RESUMEN
Cancer has been established as the "Emperor of all maladies". In recent years, medicinal chemistry has focused on identifying novel anti-cancer compounds; though discovery of these compounds appears to be a herculean task. In present study, we synthesized forty pyrazolochalcone conjugates and explored their cytotoxic activity against a panel of sixty cancer cell lines. Fifteen conjugates of the series showed excellent growth inhibition (13b-e, 13h-j, 14c-d, 15 a, 15 c-d, 16b, 16d and 18f; GI50 for MCF-7: 0.4-20 µM). Conjugates 13b, 13c, 13d, 16b and 14d were also evaluated for their cytotoxic activity in human breast cancer cell line (MCF-7). The promising candidates induced cell cycle arrest, mitochondrial membrane depolarization and apoptosis in MCF-7 cells at a 2 µM concentration. Furthermore, inhibition of PI3K/Akt/mTOR pathway-regulators such as PI3K, p-PI3K, p-AKT, and mTOR were observed; as well as upregulation of p-GSK3ß and tumor-suppressor protein, PTEN. Our study indicates that pyrazolochalcone conjugates could serve as potential leads in the development of tailored cancer therapeutics.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Chalconas/farmacología , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Chalconas/síntesis química , Chalconas/química , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Células MCF-7 , Estructura Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
A novel series of ferrocene tagged multi-functionalized 1,4-dihydropyrimidines is synthesized by base catalyzed cyclocondensation between ferrocenyl chalcones and amidines. The structures of synthesized compounds were established on the basis of (1)H NMR, (13)C NMR, FTIR spectroscopy as well as by mass spectrometry. The compounds were evaluated for in vitro anticancer activity. The most active compounds from the series displayed GI50 value equal to doxorubicin against the strain of human breast cancer cell line MDA-MB-435.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Compuestos Ferrosos/química , Pirimidinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Metalocenos , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
New dimethyltin derived antitumor drug candidates (S)- and (R)-[4-(2-hydroxy-1-phenylethylimino)pent-2-ol]dimethyltin(iv), 1 and (S)- and (R)-[2,2-dimethyl-4-phenyl-1,3,2-oxazastannolidine], 2 derived from (R)- and (S)-enantiomers of [4-(2-hydroxy-1-phenylethylimino)pent-2-ol] and 2-amino-2-phenylethanol, respectively, were synthesized and thoroughly characterized. Preliminary complex-DNA interaction studies employing various optical methods revealed that the (S)-enantiomer displayed a higher propensity towards the drug target DNA double helix. This was quantified by K(b) and K(sv) values of ligands L and L' and (S)-/(R)-1 and (S)-/(R)-2 complexes, which demonstrated a multifold increase in the case of the (S)-enantiomers in comparison to their (R)-enantiomeric forms. This clearly demonstrates the chiral preference of the (S)-enantiomer over the (R)-enantiomer, and its potency to act as a chemotherapeutic agent. Therefore, the in vitro antitumor activity of the (S)-enantiomer of 1 and 2 was evaluated by the sulforhodamine-B (SRB) assay to assess cellular proliferation against five different human cell lines viz., Hop62, DWD, K562, DU145 and MCF-7. The complex (S)-1 displayed a remarkably pronounced and specific activity for K562, while complex (S)-2 exhibited significant activity towards Hop62, DWD, DU145 and MCF-7. The in vivo antitumor activity of (S)-1 and (S)-2 was carried out, which revealed significant regression in human lung tumors.
