Francisco León

University of Florida

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Christopher R. McCurdy

University of Florida

Ignacio Brouard

Consejo Superior de Investigaciones Científicas

Jaime Bermejo

Instituto de Productos Naturales y Agrobiología

Francisco Estévez

Universidad de Las Palmas de Gran Canaria

Stephen J. Cutler

University of South Carolina

José Quintana

University of Puerto Rico System

Samir Benayache

Constantine 1 University

Fadila Benayache

Constantine 1 University

Lance Richard McMahon

Texas Tech University Health Sciences Center

Abhisheak Sharma

University of Florida

Cooperative Institutions

University of Florida

University of Mississippi

National Institutes of Health

Constantine 1 University

Universidad de La Laguna

Universidad de Las Palmas de Gran Canaria

Consejo Superior de Investigaciones Científicas

Florida College

Harvard University

Instituto de Productos Naturales y Agrobiología

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

Patterns and reasons for kratom (Mitragyna speciosa) use among current and former opioid poly-drug users

Journal of Ethnopharmacology (2019)

Darshan Singh Nelson Jeng‐Yeou Chear Suresh Narayanan Francisco León Abhisheak Sharma

10.1016/j.jep.2019.112462

Cite

Citations (79)

Structure–Activity Relationships of the Antimalarial Agent Artemisinin 10. Synthesis and Antimalarial Activity of Enantiomers of rac-5β-Hydroxy-d-Secoartemisinin and Analogs: Implications Regarding the Mechanism of Action

Molecules (2021)

Mohamed E. Jahan Francisco León Frank R. Fronczek Khaled M. Elokely John M. Rimoldi

An efficient synthesis of rac-6-desmethyl-5β–hydroxy-d-secoartemisinin 2, a tricyclic analog of R-(+)-artemisinin 1, was accomplished and the racemate was resolved into the (+)-2b and (−)-2a enantiomers via their Mosher Ester diastereomers. Antimalarial activity resided with only the artemisinin-like enantiomer R-(−)-2a. Several new compounds 9–16, 19a, 19b, 22 and 29 were synthesized from rac-2 but the C-5 secondary hydroxyl group was surprisingly unreactive. For example, the formation of carbamates and Mitsunobu reactions were unsuccessful. In order to assess the unusual reactivity of 2, a single crystal X-ray crystallographic analysis revealed a close intramolecular hydrogen bond from the C-5 alcohol to the oxepane ether oxygen (O-11). All products were tested in vitro against the W-2 and D-6 strains of Plasmodium falciparum. Several of the analogs had moderate activity in comparison to the natural product 1. Iron (II) bromide-promoted rearrangement of 2 gave, in 50% yield, the ring-contracted tetrahydrofuran 22, while the 5-ketone 15 provided a monocyclic methyl ketone 29 (50%). Neither 22 nor 29 possessed in vitro antimalarial activity. These results have implications in regard to the antimalarial mechanism of action of artemisinin.

Diastereomer

10.3390/molecules26144163

Cite

Citations (7)

Interactive Effects ofµ-Opioid and Adrenergic-α₂Receptor Agonists in Rats: Pharmacological Investigation of the Primary Kratom Alkaloid Mitragynine and Its Metabolite 7-Hydroxymitragynine

Journal of Pharmacology and Experimental Therapeutics (2022)

Samuel Obeng Francisco León Avi Patel Julio D. Zuarth Gonzalez Lucas Chaves Da Silva

