Natural Tetraponerines: A General Synthesis and Antiproliferative Activity

A stereocontrolled general methodology to access all natural tetraponerines from (+)-<b>T1</b> to (+)-<b>T8</b> is detailed. Two consecutive indium-mediated aminoallylations with the appropriate enantiomer of chiral <i>N</i>-<i>tert</i>-butylsulfinamide and a thermodynamic control at the aminal stereocenter allow the formation of each natural tetraponerine with excellent stereoselectivity. The use of 4-bromobutanal in the first aminoallylation leads to the formation of 5–6–5 tetraponerines, while 5-bromopentanal is required to build the scaffold of 6–6–5 tetraponerines. A cross-metathesis reaction of the second aminoallylation product with <i>cis</i>-3-hexene is used to elongate the side chain up to 5 carbons so as to prepare the tetraponerines <b>T5</b> to <b>T8</b>. The anticancer activity of these heavier tetraponerines against four different carcinoma human cell lines is examined, observing a promising cytotoxic activity of (+)-<b>T7</b> against breast carcinoma cell line MCF-7

Syntheses and Cytotoxicity of (<i>R</i>)- and (<i>S</i>)‑7-Methoxycryptopleurine

Two efficient protocols are described for the transformation of a key chiral homoallyllic sulfinamine intermediate in four steps into enantioenriched 7-methoxycryptopleurine. While one of the protocols relied on a rhodium catalyzed linear hydroformylation process, the alternative approach was based on a ring-closing metathesis from the corresponding <i>N-</i>allyl-sulfinamine. The cytotoxic evaluation of both enantiomers of the target compound demonstrated that the (<i>R</i>)-compound is much more potent than its antipode against the four cancer cell lines examined

<i>cis</i>-Platinum Complex Encapsulated in Self-Assembling Cyclic Peptide Dimers

A new cyclic peptide dimer that encapsulates cisplatin complexes in its internal cavity is described. The resulting complex showed cytotoxic activity at A2780 ovarian cancer cell lines independent of acquired platinum resistance

Effect of Bulky <i>N</i>‑Dibenzofuranylmethyl Substitution on the 5‑HT₂ Receptor Affinity and Efficacy of a Psychedelic Phenethylamine

The introduction of arylmethyl substituents on the amine nitrogen atom of phenethylamines and tryptamines often results in profound increases in their affinity and functional activity at 5-HT2 serotonin receptors. To probe the sensitivity of this effect to substantially larger N-substituents, ten derivatives of the well-characterized psychedelic phenethylamine 2C–B were prepared by appending different dibenzo[b,d]furylmethyl (DBFM) moieties to the basic nitrogen. The DBFM group attached to the amino group through its 1-, −2-, or 3-position decreased affinity and agonist activity at the 5-HT2A/2C receptors. Substitution through the 4-position usually favored affinity for all three 5-HT2 receptor subtypes with compound 5 exhibiting 10- and 40-fold higher affinities at the 5-HT2A and 5-HT2C receptors, respectively, but less than fourfold selectivity among the three receptor subtypes. Nevertheless, all were relatively weak partial 5-HT2AR agonists, mostly in the low micromolar range, but full or nearly full agonists at the 5-HT2C subtype as determined in a calcium mobilization assay. Molecular docking simulations suggested that the dibenzofuryl portion dives more deeply into the orthosteric binding site of the 5-HT2A than the 5-HT2C receptor, interacting with the Trp3366.48 toggle switch associated with its activation, while the phenylamine moiety lies close to the extracellular side of the receptor. In conclusion, a very bulky N-substituent on a phenethylamine 5-HT2 receptor agonist is tolerated and may increase affinity if its orientation is appropriate. However, the Gq protein-mediated potencies are generally low, with low efficacy (relative to 5-HT) at the 5-HT2A receptor, somewhat higher efficacy at the 5-HT2B subtype, and full or nearly full efficacy at the 5-HT2C subtype

Enantiospecific Recognition at the A_2B Adenosine Receptor by Alkyl 2‑Cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates

A novel family of structurally simple, potent, and selective nonxanthine A_2BAR ligands was identified, and its antagonistic behavior confirmed through functional experiments. The reported alkyl 2-cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahy-dropyrimidine-5-carboxylates (<b>16</b>) were designed by bioisosteric replacement of the carbonyl group at position 2 in a series of 3,4-dihydropyrimidin-2-ones. The scaffold (<b>16</b>) documented herein contains a chiral center at the heterocycle. Accordingly, the most attractive ligand of the series [(±)<b>16b</b>, <i>K</i>_i <b>=</b> 24.3 nM] was resolved into its two enantiomers by chiral HPLC, and the absolute configuration was established by circular dichroism. The biological evaluation of both enantiomers demonstrated enantiospecific recognition at A_2BAR, with the (<i>S</i>)-<b>16b</b> enantiomer retaining all the affinity (<i>K</i>_i <b>=</b> 15.1 nM), as predicted earlier by molecular modeling. This constitutes the first example of enantiospecific recognition at the A_2B adenosine receptor and opens new possibilities in ligand design for this receptor