Asunto(s)
Antineoplásicos/síntesis química , Complejos de Coordinación/síntesis química , Diseño de Fármacos , Compuestos Orgánicos de Estaño/síntesis química , Compuestos de Estaño/síntesis química , Animales , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/uso terapéutico , Complejos de Coordinación/toxicidad , ADN/química , ADN/metabolismo , División del ADN/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células K562 , Cinética , Neoplasias Pulmonares/tratamiento farmacológico , Células MCF-7 , Ratones , Ratones Desnudos , Compuestos Orgánicos de Estaño/uso terapéutico , Compuestos Orgánicos de Estaño/toxicidad , Concentración Osmolar , Bases de Schiff/química , Estereoisomerismo , Compuestos de Estaño/uso terapéutico , Compuestos de Estaño/toxicidad , Trasplante HeterólogoRESUMEN
New carbohydrate-conjugated heterobimetallic complexes [C(32)H(62)N(10)O(8)NiSn(2)Cl(4)]Cl(2)(1) and [C(32)H(62)N(10)O(8)CuSn(2)Cl(4)]Cl(2) (2) were synthesized and characterized by spectroscopic (IR, (1)H, (13)C, and (119)Sn NMR, EPR, UV-vis, ESI-MS) and analytical methods. The interaction studies of 2 with CT DNA were studied by using various biophysical techniques, which showed high binding affinity of 2 toward CT DNA. The extent of interaction was further confirmed by the interaction of 2 with the nucleotides viz.; 5'-AMP, 5'-CMP, 5'-GMP, and 5'-TMP, by absorption titration. (1)H, (31)P, (119)Sn NMR spectroscopy further validated the interaction mode of 2 with 5'-GMP. The electrophoresis pattern observed for 2 with supercoiled pBR322 DNA, exhibited significantly good nuclease activity following oxidative pathway. The preferential selectivity of 2 toward the major groove was observed on interaction of 2 with pBR322 DNA, in the presence of standard groove binders viz.; DAPI and methyl green. Additionally, in vitro antitumor activity of 2 was evaluated on a panel of human cancer cell lines, exhibiting remarkable cytotoxicity activity against Colo205 (colon) and MCF7 (breast) cell lines with GI(50) values <10 µg/mL.
Asunto(s)
Antineoplásicos/farmacología , Carbohidratos/química , ADN/química , ADN/efectos de los fármacos , Desoxirribonucleasas/farmacología , Compuestos Organometálicos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Sitios de Unión/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cobre/química , Desoxirribonucleasas/síntesis química , Desoxirribonucleasas/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Níquel/química , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Relación Estructura-Actividad , Estaño/químicaRESUMEN
A library of new aryl-substituted naphthalene C8-linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates with various linker architectures were designed, synthesized, and evaluated for their anticancer activity against a panel of 11 human cancer cell lines. All 32 conjugates show anticancer potential, with some of them exhibiting particularly high activity (0.01-0.19â µM). Thermal denaturation studies showed effective DNA binding capacity relative to DC-81. In assays for biological activity relating to cell-cycle distribution, these PBD conjugates induce G0/G1-phase arrest and also cause an increase in the levels of p53 and caspase-9 proteins, followed by apoptotic cell death. One conjugate in particular is the most promising candidate of the series, with the potential to be selected for further studies, either alone or in combination with existing anticancer therapies.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzodiazepinas/farmacología , Naftalenos/farmacología , Neoplasias/tratamiento farmacológico , Pirroles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Benzodiazepinas/síntesis química , Benzodiazepinas/química , Caspasa 9/metabolismo , Línea Celular Tumoral , Diseño de Fármacos , Humanos , Naftalenos/química , Neoplasias/metabolismo , Neoplasias/patología , Pirroles/síntesis química , Pirroles/química , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
A series of new 4ß-carbamoyl epipodophyllotoxin analogues have been synthesized and evaluated for their anticancer activity against eleven cancer cell lines including Zr-75-1, MCF7, KB, Gurav, DWD, Colo 205, A-549, Hop62, PC3, SiHa and A-2780. Most of the compounds exhibited better growth-inhibition activities against tested cell lines than that of etoposide. Further, compounds 6g and 6i are also evaluated for their DNA topoisomerase-II (topo-II) inhibition activity and they exhibited significant inhibition of topo-II catalytic activity comparable to etoposide.
