Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects.

We have previously reported the total synthesis and structure-activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARß/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARß/δ and partial PPARγ activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities.

Benzopyran hydrazones with dual PPARα/γ or PPARα/δ agonism and an anti-inflammatory effect on human THP-1 macrophages.

Peroxisome proliferator-activated receptors (PPARs) play a major role in regulating inflammatory processes, and dual or pan-PPAR agonists with PPARγ partial activation have been recognised to be useful to manage both metabolic syndrome and metabolic dysfunction-associated fatty liver disease (MAFLD). Previous works have demonstrated the capacity of 2-prenylated benzopyrans as PPAR ligands. Herein, we have replaced the isoprenoid bond by hydrazone, a highly attractive functional group in medicinal chemistry. In an attempt to discover novel and safety PPAR activators, we efficiently prepared benzopyran hydrazone/hydrazine derivatives containing benzothiazole (series 1) or 5-chloro-3-(trifluoromethyl)-2-pyridine moiety (series 2) with a 3- or 7-carbon side chain at the 2-position of the benzopyran nucleus. Benzopyran hydrazones 4 and 5 showed dual hPPARα/γ agonism, while hydrazone 14 exerted dual hPPARα/δ agonism. These three hydrazones greatly attenuated inflammatory markers such as IL-6 and MCP-1 on the THP-1 macrophages via NF-κB activation. Therefore, we have discovered novel hits (4, 5 and 14), containing a hydrazone framework with dual PPARα/γ or PPARα/δ partial agonism, depending on the length of the side chain. Benzopyran hydrazones emerge as potential lead compounds which could be useful for treating metabolic diseases.

Synthesis of 2-aminopropyl benzopyran derivatives as potential agents against triple-negative breast cancer.

Synthesis of three series of 2-aminopropyl derivatives containing a benzopyran nucleus was performed to evaluate their performance against triple-negative breast cancer cell lines (MDA-MB-231 and MDA-MB-436) and normal breast epithelial cells (MCF10A). For the three series, the cytotoxic activity was as follows: N-methylated derivatives (tertiary amines) 5b, 6b, and 7b > secondary amine benzopyrans 5, 6, and 7 > quaternary amine salts 5c, 6c, and 7c > free phenolic derivatives 5a, 6a, and 7a. The structure-activity relationship showed the importance of the presence of an amine group and a p-fluorobenzyloxy substituent in the chromanol ring (IC50 values from 1.5 µM to 58.4 µM). In addition, 5a, 5b, 6a, and 7b displayed slight selectivity towards tumor cells. Compounds 5, 5a, 5b, 6, 6a, 6c, 7, and 7b showed apoptotic/necrotic effects due to, at least in part, an increase in reactive oxygen species generation, whereas 5b, 5c, 6b, 7a, and 7c caused cell cycle arrest in the G1 phase. Further cell-based mechanistic studies revealed that 5a, 6a, and 7b, which were the most promising compounds, downregulated the expression of Bcl-2, while 5b downregulated the expression of cyclins CCND1 and CCND2. Therefore, 2-aminopropyl benzopyran derivatives emerge as new hits and potential leads for developing useful agents against breast cancer.

Anti-inflammatory effects and improved metabolic derangements in ob/ob mice by a newly synthesized prenylated benzopyran with pan-PPAR activity.

BACKGROUND AND PURPOSE: Selective peroxisome proliferator-activated receptors (PPARs) are widely used to treat metabolic complications; however, the limited effect of PPARα agonists on glucose metabolism and the adverse effects associated with selective PPARγ activators have stimulated the development of novel pan-PPAR agonists to treat metabolic disorders. Here, we synthesized a new prenylated benzopyran (BP-2) and evaluated its PPAR-activating properties, anti-inflammatory effects and impact on metabolic derangements. EXPERIMENTAL APPROACH: BP-2 was used in transactivation assays to evaluate its agonism to PPARα, PPARß/δ and PPARγ. A parallel-plate flow chamber was employed to investigate its effect on TNFα-induced leukocyte-endothelium interactions. Flow cytometry and immunofluorescence were used to determine its effects on the expression of endothelial cell adhesion molecules (CAMs) and chemokines and p38-MAPK/NF-κB activation. PPARs/RXRα interactions were determined using a gene silencing approach. Analysis of its impact on metabolic abnormalities and inflammation was performed in ob/ob mice. KEY RESULTS: BP-2 displayed strong PPARα activity, with moderate and weak activity against PPARß/δ and PPARγ, respectively. In vitro, BP-2 reduced TNFα-induced endothelial ICAM-1, VCAM-1 and fractalkine/CX3CL1 expression, suppressed mononuclear cell arrest via PPARß/δ-RXRα interactions and decreased p38-MAPK/NF-κB activation. In vivo, BP-2 improved the circulating levels of glucose and triglycerides in ob/ob mice, suppressed T-lymphocyte/macrophage infiltration and proinflammatory markers in the liver and white adipose tissue, but increased the expression of the M2-like macrophage marker CD206. CONCLUSION AND IMPLICATIONS: BP-2 emerges as a novel pan-PPAR lead candidate to normalize glycemia/triglyceridemia and minimize inflammation in metabolic disorders, likely preventing the development of further cardiovascular complications.