Discovery of 3,4-Dihydropyrimidin-2(1<i>H</i>)‑ones As a Novel Class of Potent and Selective A_2B Adenosine Receptor Antagonists

We describe the discovery and optimization of 3,4-dihydropyrimidin-2­(1<i>H</i>)-ones as a novel family of (nonxanthine) A_2B receptor antagonists that exhibit an unusually high selectivity profile. The Biginelli-based hit optimization process enabled a thoughtful exploration of the structure–activity and structure–selectivity relationships for this chemotype, enabling the identification of ligands that combine structural simplicity with excellent hA_2B AdoR affinity and remarkable selectivity profiles

Effect of Nitrogen Atom Substitution in A₃ Adenosine Receptor Binding: <i>N</i>‑(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists

We report the first family of 2-acetamidopyridines as potent and selective A₃ adenosine receptor (AR) antagonists. The computer-assisted design was focused on the bioisosteric replacement of the N1 atom by a CH group in a previous series of diarylpyrimidines. Some of the generated 2-acetamidopyridines elicit an antagonistic effect with excellent affinity (<i>K</i>_i < 10 nM) and outstanding selectivity profiles, providing an alternative and simpler chemical scaffold to the parent series of diarylpyrimidines. In addition, using molecular dynamics and free energy perturbation simulations, we elucidate the effect of the second nitrogen of the parent diarylpyrimidines, which is revealed as a stabilizer of a water network in the binding site. The discovery of 2,6-diaryl-2-acetamidopyridines represents a step forward in the search of chemically simple, potent, and selective antagonists for the hA₃AR, and exemplifies the benefits of a joint theoretical–experimental approach to identify novel hA₃AR antagonists through succinct and efficient synthetic methodologies

Effect of Nitrogen Atom Substitution in A₃ Adenosine Receptor Binding: <i>N</i>‑(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists

We report the first family of 2-acetamidopyridines as potent and selective A₃ adenosine receptor (AR) antagonists. The computer-assisted design was focused on the bioisosteric replacement of the N1 atom by a CH group in a previous series of diarylpyrimidines. Some of the generated 2-acetamidopyridines elicit an antagonistic effect with excellent affinity (<i>K</i>_i < 10 nM) and outstanding selectivity profiles, providing an alternative and simpler chemical scaffold to the parent series of diarylpyrimidines. In addition, using molecular dynamics and free energy perturbation simulations, we elucidate the effect of the second nitrogen of the parent diarylpyrimidines, which is revealed as a stabilizer of a water network in the binding site. The discovery of 2,6-diaryl-2-acetamidopyridines represents a step forward in the search of chemically simple, potent, and selective antagonists for the hA₃AR, and exemplifies the benefits of a joint theoretical–experimental approach to identify novel hA₃AR antagonists through succinct and efficient synthetic methodologies

A Positive Allosteric Modulator of the Serotonin 5‑HT_2C Receptor for Obesity

The 5-HT_2CR agonist lorcaserin, clinically approved for the treatment of obesity, causes important side effects mainly related to subtype selectivity. In the search for 5-HT_2CR allosteric modulators as safer antiobesity drugs, a chemical library from Vivia Biotech was screened using ExviTech platform. Structural modifications of identified hit VA240 in synthesized analogues <b>6</b>–<b>41</b> afforded compound <b>11</b> (<i>N</i>-[(1-benzyl-1<i>H</i>-indol-3-yl)­methyl]­pyridin-3-amine, VA012), which exhibited dose-dependent enhancement of serotonin efficacy, no significant off-target activities, and low binding competition with serotonin or other orthosteric ligands. PAM <b>11</b> was very active in feeding inhibition in rodents, an effect that was not related to the activation of 5-HT_2AR. A combination of <b>11</b> with the SSRI sertraline increased the anorectic effect. Subchronic administration of <b>11</b> reduced food intake and body weight gain without causing CNS-related malaise. The behavior of compound <b>11</b> identified in this work supports the interest of a serotonin 5-HT_2CR PAM as a promising therapeutic approach for obesity

Modulation of cAMP-Specific PDE without Emetogenic Activity: New Sulfide-Like PDE7 Inhibitors

A forward chemical genetic approach was followed to discover new targets and lead compounds for Parkinson’s disease (PD) treatment. By analysis of the cell protection produced by some small molecules, a diphenyl sulfide compound was revealed to be a new phosphodiesterase 7 (PDE7) inhibitor and identified as a new hit. This result allows us to confirm the utility of PDE7 inhibitors as a potential pharmacological treatment of PD. On the basis of these data, a diverse family of diphenyl sulfides has been developed and pharmacologically evaluated in the present work. Moreover, to gain insight into the safety of PDE7 inhibitors for human chronic treatment, we evaluated the new compounds in a surrogate emesis model, showing nonemetic effects