Asunto(s)
Antineoplásicos/síntesis química , Podofilotoxina/análogos & derivados , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Línea Celular Tumoral , ADN-Topoisomerasas de Tipo II/química , ADN-Topoisomerasas de Tipo II/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Etopósido/toxicidad , Humanos , Neoplasias/tratamiento farmacológico , Podofilotoxina/uso terapéutico , Podofilotoxina/toxicidad , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/uso terapéutico , Inhibidores de Topoisomerasa II/toxicidadRESUMEN
The new heterobimetallic Ni(II)-Sn(2)(IV) (1), Cu(II)-Sn(2)(IV) (2) and Zn(II)-Sn(2)(IV) (3) complexes, containing D-glucosamine, 1,8-diamino-3,6-diazaoctane and imidazole were isolated and characterized by spectral and analytical methods. The proposed geometry of Ni(II) and Cu(II) in 1 and 2 was square pyramidal, Zn(II) in 3 exhibited tetrahedral while Sn(IV) exhibits hexacoordinate environment, respectively. The X-ray powder diffraction (XRPD) confirmed the amorphous nature of all the complexes. The interaction studies of 2 and 3 with CT DNA were carried out by various biophysical techniques to show the mode of binding. The interaction of 2 and 3 with nucleotides viz 5'-GMP and 5'-TMP, respectively were further confirmed by (1)H, (31)P and (119)Sn NMR spectroscopy. The complex 2 exhibited effective cleavage activity with pBR322 DNA. Furthermore, the cytotoxicity of 2 was examined on a panel of human tumor cell lines of different histological origins and showed good activity against Colo205 and A2780 (GI50 < 10 µg/ml).
Asunto(s)
Carbohidratos/química , Cobre/química , ADN/química , Estroncio/química , Zinc/química , Línea Celular Tumoral , Espectroscopía de Resonancia por Spin del Electrón , Humanos , Enlace de Hidrógeno , Hidrólisis , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Espectrofotometría Infrarroja , Difracción de Rayos XRESUMEN
A series of 2,5-diaryloxadiazole linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates have been prepared and evaluated for their anticancer activity. These conjugates have shown promising activity with GI50 values ranging from <0.1 to 0.29 microM. It is observed that some of these conjugates particularly 4a, 4d, 4i and 4l exhibit significant anticancer activity. Some detailed biological assays relating to the cell cycle aspects associated to Bax and caspases have been examined with a view to understand the mechanism of action of these conjugates.
Asunto(s)
Antineoplásicos/síntesis química , Apoptosis , Benzodiazepinas/química , Mitocondrias/efectos de los fármacos , Oxadiazoles/química , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Benzodiazepinas/síntesis química , Benzodiazepinas/uso terapéutico , Caspasas/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Quinasa 2 Dependiente de la Ciclina/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Neoplasias/tratamiento farmacológico , Oxadiazoles/síntesis química , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína X Asociada a bcl-2/metabolismoRESUMEN
A series of benzothiazole and benzoxazole linked pyrrolobenzodiazepine conjugates attached through different alkane or alkylamide spacers was prepared. Their anticancer activity, DNA thermal denaturation studies, restriction endonuclease digestion assay and flow cytometric analysis in human melanoma cell line (A375) were investigated. One of the compounds of the series 17d showed significant anticancer activity with promising DNA-binding ability and apoptosis caused G0/G1 phase arrest at sub-micromolar concentrations. To ascertain the binding mode and understand the structural requirement of DNA binding interaction, molecular docking studies using GOLD program and more rigorous 2 ns molecular dynamic simulations using Molecular Mechanics-Poisson-Boltzman Surface Area (MM-PBSA) approach including the explicit solvent were carried out. Further, the compound 17d was evaluated for in vivo efficacy studies in human colon cancer HT29 xenograft mice.
