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 EC50 and/or IC50 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.
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.
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).
We synthesized new N-phenylethyl-1H-indole-2-carboxamides as the first SAR study of allosteric modulators of the CB1 receptor. The presence of the carboxamide functionality was required in order to ...obtain a stimulatory effect. The maximum stimulatory activity on CB1 was exerted by carboxamides 13 (EC50 = 50 nM) and 21 (EC50 = 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.
A series of (1H-benzod1,2,3triazol-1-yl)(4-benzylpiperazin-1-yl)methanones and of (1H-benzod1,2,3triazol-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 IC50 value of 0.54nM on MAGL, combined with a 1000-fold selectivity versus FAAH, while compounds 11 and 16 acted as potent dual FAAH-MAGL inhibitors (IC50<10nM). In the phenylpiperazinyl series, compounds 37, 38, 42, and 43 displayed IC50 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 (IC50<20nM) 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.
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.
Display omitted A new series of carbamoyl tetrazoles has been synthesized and evaluated as inhibitors of FAAH and MAGL and as TRPV1 and TRPA1 modulators.
► A series of 30 new biaryl tetrazolyl ureas has been synthesized. ► Some of the prepared compounds inhibited FAAH potently and selectively over MAGL. ► The action on TRPV1 and TRPA1 channels was also investigated. ► Results were discussed using covalent docking.
The evaluation of a series of (−)-menthylamine derivatives led to the identification of some potent TRPM8 antagonists with IC
50 values versus icilin and (−)-menthol between 20
nM and 0.7
μM and ...between 4- and ∼150-fold selective versus TRPV1 and TRPA1 activation.
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
μM, and were between 4- and ∼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.
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 channels.
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.
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 25.4 μm. Herein we report the synthesis and biochemical evaluations, with two orthogonal in 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.
Switching inhibitory activity: By starting from the reported histone deacetylase (HDAC) inhibitor SW55 (HDAC1 IC50: 52.7 nm; HDAC6 IC50: 107.0 nm), we were able, with broad structural modifications and also by exploiting the versatility of the radical arylation with aryldiazonium salts, to increase the inhibitory potency against the histone demethylase KDM4A into the low‐micromolar range (SW55 KDM4A IC50: 25.4 μm; 16 p and 16 r KDM4A IC50: 6.8 μm). More importantly, we were able to decrease, and for some compounds even abolish, histone deacetylase activity.
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