays with [(3)H]GR113808 (1) as the 5-HT(4) receptor radioligand. The affinity values (K(i) or inhibition percentages) were affected by both the substituent on the aromatic ring and the substituent on the lateral piperidine chain. A methyl group on the tricyclic ring produced a marked increase in affinity while an N-propyl or N-butyl group gave compounds with nanomolar affinities. Among the most potent ligands, 34d was selected for further pharmacological studies and evaluated in vivo. This compound acts as an antagonist/weak partial agonist in COS-7 cells stably expressing the 5-HT(4(a)) receptor and is of great interest as a peripheral antinociceptive agent.
Asunto(s)
Pirazinas/síntesis química , Pirazinas/farmacología , Antagonistas del Receptor de Serotonina 5-HT4 , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacología , Animales , Células COS , Chlorocebus aethiops , Humanos , Indoles/metabolismo , Modelos Moleculares , Estructura Molecular , Pirazinas/metabolismo , Ensayo de Unión Radioligante , Antagonistas de la Serotonina/metabolismo , Sulfonamidas/metabolismoRESUMEN
Monocinnamoyl esters at position 2 of (+/-)-cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one and their acetyl derivatives at position 1 were prepared as stabilized analogues of the anticancer alkylating agent S23906-1. Monocinnamoyl esters at position 2 were slower DNA alkylators than the reference 2-monoacetate. Mixed esters bearing an acetyl ester group at position 1 and a cinnamoyl ester group at position 2 alkylated DNA slower than S23906-1. A strong correlation was observed between cytotoxicity and DNA alkylation kinetics, with slower alkylators displaying more potent antiproliferative activities. The most cytotoxic compounds proved to be significantly active in vivo against murine C-38 adenocarcinoma implanted in mice, but less potent than S23906-1.
Asunto(s)
Acronina/análogos & derivados , Acronina/toxicidad , Antineoplásicos Alquilantes/síntesis química , Antineoplásicos Alquilantes/toxicidad , Acronina/síntesis química , Acronina/química , Acronina/farmacología , Animales , Antineoplásicos Alquilantes/química , Línea Celular Tumoral , ADN/química , Cinética , Ratones , Ratones Endogámicos C57BL , Trasplante HomólogoRESUMEN
Herein, we describe the structure-activity relationship study of a new 1-(arylalkyl)-11H-benzo[f]-1,2-dihydropyrido[3,2,c][1,2,5]oxathiazepine 5,5-dioxide series of antimitotic agents. The pharmacological results obtained from previous works allowed us to identify compound 1 as a new cytotoxic agent inhibiting tubulin polymerization. We have undertaken the synthesis of its non-methylated analogue 7 and have extended our investigations to a novel, structurally related benzopyridooxathiazepine dioxide series. Among all analogues synthesized in this study, compound 10b was the most promising, being 12-fold more potent than compound 1. Its activity over a panel of five tumoral cell lines was in the nanomolar range for all of the histological types tested and flow cytometric studies performed on L1210 cells showed an accumulation of the cells in the G2/M phases of the cell cycle with a significant percentage of tetraploid cells (8N DNA content). This interesting pharmacological profile, resulting from inhibition of tubulin polymerization, encouraged us to perform preliminary in vivo studies.
Asunto(s)
Antimitóticos/química , Antineoplásicos/química , Tiazepinas/química , Tiazepinas/farmacología , Moduladores de Tubulina/química , Animales , Antimitóticos/síntesis química , Antimitóticos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Ciclo Celular , Línea Celular Tumoral , Humanos , Ratones , Relación Estructura-Actividad , Tiazepinas/síntesis química , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/farmacologíaRESUMEN
Rebeccamycin derivative 1 bearing a sugar moiety linked to both indole nitrogens and an amino substituent on the carbohydrate unit was synthesized in three steps from the bacterial metabolite. This compound was found to be a highly potent checkpoint kinase 1 inhibitor with an IC(50) value of 2.8nM.
Asunto(s)
Carbazoles/química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Quinasas/efectos de los fármacos , Animales , Carbohidratos/química , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Humanos , Indoles/química , Concentración 50 InhibidoraRESUMEN
Compounds possessing the epoxyfuran system present in the natural cytotoxic dihydrofuroxanthone psorospermin (4) fused onto the acridone or benzo[b]acridone chromophores present in the antitumor acronycine (1) and S23906-1 (3) were prepared. The basic furoacridone and benzofuroacridone cores bearing an isopropenyl substituent at a convenient position were synthesized by condensation of 1,3-dihydroxyacridone (7) or 1,3-dihydroxybenz[b]acridin-12(5H)-one (9) with (E)-1,4-dibromo-2-methylbut-2-ene. In both series, the (2R*,1'S*) epoxides, with the same relative configuration as psorospermin, were the most active compounds, exhibiting cytotoxic properties with IC50 values in the 10-100 nM range. As in the acronycine and psorospermin series, the new compounds act through alkylation of the DNA guanine units. However, a strong difference was noted in the DNA alkylation site between the benzopyranoacridone S23906-1, which alkylates DNA guanine units at position N-2 in the minor groove, and the new 13H-benzo[b]furo[3,2-h]acridin-6-one derived epoxide 21, which alkylates DNA guanine units at position N-7 in the major groove.