Asunto(s)
Antineoplásicos/síntesis química , Benzodiazepinas/química , Benzodiazepinas/síntesis química , Benzotiazoles/química , Benzoxazoles/química , ADN/química , Pirroles/química , Pirroles/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Apoptosis , Benzodiazepinas/uso terapéutico , Sitios de Unión , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Fase G1 , Humanos , Ratones , Simulación de Dinámica Molecular , Desnaturalización de Ácido Nucleico , Pirroles/uso terapéutico , Fase de Descanso del Ciclo Celular , Programas Informáticos , Trasplante HeterólogoRESUMEN
A series of 3,5-diaryl-isoxazoline/isoxazole linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates were prepared. These conjugates showed potent anticancer activity with GI(50) values in the range of <0.1-3.6 microM. Some of these PBD conjugates (6a-c) with promising anticancer activity were further investigated on the cell cycle distribution. Moreover, these PBD conjugates exhibited G0/G1 arrest, enhancement in the levels of p53 protein as well as mitochondrial-mediated intrinsic pathway, leading to release of cytochrome c, activation of caspase-3, cleavage of PARP and subsequent apoptotic cell death. Hence these PBD conjugates with 6a being the most potent one could be be taken up for preclinical studies either alone or in combination with existing therapies.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Benzodiazepinas/química , Benzodiazepinas/farmacología , Diseño de Fármacos , Isoxazoles/química , Isoxazoles/farmacología , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Benzodiazepinas/síntesis química , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Isoxazoles/síntesis químicaRESUMEN
A series of novel anthranilamide linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates were prepared and evaluated for their anticancer activity. The effects of three promising PBD conjugates on cell cycle of cancerous cell line A375 were investigated. These promising compounds showed the characteristic features of apoptosis like enhancement in the levels of p53 and activation of caspase-3.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis , Benzodiazepinas/química , Pirroles/química , ortoaminobenzoatos/síntesis química , ortoaminobenzoatos/farmacología , Caspasa 3/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Citometría de Flujo , Humanos , Proteína p53 Supresora de Tumor/metabolismo , ortoaminobenzoatos/químicaRESUMEN
A series of novel quinazolinone linked pyrrolobenzodiazepine (PBD) conjugates were synthesized. These compounds 4a-f and 5a-f were prepared in good yields by linking C-8 of DC-81 with quinazolinone moiety through different alkane spacers. These conjugates were tested for anticancer activity against 11 human cancer cell lines and found to be very potent anticancer agents with GI(50) values in the range of <0.1-26.2microM. Among all the PBD conjugates, one of the conjugate 5c was tested against a panel of 60 human cancer cells. This compound showed activity for individual cancer cell lines with GI(50) values of <0.1microM. The thermal denaturation studies exhibited effective DNA binding ability compared to DC-81 and these results are further supported by molecular modeling studies. The detailed biological aspects of these conjugates on A375 cell line were studied. It was observed that compounds 4b and 5c induced the release of cytochrome c, activation of caspase-3, cleavage of PARP and subsequent cell death. Further, these compounds when treated with A375 cells showed the characteristic features of apoptosis like enhancement in the levels of p53, p21 and p27 inhibition of cyclin dependent kinase-2 (CDK2) and suppression of NF-kappaB. Moreover, these two compounds 4b and 5c control the cell proliferation by regulating anti-apoptotic genes like (B-cell lymphoma 2) Bcl-2. Therefore, the data generated suggests that these PBD conjugates activate p53 and inhibit NF-kappaB and thereby these compounds could be promising anticancer agents with better therapeutic potential for the suppression of tumours.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Benzodiazepinas/química , Diseño de Fármacos , Pirroles/química , Quinazolinonas/química , Antineoplásicos/química , Benzodiazepinas/farmacología , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Simulación de Dinámica Molecular , Estructura Molecular , Pirroles/farmacología , Quinazolinonas/farmacología , Estereoisomerismo , Células Tumorales CultivadasRESUMEN
Eight novel 1-(substituted acetyl)-4-(10-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6] cyclohepta [1,2-b] pyridine-11-ylidene)piperidines were designed by incorporating zinc binding groups to enhance activity. The designed molecules were synthesized and were evaluated for antitumor activity in vitro in five cell lines and for farnesyl protein transferase inhibition. Test compounds (6a-h) exhibited antitumor activity in most of the cell lines but were less potent than adriamycin. Compound 6e was most active with IC(50) values of <15 µM in two cell lines tested. Test compounds also exhibited potent FPT inhibitory activity and 6c was most potent with IC(50) value of <30 µM.
