RESUMEN
Upregulation of cathepsin L in a variety of tumors and its ability to promote cancer cell invasion and migration through degradation of the extracellular matrix suggest that cathepsin L is a promising biological target for the development of anti-metastatic agents. Based on encouraging results from studies on benzophenone thiosemicarbazone cathepsin inhibitors, a series of fourteen benzoylbenzophenone thiosemicarbazone analogues were designed, synthesized, and evaluated for their inhibitory activity against cathepsins L and B. Thiosemicarbazone inhibitors 3-benzoylbenzophenone thiosemicarbazone 1, 1,3-bis(4-fluorobenzoyl)benzene thiosemicarbazone 8, and 1,3-bis(2-fluorobenzoyl)-5-bromobenzene thiosemicarbazone 32 displayed the greatest potency against cathepsin L with low IC50 values of 9.9 nM, 14.4 nM, and 8.1 nM, respectively. The benzoylbenzophenone thiosemicarbazone analogues evaluated were selective in their inhibition of cathepsin L compared to cathepsin B. Thiosemicarbazone analogue 32 inhibited invasion through Matrigel of MDA-MB-231 breast cancer cells by 70% at 10 µM. Thiosemicarbazone analogue 8 significantly inhibited the invasive potential of PC-3ML prostate cancer cells by 92% at 5 µM. The most active cathepsin L inhibitors from this benzoylbenzophenone thiosemicarbazone series (1, 8, and 32) displayed low cytotoxicity toward normal primary cells [in this case human umbilical vein endothelial cells (HUVECs)]. In an initial in vivo study, 3-benzoylbenzophenone thiosemicarbazone (1) was well-tolerated in a CDF1 mouse model bearing an implanted C3H mammary carcinoma, and showed efficacy in tumor growth delay. Low cytotoxicity, inhibition of cell invasion, and in vivo tolerability are desirable characteristics for anti-metastatic agents functioning through an inhibition of cathepsin L. Active members of this structurally diverse group of benzoylbenzophenone thiosemicarbazone cathepsin L inhibitors show promise as potential anti-metastatic, pre-clinical drug candidates.
Asunto(s)
Antineoplásicos/síntesis química , Catepsina L/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Tiosemicarbazonas/química , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Benzofenonas/química , Sitios de Unión , Catepsina B/antagonistas & inhibidores , Catepsina B/metabolismo , Catepsina L/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Inhibidores de Cisteína Proteinasa/farmacología , Inhibidores de Cisteína Proteinasa/uso terapéutico , Diseño de Fármacos , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Concentración 50 Inhibidora , Isomerismo , Cinética , Neoplasias Mamarias Animales/tratamiento farmacológico , Ratones , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/uso terapéutico , Trasplante HeterólogoRESUMEN
The macrocyclic diarylether heptanoid (MDEH) natural products have been used in folk medicine for centuries. MDEHs are reported to exert anti-tumor properties by inhibiting the activation of NF-κB. Here we report the synthesis of a small MDEH library (first reported synthesis of racemic platycarynol) using a Grubbs cross metathesis/Ullmann cyclization strategy. Evaluation of the library led to the identification of MDEH 9b which sensitizes pancreatic cancer cells to gemcitabine mediated growth inhibition and apoptosis.
Asunto(s)
Éter/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Antineoplásicos/farmacología , Apoptosis , Productos Biológicos/química , Productos Biológicos/farmacología , Línea Celular , Química Farmacéutica/métodos , Diseño de Fármacos , Células HEK293 , Humanos , Modelos Químicos , FN-kappa B/metabolismo , Factores de Tiempo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
A small library of 36 functionalized benzophenone thiosemicarbazone analogs has been prepared by chemical synthesis and evaluated for their ability to inhibit the cysteine proteases cathepsin L and cathepsin B. Inhibitors of cathepsins L and B have the potential to limit or arrest cancer metastasis. The six most active inhibitors of cathepsin L (IC50<85 nM) in this series incorporate a meta-bromo substituent in one aryl ring along with a variety of functional groups in the second aryl ring. These six analogs are selective for their inhibition of cathepsin L versus cathepsin B (IC50>10,000 nM). The most active analog in the series, 3-bromophenyl-2'-fluorophenyl thiosemicarbazone 1, also efficiently inhibits cell invasion of the DU-145 human prostate cancer cell line.
Asunto(s)
Catepsina B/antagonistas & inhibidores , Catepsina L/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/farmacología , Diseño de Fármacos , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/farmacología , Dominio Catalítico , Inhibidores de Cisteína Proteinasa/química , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Tiosemicarbazonas/químicaRESUMEN
An environmentally benign PMA supported on SiO(2) is found to be an efficient catalyst for the chemoselective deprotection of TBDMS ethers under very mild conditions. Various labile functional groups such as isopropylidene acetal, OTBDPS, OTHP, Oallyl, OBn, alkene, alkyne, OAc, OBz, N-Boc, N-Cbz, N-Fmoc, mesylate, and azide are found to be stable under the reaction conditions. This "truly catalytic" heterogeneous reaction does not require aqueous workup, and the supported catalyst and the solvent can be readily recovered and recycled.