Synthesis of 2-Prenylated Alkoxylated Benzopyrans by Horner-Wadsworth-Emmons Olefination with PPARα/γ Agonist Activity.

We have synthesized series of 2-prenylated benzopyrans as analogues of the natural polycerasoidol, a dual PPARα/γ agonist with anti-inflammatory effects. The prenylated side chain consists of five or nine carbons with an α-alkoxy-α,ß-unsaturated ester moiety. Prenylation was introduced via the Grignard reaction, followed by Johnson-Claisen rearrangement, and the α-alkoxy-α,ß-unsaturated ester moiety was introduced by the Horner-Wadsworth-Emmons reaction. Synthetic derivatives showed high efficacy to activate both hPPARα and hPPARγ as dual PPARα/γ agonists. These prenylated benzopyrans emerge as lead compounds potentially useful for preventing cardiometabolic diseases.

1-(2'-Bromobenzyl)-6,7-dihydroxy-N-methyl-tetrahydroisoquinoline and 1,2-Demethyl-nuciferine as Agonists in Human D2 Dopamine Receptors.

Certain D2-like dopamine receptor (DR) agonists are useful therapeutically as antiparkinsonian drugs, whereas D2-like DR antagonists or partial agonists are proven effective as antipsychotics. Two isoquinoline derivatives, 1-(2'-bromobenzyl)-6,7-dihydroxy-N-methyl-tetrahydroisoquinoline (Br-BTHIQ, 1) and 1,2-demethyl-nuciferine (aporphine, 2), were herein synthesized, and their dopaminergic affinity in cloned human D2R, D3R, and D4R subtypes and their behavior as agonists/antagonists were evaluated. They showed affinity values (Ki) for hD2, hD3, and hD4 DR within the nanomolar range. The trends in affinity were hD4R ≫ hD3R > hD2R for Br-BTHIQ (1) and hD2R > hD4R > hD3R for 1,2-demethyl-nuciferine (2). The functional assays of cyclic adenosine monophosphate signaling at human D2R showed a partial agonist effect for Br-BTHIQ (1) and full agonist behavior for aporphine (2), with half maximal effective concentration values of 2.95 and 10.2 µM, respectively. Therefore, both isoquinolines 1 and 2 have emerged as lead molecules for the synthesis of new therapeutic drugs that ultimately may be useful to prevent schizophrenia and Parkinson's disease, respectively.

Synthesis of benzopyran derivatives as PPARα and/or PPARγ activators.

We describe the synthesis of 26 compounds, small polycerasoidol analogs, that are Lipinski's rule-of-five compliant. In order to confirm key structural features to activate PPARα and/or PPARγ, we have adopted structural modifications in the following parts: (i) the benzopyran core (hydrophobic nucleus) by benzopyran-4-one, dihydrobenzopyran or benzopyran-4-ol; (ii) the side chain at 2-position by shortening to C3, C4 and C5-carbons versus C-9-carbons of polycerasoidol; (iii) the carboxylic group (polar head) by oxygenated groups (hydroxyl, acetoxy, epoxide, ester, aldehyde) or non-oxygenated motifs (allyl and alkyl). Benzopyran-4-ones 6, 12, 13 and 17 as well as dihydrobenzopyrans 22, 24 and 25 were able to activate hPPARα, whereas benzopyran-4-one (7) with C5-carbons in the side chain exhibited hPPARγ agonism. According to our previous docking studies, SAR confirm that the hydrophobic nucleus (benzopyran-4-one or dihydrobenzopyran) is essential to activate PPARα and/or PPARγ, and the flexible linker (side alkyl chain) should containg at least C5-carbon atoms to activate PPARγ. By contrast, the polar head ("carboxylic group") tolerated several oxygenated groups but also non-oxygenated motifs. Taking into account these key structural features, small polycerasoidol analogs might provide potential active molecules useful in the treatment of dyslipidemia and/or type 2 diabetes.