Asunto(s)
Acridonas/química , Acronina/síntesis química , Acronina/farmacología , Benzofuranos/química , Xantonas/síntesis química , Xantonas/farmacología , Acronina/análogos & derivados , Acronina/química , Animales , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Estructura Molecular , Estereoisomerismo , Células Tumorales Cultivadas , Xantonas/químicaRESUMEN
Rebeccamycin is an indolocarbazole class inhibitor of topoisomerase I. In the course of structure-activity relationship studies on rebeccamycin derivatives, we have synthesized analogs with the sugar moiety attached to either one or both indole nitrogens. Some analogs, especially those with substitutions at the 6' position of the carbohydrate moiety, exhibit potent inhibitory activity toward checkpoint kinase 1 (Chk1), a kinase that has a major role in the G(2)/M checkpoint in response to DNA damage. Some of these compounds retained a genotoxic activity either through intercalation into the DNA and/or by topoisomerase I-mediated DNA cleavage. We explored the structure-activity relationship between these compounds and their multiple targets. These rebeccamycin derivatives represent a novel class of potential antitumor agents that have a dual effect and might selectively induce the death of cancer cells.
Asunto(s)
Antineoplásicos/química , Carbazoles/química , Daño del ADN , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas/metabolismo , Animales , Antineoplásicos/farmacología , Carbazoles/farmacología , Proliferación Celular/efectos de los fármacos , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , ADN/química , División del ADN/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-Actividad , Inhibidores de Topoisomerasa IRESUMEN
Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. Inhibiting the catalytic activity of these proteins has become one of the major therapeutic concepts in contemporary drug discovery. We report here the design and the synthesis of novel 6-substituted-5-benzyloxy-4-oxo-4H-pyran-2-carboxamides as potential inhibitors of Src kinase. The synthesis of these derivatives and the preliminary results of biological activity will be discussed.
Asunto(s)
Amidas/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Familia-src Quinasas/antagonistas & inhibidores , Amidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Dominio Catalítico , Descubrimiento de Drogas , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-ActividadRESUMEN
In the course of structure-activity relationship studies on granulatimide analogues, new pyrrolo[3,4-c]carbazoles have been synthesized in which the imidazole heterocycle was replaced by a five-membered ring lactam system or a dimethylcyclopentanedione. Moreover, the synthesis of an original structure in which a sugar moiety is attached to the indole nitrogen and to a six-membered D ring via an oxygen is reported. The inhibitory activities of the newly synthesized compounds toward checkpoint kinase 1 and their in vitro antiproliferative activities toward three tumor cell lines: murine leukemia L1210, and human colon carcinoma HT29 and HCT116 are described.
Asunto(s)
Carbazoles/síntesis química , Carbazoles/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Pirroles/química , Adenosina Trifosfato/química , Sitios de Unión , Carbazoles/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Humanos , Imidas/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/metabolismoRESUMEN
In order to explore the structure-activity relationships in the acronycine series, simplified analogues of cis-1,2-diacetoxy-1,2-dihydroacronycine and cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine (S23906-1, under clinical trials) lacking the fused pyran ring, but possessing an acetoxymethyl leaving group at position 4 were prepared. These new analogues only displayed marginal antiproliferative activity compared to the parent compounds. The presence of the angularly fused dimethylpyran ring appears as an indispensable structural requirement to observe significant cytotoxic activity in this series.
Asunto(s)
Acronina/análogos & derivados , Acronina/farmacología , Antineoplásicos/farmacología , Acronina/síntesis química , Acronina/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
We describe here an efficient synthesis of new 5-azaindolocarbazoles designed for cytotoxic and Chk1 inhibiting properties. The synthesis of 'symmetrical' and 'dissymmetrical' structures is discussed. Concerning the dissymmetrical 5-azaindolocarbazoles derivatives, with both an indole moiety and a 5-azaindole moiety, the synthesis was achieved using two very efficient key steps. The first one is a Stille reaction with a 3-trimethylstannyl-5-azaindole derivative and the second one a photochemical step leading to the proposed polycyclic structure. Various pharmacomodulations were performed to investigate the structure-activity relationships (SAR). Several substituents such as OBn, OH, and methylenedioxy groups were successfully introduced on the indole moiety of the 5-azaindolocarbazole. Compounds with or without substituents on the nitrogen atom of the maleimide were prepared, as well as derivatives with glucopyranosyl substituent on the nitrogen atom of the indole moiety. The cytotoxicity of these new compounds was evaluated on two cell lines (L1210, HT29). Several compounds showed cytotoxicity in the sub-micromolar range. Among the most cytototoxic was the 1,3-dioxolo[4,5-b]-6-(2-dimethylaminoethyl)-1H-pyrido[3',4':4,5]pyrrolo[3,2-i]pyrrolo[3,4-g]carbazole-5,7(6H,12H)-dione (35, IC(50)=195 nM on L1210). The compounds were also investigated for their Chk1 inhibiting activity. Compounds without any substitution on the maleimide moiety were the most potent. This is the case of compounds 45-47 with IC(50) of, respectively, 72, 27, and 14nM toward Chk1. Compound 46, which exhibits moderate cytotoxicity, appears to be a good candidate for development in a multi-drug anticancer therapy.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Aza/farmacología , Carbazoles/farmacología , Inhibidores Enzimáticos/farmacología , Indoles/farmacología , Proteínas Quinasas/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Compuestos Aza/síntesis química , Compuestos Aza/química , Carbazoles/síntesis química , Carbazoles/química , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Indoles/síntesis química , Indoles/química , Concentración 50 Inhibidora , Estructura Molecular , Proteínas Quinasas/química , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
In the course of an automated screening for small molecules presenting cytotoxic activity, eight new cyclophanes named kermadecins A-H (1-8), have been isolated from the bark of a New Caledonian plant, Kermadecia elliptica, Proteaceae. A LC/APCI-MS study performed on kermadecins A, B and C, provided a reliable method for the detection of other analogues existing in small quantities in the extract. This led to the isolation of five other members of this chemical series. The structures were elucidated by extensive mono- and bi-dimensional spectroscopy and mass spectrometry. The cytotoxic activity of four of them was evaluated on various cell lines.