RESUMEN
Overexpression of the histone lysine demethylase KDM4A, which regulates H3K9 and H3K36 methylation states, has been related to the pathology of several human cancers. We found that a previously reported hydroxamate-based histone deacetylase (HDAC) inhibitor (SW55) was also able to weakly inhibit this demethylase with an IC50 value of 25.4â µm. Herein we report the synthesis and biochemical evaluations, with two orthogonal inâ vitro assays, of a series of derivatives of this lead structure. With extensive chemical modifications on the lead structure, also by exploiting the versatility of the radical arylation with aryldiazonium salts, we were able to increase the potency of the derivatives against KDM4A to the low-micromolar range and, more importantly, to obtain demethylase selectivity with respect to HDACs. Cell-permeable derivatives clearly showed a demethylase-inhibition-dependent antiproliferative effect against HL-60 human promyelocytic leukemia cells.
Asunto(s)
Ácidos Hidroxámicos/farmacología , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Humanos , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/química , Histona Demetilasas con Dominio de Jumonji/metabolismo , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The term epigenetics is defined as heritable changes in gene expression that are not due to alterations of the DNA sequence. In the last years, it has become more and more evident that dysregulated epigenetic regulatory processes have a central role in cancer onset and progression. In contrast to DNA mutations, epigenetic modifications are reversible and, hence, suitable for pharmacological interventions. Reversible histone methylation is an important process within epigenetic regulation, and the investigation of its role in cancer has led to the identification of lysine methyltransferases and demethylases as promising targets for new anticancer drugs. In this review, we describe those enzymes and their inhibitors that have already reached the first stages of clinical trials in cancer therapy, namely the histone methyltransferases DOT1L and EZH2 as well as the demethylase LSD1.
Asunto(s)
Antineoplásicos/farmacología , Histona Demetilasas/antagonistas & inhibidores , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Epigénesis Genética/efectos de los fármacos , Histona Metiltransferasas , Humanos , Metiltransferasas/antagonistas & inhibidores , Neoplasias/enzimología , Neoplasias/genéticaRESUMEN
In the present study, we have further extended the structure-activity relationships for the tetrazolyl ureas class of compounds as potential FAAH and/or MAGL inhibitors, by replacing the dimethylamino group of the parent compounds 1 and 2 with bulkier groups or by introducing on the distal phenyl ring of 1 and 2 a selected set of substituents. Some of the new compounds (16, 20, 21, 25, and 28) inhibited FAAH potently (IC50 = 3.0-9.7 nM) and selectively (39- to more than 141-fold) over MAGL, while tetrazole 27 turned out to be a promising dual FAAH-MAGL inhibitor of potential therapeutic use. Covalent docking studies on FAAH indicated that the binding modes of tetrazoles 1-32 did not display a unique pattern. The ability of tetrazoles 1-32 to act as TRPV1 and TRPA1 modulators was also investigated.
Asunto(s)
Endocannabinoides/antagonistas & inhibidores , Endocannabinoides/metabolismo , Tetrazoles/química , Tetrazoles/farmacología , Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/química , Amidohidrolasas/metabolismo , Animales , Células COS , Canales de Calcio/metabolismo , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Células HEK293 , Humanos , Activación del Canal Iónico/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Monoacilglicerol Lipasas/antagonistas & inhibidores , Monoacilglicerol Lipasas/química , Monoacilglicerol Lipasas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Ratas , Relación Estructura-Actividad , Canal Catiónico TRPA1 , Canales Catiónicos TRPV/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo , Urea/química , Urea/farmacologíaRESUMEN
A series of (1H-benzo[d][1,2,3]triazol-1-yl)(4-benzylpiperazin-1-yl)methanones and of (1H-benzo[d][1,2,3]triazol-1-yl)(4-phenylpiperazin-1-yl)methanones has been prepared and tested on human fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). In the benzylpiperazinyl series, compound 29 (ML30) exhibited an IC(50) value of 0.54 nM on MAGL, combined with a 1000-fold selectivity versus FAAH, while compounds 11 and 16 acted as potent dual FAAH-MAGL inhibitors (IC(50)<10 nM). In the phenylpiperazinyl series, compounds 37, 38, 42, and 43 displayed IC(50) values against MAGL in the nanomolar range, whilst being between one and two orders of magnitude less potent on the FAAH, while compounds 31 and 32 were potent FAAH inhibitors (IC(50)<20 nM) and over 12-fold selective versus MAGL. The key structural determinants driving the structure-activity relationships were explored by the minimization of the inhibitors inside the active site of both enzymes.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Monoacilglicerol Lipasas/antagonistas & inhibidores , Piperazinas/farmacología , Triazoles/farmacología , Amidohidrolasas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Humanos , Modelos Moleculares , Estructura Molecular , Monoacilglicerol Lipasas/metabolismo , Piperazinas/síntesis química , Piperazinas/química , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/químicaRESUMEN
We synthesized new N-phenylethyl-1H-indole-2-carboxamides as the first SAR study of allosteric modulators of the CB(1) receptor. The presence of the carboxamide functionality was required in order to obtain a stimulatory effect. The maximum stimulatory activity on CB(1) was exerted by carboxamides 13 (EC(50) = 50 nM) and 21 (EC(50) = 90 nM) bearing a dimethylamino or piperidinyl group, respectively, at position 4 of the phenethyl moiety and a chlorine atom at position 5 of the indole.