RESUMEN
A series of triazolobenzothiadiazine-pyrrolobenzodiazepine conjugates linked through different alkane spacers have been prepared. These compounds have exhibited significant cytotoxicity against most of the cell lines examined. Compound 5a displays GI(50) values from 1.83 to 2.38 microM against seven human tumour cell lines, and is identified as a promising lead compound from this series. Their DNA thermal denaturation studies have also been carried out, and one of the compounds 5c elevates the DNA helix melting temperature of the CT-DNA by 2.6 degrees C after incubation for 36 h.
Asunto(s)
Antineoplásicos/síntesis química , Benzodiazepinas/química , Benzodiazepinas/farmacología , Benzotiadiazinas/síntesis química , Benzotiadiazinas/farmacología , ADN/metabolismo , Pirroles/química , Pirroles/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Benzodiazepinas/síntesis química , Benzotiadiazinas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN/química , ADN de Neoplasias/química , ADN de Neoplasias/metabolismo , Humanos , Espectroscopía de Resonancia Magnética , Neoplasias de la Boca/tratamiento farmacológico , Desnaturalización de Ácido Nucleico/efectos de los fármacos , Pirroles/síntesis química , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en TándemRESUMEN
A series of pyrrolobenzodiazepine-naphthalimide conjugates tethered through a piperazine ring system have been designed, synthesized, and evaluated for their anticancer activity. These new conjugates exhibit very high DNA binding affinity and cytotoxic activity against a number of cell lines.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , ADN/química , Naftalimidas/química , Naftalimidas/farmacología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Desnaturalización de Ácido Nucleico , Relación Estructura-ActividadRESUMEN
A novel class of molecules with structure N-[3-(heteroaryl)propyl]-6-methoxynaphthalene-2-carboxamides 8-13 were synthesized by condensing 6-methoxy-2-naphthoyl chloride 1 with 3-(heteroaryl)propyl amines 2-7. Compounds 8-12 were evaluated in vitro, in P388 murine lymphocytic leukemia cell line (P388) using SRB assay for cytotoxicity and in adriamycin resistant P388 murine lymphocytic leukemia cell line (P388/ADR) using MTT assay for resistant reversal activity. Compounds 8-12 were non-toxic at lower dose of 20 microg/ml, and effectively reversed adriamycin resistance. However, at higher doses (40, 80 microg/ml) they showed significant cytotxicity and hence reversal potency was not determined at these concentrations.
