RESUMEN

In the present study, natural phaeosphaeride A (PPA) derivatives are synthesized. Anti-tumor studies are carried out on the PC3, K562, HCT-116, THP-1, MCF-7, A549, NCI-H929, Jurkat, and RPMI8226 tumor cell lines, and on the human embryonic kidney (HEK293) cell line. All the compounds synthesized turned out to have better efficacy than PPA towards the tumor cell lines listed. Among them, three compounds exhibited an ability to overcome the drug resistance of tumor cells associated with the overexpression of the P-glycoprotein by modulating the work of this transporter. Luminex xMAP technology was used to assess the effect of five synthesized compounds on the activation of intracellular kinase cascades in A431 cells. MILLIPLEX MAP Multi-Pathway Magnetic Bead 9-Plex was used, which allowed for the simultaneous detection of the following nine phosphorylated protein markers of the main intracellular signaling pathways: a universal transcription factor that controls the expression of immune-response genes, apoptosis and cell cycle NFκB (pS536); cAMP-dependent transcription factor (CREB (pS133); mitogen-activated kinase p38 (pT180/pY182); stress-activated protein kinase JNK (pT183/pY185); ribosomal SK; transcription factors STAT3 (pS727) and STAT5A/B (pY694/699); protein kinase B (Akt) (pS473); and kinase regulated by extracellular signals ERK1/2 (pT185/pY187). The effect of various concentrations of PPA derivatives on the cell culture was studied using xCelligence RTCA equipment. The compounds were found to modulate JNK, ERK1/2, and p38 signaling pathways. The set of activated kinase cascades suggests that oxidative stress is the main probable mechanism of the toxic action of PPA derivatives.

RESUMEN

New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor studies were carried out on the U937, HCT-116, PC3, MCF-7, A549, К562, NCI-H929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All the compounds synthesized were found to have better efficacy than PPA towards the tumor cell lines mentioned. Compound 6 (IC50 = 0.59 ±â€¯0.27 µM) was observed to be 11 times more active than PPA (IC50 = 6.5 ±â€¯0.30 µM) towards the NCI-H929 cell line, with a therapeutic index of 18. Compound 6 was determined to be over half and 16 times more active than etoposide towards the NCI-H929 (IC50 = 0.9 ±â€¯0.05 µM) and A549 (IC50 = 100 ±â€¯7.0 µM) cell lines, respectively.

Asunto(s)

Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Relación Estructura-Actividad

RESUMEN

New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor activity studies were carried out on the HCT-116, PC3, MCF-7, A549, К562, NCI-Н929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All of the compounds synthesized were found to have better efficacy than PPA towards the tumor cell lines mentioned. Compound 6 was potent against six cancer cell lines, HCT-116, PC-3, K562, NCI-H929, Jurkat, and RPMI8226, showing a 47, 13.5, 16, 4, 1.5, and 7-fold increase in anticancer activity comparative to those of etoposide, respectively. Compound 1 possessed selectivity toward the NCI-H929 cell line (IC50 = 1.35 ± 0.69 µM), while product 7 was selective against three cancer cell lines, HCT-116, MCF-7, and NCI-H929, each having IC50 values of 1.65 µM, 1.80 µM and 2.00 µM, respectively.

Asunto(s)

Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Células A549 , Antineoplásicos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Células Jurkat , Células MCF-7 , Estructura Molecular , Relación Estructura-Actividad

RESUMEN

Derivatives of phaeosphaeride A (PPA) were synthesised and characterised; then anti-cancer studies were carried out on the A549 cancer cell line. It was found that the acetyl derivative (compound 3) displayed comparable in vitro cytotoxicity to that of PPA (EC50=49±7 µM and EC50=46±5 µM, respectively), while chloroacetyl derivative 6 (EC50=33±7 µM) was found to have better efficacy towards the A549 cancer cell line.

Asunto(s)

Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular

RESUMEN

The asymmetric unit of the title compound, C15H23NO5, contains two independent mol-ecules. Phaeosphaeride A contains two primary sections, an alkyl chain consisting of five C atoms and a cyclic system consisting of fused five- and six-membered rings with attached substituents. In the crystal, the mol-ecules form layered structures. Nearly planar sheets, parallel to the (001) plane, form bilayers of two-dimensional hydrogen-bonded networks with the hy-droxy groups located on the inter-ior of the bilayer sheets. The network is constructed primarily of four O-H⋯O hydrogen bonds, which form a zigzag pattern in the (001) plane. The butyl chains inter-digitate with the butyl chains on adjacent sheets. The crystal was twinned by a twofold rotation about the c axis, with refined major-minor occupancy fractions of 0.718 (6):0.282 (6).

RESUMEN

Retinoids are a class of compounds with structural similarity to vitamin A. These compounds inhibit the proliferation of many cancer cell lines but have had limited medical application as they are often toxic at therapeutic levels. Efforts to synthesize retinoids with a greater therapeutic index have met with limited success. 4-[(1E)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-propen-1-yl]benzoic acid (TTNPB) is one of the most biologically active all-trans-retinoic acid (atRA) analogues and is highly teratogenic. In this study, we show that modification of the TTNPB carboxyl group with an N-(4-hydroxyphenyl)amido (4HPTTNPB) or a 4-hydroxybenzyl (4HBTTNPB) group changes the activity of the compound in cell culture and in vivo. Unlike TTNPB, both compounds induce apoptosis in cancer cells and bind poorly to the retinoic acid receptors (RARs). Like the similarly modified all-trans-retinoic acid (atRA) analogues N-(4-hydroxyphenyl)retinamide (4-HPR/fenretinide) and 4-hydroxybenzylretinone (4-HBR), 4HBTTNPB is a potent activator of components of the ER stress pathway. The amide-linked analogue, 4HPTTNPB, is less toxic to developing embryos than the parent TTNPB, and most significantly, the 4-hydroxybenzyl-modified compound (4HBTTNPB) that cannot be hydrolyzed in vivo to the parent TTNPB compound is nearly devoid of teratogenic liability.

Asunto(s)

Antineoplásicos/síntesis química , Benzoatos/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Retículo Endoplásmico/efectos de los fármacos , Fenretinida/uso terapéutico , Receptores de Ácido Retinoico/metabolismo , Retinoides/síntesis química , Vitamina A/análogos & derivados , Administración Oral , Amidas/química , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Benzoatos/efectos adversos , Benzoatos/uso terapéutico , Unión Competitiva , Neoplasias de la Mama/patología , División Celular/efectos de los fármacos , Línea Celular Tumoral , Retículo Endoplásmico/metabolismo , Femenino , Fenretinida/síntesis química , Humanos , Fenol/química , Embarazo , Ratas , Ratas Sprague-Dawley , Retinoides/efectos adversos , Retinoides/uso terapéutico , Teratógenos , Factor de Transcripción CHOP/biosíntesis , Vitamina A/síntesis química , Vitamina A/uso terapéutico

RESUMEN

The title compound, C(5)H(6)BrNO(4)S, crystallizes in the centrosymmetric space group P2(1)/c. Three weak C-H.O hydrogen bonds dominate the packing of the molecules in the solid. These weak hydrogen bonds and a short intermolecular O...Br contact of 3.003 (2) A are discussed using a Mulliken population analysis.