Polycerasoidol, a Natural Prenylated Benzopyran with a Dual PPARα/PPARγ Agonist Activity and Anti-inflammatory Effect.

Dual peroxisome proliferator-activated receptor-α/γ (PPARα/γ) agonists regulate both lipid and glucose homeostasis under different metabolic conditions and can exert anti-inflammatory activity. We investigated the potential dual PPARα/γ agonism of prenylated benzopyrans polycerasoidol (1) and polycerasoidin (2) and their derivatives for novel drug development. Nine semisynthetic derivatives were prepared from the natural polycerasoidol (1) and polycerasoidin (2), which were evaluated for PPARα, -γ, -δ and retinoid X receptor-α activity in transactivation assays. Polycerasoidol (1) exhibited potent dual PPARα/γ agonism and low cytotoxicity. Structure-activity relationship studies revealed that a free phenol group at C-6 and a carboxylic acid at C-9' were key features for dual PPARα/γ agonism activity. Molecular modeling indicated the relevance of these groups for optimal ligand binding to the PPARα and PPARγ domains. In addition, polycerasoidol (1) exhibited a potent anti-inflammatory effect by inhibiting mononuclear leukocyte adhesion to the dysfunctional endothelium in a concentration-dependent manner via RXRα/PPARγ interactions. Therefore, polycerasoidol (1) can be considered a hit-to-lead molecule for the further development of novel dual PPARα/γ agonists capable of preventing cardiovascular events associated with metabolic disorders.

Synthesis of pyrido[2,1-a]isoquinolin-4-ones and oxazino[2,3-a]isoquinolin-4-ones: new inhibitors of mitochondrial respiratory chain.

Benzo[a]quinolizine is an important heterocyclic framework that can be found in numerous bioactive compounds. The general scheme for the synthesis of these compounds was based on the preparation of the appropriate dihydroisoquinolines by Bischler-Napieralski cyclization with good yields, followed by the Pemberton method to form the oxazinones or pyridones derivatives via acyl-ketene imine cyclocondensation. All the synthesized compounds were assayed in vitro for their ability to inhibit mitochondrial respiratory chain. Most of the tested compounds were able to inhibit the integrated electron transfer chain, measured as NADH oxidation, which includes complexes I, III and IV, in the low micromolar range. Oxazino[2,3-a]isoquinolin-4-ones displayed greater activity than their pyrido[2,1-a]isoquinolin-4-ones analogs. Indeed, the presence of a furan ring in C2 position of oxazino[2,3-a]isoquinolin-4-ones provided the compound (1g) with the most potent biological activity. Therefore, these compounds and especially the oxazinone derivatives are in the tendency of the new less toxic antitumor agents that target mitochondrial electron transport chain in a middle range potency.

New antitumoral acetogenin 'Guanacone type' derivatives: isolation and bioactivity. Molecular dynamics simulation of diacetyl-guanacone.

We describe herein the isolation and semisynthesis of four acetogenin derivatives (1-4) as well as their ability to inhibit the mitochondrial respiratory chain and several tumor cell lines. In addition, four nanoseconds (ns) of MD simulation of compound 4, in a fully hydrated POPC bilayer, is reported.

Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines.

A series of 1-substituted 3,4-dihydroisoquinolines were synthesized and tested in vitro against the leukemia L 1210 cell line to evaluate their ability to perturb the cell cycle by arresting cells in the G1 phase. 1-Benzoylimines, 1-phenylimines, and 1-alkylimines were synthesized. The most powerful cytotoxic derivatives, 1-benzoyl-3,4-dihydroisoquinolines (1-26), were obtained from amides I via 1-benzyl-3,4-dihydroisoquinoline in good yield by a direct selective oxidation of the benzylic carbon of the corresponding imines through 10% Pd/C in acetonitrile. SAR studies let us to identify the essential structural features for cytotoxic activity. The most bioactive compounds (with IC(50) < 5 microM) were BzDHIQ (13, 22, 21, 8, 9, 11, 1, 20, 6, and 19), and they are characterized by the following: (i) An alpha-ketoimine moiety is necessary for potent antiproliferative activity (1-phenyl- and 1-alkyl-3,4-dihydroisoquinoline derivatives, 34-40, are less active). (ii) An hydrophobic, benzyloxy, alkyloxy, or allyloxy group at the C-6 position seems to be relevant for cytotoxicity. (iii) Regarding the influence of the benzoylic moiety, both the unsubstituted (13, 8, 9, 11, 1, and 6) and the 3'-monosubstituted (22, 21, 20, and 19) compounds were more potent than compounds with other substitutions.