Asunto(s)
Amidas/síntesis química , Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Naftalenos/síntesis química , Amidas/farmacología , Naftalenos/farmacología , Relación Estructura-ActividadRESUMEN
Thalidomide's reported ability to inhibit tumor angiogenesis has led to clinical trials determining its effectiveness in combating various types of cancer. Since thalidomide exhibits low oral bioavailability due to limitations in solubility, inclusion complexation using sulfobutyl ether-7 beta-cyclodextrin was used to improve the delivery of thalidomide. Our main goals were to increase the solubility, bioavailability as well as chemical stability of thalidomide through complexation with anionic beta-cyclodextrin, to characterize the complex in solid state using differential scanning calorimetry, X-ray powder diffractometry, and to explore thalidomide's antitumorigenic and antiangiogenesis potential when administered orally as free and in combination with cyclodextrin to experimental animals. The aqueous solubility and aqueous alkaline stability of thalidomide was markedly increased by the SBE7betaCD complexation. Thalidomide administered orally in combination with SBE7betaCD, led to a significant delay in tumor formation as a result of improved cellular drug absorption, distribution through solubilization in experimental animals. The improved pharmacological efficacy of the thalidomide-cyclodextrin complex compared to free thalidomide in mouse melanoma model suggest that such a delivery system may be useful for the improved therapeutics of thalidomide, in vivo.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Melanoma Experimental/tratamiento farmacológico , Talidomida/uso terapéutico , beta-Ciclodextrinas/química , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/farmacocinética , Animales , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Femenino , Melanoma Experimental/irrigación sanguínea , Melanoma Experimental/patología , Ratones , Neovascularización Patológica , Solubilidad , Talidomida/administración & dosificación , Talidomida/farmacocinética , Difracción de Rayos X , beta-Ciclodextrinas/administración & dosificaciónRESUMEN
Pyrrolobenzodiazepine-diethylphosphonate conjugates have been designed and synthesized that link through two different types of spacers that are simple alkane chain and also a piperazine moiety side-armed with the alkane chains. These pyrrolobenzodiazepine conjugates have exhibited remarkable DNA-binding affinity and improved solubility in water, a representative compound 7d showing promising in vitro cytotoxicity.
Asunto(s)
Benzodiazepinas/síntesis química , Benzodiazepinas/toxicidad , ADN/química , Organofosfonatos/química , Pirroles/síntesis química , Pirroles/toxicidad , Aminación , Animales , Benzodiazepinas/química , Bovinos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Dimerización , Humanos , Estructura Molecular , Desnaturalización de Ácido Nucleico , Pirroles/química , Relación Estructura-Actividad , TemperaturaRESUMEN
1,2,3-Triazole based molecules are useful pharmacophores for several DNA-alkylating and cross-linking agents. A series of A/C8, C/C2 and A/C8-C/C2-linked 1,2,3-triazole-PBD conjugates have been synthesized by employing 'click' chemistry. These molecules have exhibited promising DNA-binding affinity and anticancer activity in selected human cancer cell lines.
Asunto(s)
Antineoplásicos/síntesis química , Benzodiazepinas/síntesis química , ADN/química , Pirroles/síntesis química , Triazoles/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Benzodiazepinas/química , Benzodiazepinas/farmacología , Línea Celular Tumoral , ADN/metabolismo , Humanos , Cinética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Pirroles/química , Pirroles/farmacología , Triazoles/química , Triazoles/farmacologíaRESUMEN
Four N-(benzenesulfonyl)-L-glutamic acid bis(p-substituted phenylhydrazides) were synthesized and evaluated for anticancer activity in vitro in DU-145 and PC-3 prostate cancer and in COLO-205 colon cancer cell lines by MTT assay. The analog with the nitro group substitution exhibited potent activity (% Inhibition 84.7 and 72.0 in DU-145 and PC-3 respectively at 80 mug/ml concentration). Another series of substituted 1-(benzenesulfonyl)-5-oxopyrrolidine 2-carboxamides (11a-f) were synthesized and evaluated for anticancer activity in vitro in colon (COLO-205), breast (Zr-75-1) and prostate (PC-3) cancer cell lines by MTT assay using adriamycin as standard. Test compounds 11a-c showed potent activity (% Inhibition 61.2 to 79.2 at 20 mug/ml and 67.2 to 87.2 at 40 mug/ml) in PC-3 cell line which is superior to the activity of Adriamycin. In comparison compounds 11d-f were less potent. In Zr-75-1 cell line 11a-e showed % inhibition ranging from 32.4 to 54.9 at 10 mug/ml concentration while in COLO-205 cell line 11a-f showed poor activity.