Pharmacochemistry Laboratory

  Research Topics

Research Topics

The research topics that we have developed in recent years can be grouped into the following sections:

a) Synthesis of prenylated Benzopyrans with affinity for nuclear receptors. Peroxisome proliferator-activated α/γ dual receptor agonists (PPAR α/γ) regulate both lipid and glucose homeostasis under different metabolic conditions and may exert anti-inflammatory activity. We have studied the dual PPAR α/γ agonist potential of natural prenylated benzopyrans, polycerasoidol and polycerasoidin and their derivatives, for the development of new drugs. Polycerasoidol exhibited a potent PPAR α/γ dual agonist effect and low cytotoxicity. Structure-activity relationship studies revealed that a free phenol group and a carboxylic acid were key characteristics for PPAR α/γ dual agonist activity. Molecular modeling indicated the relevance of these groups for optimal ligand binding to the PPARα and PPARγ domains. Furthermore, polycerasoidol exhibited a powerful anti-inflammatory effect by inhibiting the adhesion of mononuclear leukocytes to the dysfunctional endothelium in a concentration-dependent manner through RXRα / PPARγ interactions. Therefore, it can be considered as a new PPAR α/γ dual agonist capable of preventing cardiovascular accidents associated with metabolic disorders.

Bermejo, A., et al. Polycerasoidol, a Natural Prenylated Benzopyran with a Dual PPARα/PPARγ Agonist Activity and Anti-inflammatory Effect Journal of Natural Products 2019, 82, 1802-1812.

b) Synthesis and isolation of Dopaminergic Isoquinoline. Certain D2-type dopamine receptor (DR) agonists are used therapeutically as antiparkinsonians, while D2-type DR antagonists or partial agonists are effective as antipsychotics. We recently synthesized isoquinoline with naturally-derived skeleton-inspired structures: 1- (2'-bromobenzyl) -6,7-dihydroxy-N-methyl-tetrahydroisoquinoline (Br-BTHIQ) and 1,2-demethyl-nuciferin (aporphine). The affinity for 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 affinity trends were hD4R >> hD3R> hD2R for Br-BTHIQ, and hD2R> hD4R> hD3R for 1,2-demethyl-nuciferin. Functional cAMP signaling assays in human D2R showed partial agonist effect for Br-BTHIQ and complete agonist behavior for aporphine. Both isoquinolines can be considered as useful new drugs to prevent schizophrenia and Parkinson's disease, respectively

  Silva, A. G., et al. 1(2′-Bromobenzyl)-6,7-dihydroxyNmethyl-tetrahydroisoquinoline and 1,2 Demethyl-nuciferine as Agonists in Human D2 Dopamine Receptors. Journal of Natural Products 2020, 83, 127−133.

c) Acetogenins (ACG) Antitumor and Natural Insecticides. These original MSAs have been studied for many years by our research group. We have recently carried out a review work on this important group of active secondary metabolites, potent specific inhibitors of mitochondrial complex I (range nM), abundant in seeds of tropical fruits within the Annonaceae family, such as custard apple or soursop, Annona cherimolia and A. muricata, respectively. The possible application of GCAs as new antitumor agents and as insecticides places them at the center of numerous studies around the world.

Neske, A. et al. Acetogenins from Annonaceae family. Their potential biological applications.
2020, 174, 112332.

d) Qualitative and quantitative analysis of metabolites by UHPLC-MS / MS.
In our laboratory we use an ultra-high chromatographic resolution (UHPLC) analytical system coupled to a photodiode mass detector (PDA) and a triple quadrupole tandem mass detector (MS / MS), equipped with an electrospray ionization source (ESI). The triple quadrupole instrumentation allows a targeted analysis by SIM (Scan Selected Ion Monitoring) and MRM (Multiple Reaction Monitoring), allowing a quantitative differential analysis of the metabolites or compounds (analytes) of interest. Among the possible applications we highlight:

* Identification and quantification of organic analytes in complex samples.
* Analysis of natural products: polyphenols, cannabinoids, sterols, fatty acids, alkaloids, etc.
* Characterization of reaction mixtures in organic synthesis.
* Analysis of drugs and their metabolites.
* Environmental analysis: analysis of surface and waste water, detection of pesticides, herbicides and insecticides, etc.
* Relative and absolute quantification of small molecules.

 Análisis UHPLC-MS/MS (columna C-18) de la muestra de Cúrcuma