Asunto(s)
Amidas/síntesis química , Indoles/síntesis química , Receptor Cannabinoide CB1/metabolismo , Regulación Alostérica , Amidas/química , Amidas/farmacología , Membrana Celular/metabolismo , Humanos , Indoles/química , Indoles/farmacología , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacología , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/farmacología , Ensayo de Unión Radioligante , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
A series of thirty-three thymol, p-cymene-3-carboxylic acid, and 3-amino-p-cymene derivatives was synthesized and tested on TRPA1, TRPM8, and TRPV3 channels. Most of them acted as strong modulators of TRPA1, TRPM8, and TRPV3 channels with EC(50) and/or IC(50) values distinctly lower than those of thymol and related monoterpenoids. Some of the compounds examined, that is, 3c, 4e, f, 6b, and 8b exhibited an appreciable subtype-selectivity.
Asunto(s)
Timol/farmacología , Canales de Potencial de Receptor Transitorio/efectos de los fármacos , Animales , Línea Celular , Humanos , Ratas , Timol/químicaRESUMEN
The single enantiomers of two pyrimidine-based HIV-1 non-nucleoside reverse transcriptase inhibitors, 1 (MC1501) and 2 (MC2082), were tested in both cellular and enzyme assays. In general, the R forms were more potent than their S counterparts and racemates and (R)-2 was more efficient than (R)-1 and the reference compounds, with some exceptions. Interestingly, (R)-2 displayed a faster binding to K103N RT with respect to WT RT, while (R)-1 showed the opposite behavior.
Asunto(s)
Fármacos Anti-VIH/química , Derivados del Benceno/química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Pirimidinonas/química , Fármacos Anti-VIH/farmacología , Derivados del Benceno/farmacología , Línea Celular , Pruebas de Enzimas , Transcriptasa Inversa del VIH/química , VIH-1/genética , Humanos , Cinética , Modelos Moleculares , Mutación , Pirimidinonas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
In order to explore the structural determinants for the TRPV1 and TRPA1 agonist properties of gingerols, a series of nineteen analogues (1b-5) of racemic [6]-gingerol (1a) was synthesized and tested on TRPV1 and TRPA1 channels. The exploration of the structure-activity relationships, by modulating the three pharmacophoric regions of [6]-gingerol, led to the identification of some selective TRPV1 agonists/desensitizers of TRPV1 channels (3a, 3f, and 4) and of some full TRPA1 antagonists (2c, 2d, 3b, and 3d).
Asunto(s)
Catecoles/síntesis química , Alcoholes Grasos/síntesis química , Proteínas del Tejido Nervioso/agonistas , Canales Catiónicos TRPV/agonistas , Canales de Potencial de Receptor Transitorio/agonistas , Canales de Calcio , Catecoles/química , Catecoles/farmacología , Alcoholes Grasos/química , Alcoholes Grasos/farmacología , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Unión Proteica/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Canal Catiónico TRPA1 , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidoresRESUMEN
A series of twenty-two (-)-menthylamine derivatives was synthesized and tested on TRPM8, TRPV1, and TRPA1 channels. Five of the novel compounds, that is, 1d, 1f, 2b, 2c, and 2e behaved as potent TRPM8 antagonists with IC(50) values versus icilin and (-)-menthol between 20 nM and 0.7 microM, and were between 4- and approximately 150-fold selective versus TRPV1 and TRPA1 activation. Compound 1d also induced caspase 3/7 release in TRPM8-expressing LNCaP prostate carcinoma cells, but not in non-TRPM8 expressing DU-145 cells. Five other derivatives, that is, 1a, 1g, 1h, 2f, and 2h were slightly less potent than previous compounds but still relatively selective versus TRPV1 and TRPA1.
Asunto(s)
Antineoplásicos/química , Mentol/análogos & derivados , Canales Catiónicos TRPM/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular Tumoral , Humanos , Mentol/síntesis química , Mentol/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Canales Catiónicos TRPM/metabolismoRESUMEN
The evaluation of a series of piperazinyl carbamates and ureas, designed on the basis of previously reported TRPV1 antagonists and FAAH inhibitors, led to the identification of some 'dual-action' compounds targeting both FAAH and TRPV1 or TRPA1 receptors.