The primary kratom alkaloid mitragynine is proposed to act through multiple mechanisms, including actions at µ-opioid receptors (MORs) and adrenergic-α₂ receptors (Aα₂Rs), as well as conversion in vivo to a MOR agonist metabolite (i.e., 7-hydroxymitragynine). Aα₂R and MOR agonists can produce antinociceptive synergism. Here, contributions of both receptors to produce mitragynine-related effects were assessed by measuring receptor binding in cell membranes and, in rats, pharmacological behavioral effect antagonism studies. Mitragynine displayed binding affinity at both receptors, whereas 7-hydroxymitragynine only displayed MOR binding affinity. Compounds were tested for their capacity to decrease food-maintained responding and rectal temperature and to produce antinociception in a hotplate test. Prototypical MOR agonists and 7-hydroxymitragynine, but not mitragynine, produced antinociception. MOR agonist and 7-hydroxymitragynine rate-deceasing and antinociceptive effects were antagonized by the opioid antagonist naltrexone but not by the Aα₂R antagonist yohimbine. Hypothermia only resulted from reference Aα₂R agonists. The rate-deceasing and hypothermic effects of reference Aα₂R agonists were antagonized by yohimbine but not naltrexone. Neither naltrexone nor yohimbine antagonized the rate-decreasing effects of mitragynine. Mitragynine and 7-hydroxymitragynine increased the potency of the antinociceptive effects of Aα₂R but not MOR reference agonists. Only mitragynine produced hypothermic effects. Isobolographic analyses for the rate-decreasing effects of the reference Aα₂R and MOR agonists were also conducted. These results suggest mitragynine and 7-hydroxymitragynine may produce antinociceptive synergism with Aα₂R and MOR agonists. When combined with Aα₂R agonists, mitragynine could also produce hypothermic synergism.

SIGNIFICANCE STATEMENT

Mitragynine is proposed to target the µ-opioid receptor (MOR) and adrenergic-α₂ receptor (Aα₂R) and to produce behavioral effects through conversion to its MOR agonist metabolite 7-hydroxymitragynine. Isobolographic analyses indicated supra-additivity in some dose ratio combinations. This study suggests mitragynine and 7-hydroxymitragynine may produce antinociceptive synergism with Aα₂R and MOR agonists. When combined with Aα₂R agonists, mitragynine could also produce hypothermic synergism.

10.1124/jpet.122.001192

Cite

Citations (18)

Natural Corynanthe-Type Cholinesterase Inhibitors from Malaysian Uncaria attenuata Korth.: Isolation, Characterization, In Vitro and In Silico Studies

Metabolites (2023)

Nelson Jeng‐Yeou Chear Tan Ai Fein Ching-Ga Kooi Yeong Khaw Francisco León Wen‐Nee Tan

The Uncaria genus is notable for its therapeutic potential in treating age-related dementia, such as Alzheimer's disease. A phytochemical study of the leaves of Malaysian Uncaria attenuata Korth., afforded an undescribed natural corynanthe-type oxindole alkaloid, isovillocarine D (1) together with two known indole alkaloids, villocarine A (2) and geissoschizine methyl ether (3), and their structural identification was performed with extensive mono- and bidimensional NMR and MS spectroscopic methods. The isolated alkaloids were evaluated for their acetylcholinesterase (AChE)- and butyrylcholinesterase (BChE)-inhibitory activity. The results indicated that compound (2) was the most potent inhibitor against both AChE and BChE, with IC50 values of 14.45 and 13.95 µM, respectively, whereas compounds (1) and (3) were selective BChE inhibitors with IC50 values of 35.28 and 17.65 µM, respectively. In addition, molecular docking studies revealed that compound (2) interacts with the five main regions of AChE via both hydrogen and hydrophobic bonding. In contrast to AChE, the interactions of (2) with the enzymatic site of BChE are established only through hydrophobic bonding. The current finding suggests that U. attenuata could be a good source of bioactive alkaloids for treating age-related dementia.

Cholinesterase

Isolation

10.3390/metabo13030390

Cite

Citations (1)

The Lofexidine‐Like Discriminative Effects of the Primary Kratom Alkaloid Mitragynine in Rats

The FASEB Journal (2021)

Avi Patel Samuel Obeng Lea R. Gamez-Jimenez Nicholas Ho Manuel Alvarez

The primary kratom alkaloid mitragynine has received attention due to its µ-opioid receptor (MOR) activity; however, the antinociceptive effects of mitragynine in mice were blocked by the adrenergic-α2 receptor (Aα2R) antagonist idazoxan. Here we examined the Aα2R pharmacology of mitragynine with radioligand receptor binding in human cell membranes and drug discrimination, the hot plate test (antinociception), and measurement of rectal temperature (hypothermia) in rats. The affinity of mitragynine at human MOR (Ki=706 nM) was 2- to 10-fold higher than its affinity at other opioid (k and d) and adrenergic (a2A and a2C) receptors. In rats discriminating mitragynine (32mg/kg, i.p.) from vehicle, MOR agonists (morphine, fentanyl, and methadone), Aα2R agonists (lofexidine and clonidine), and Aα2R antagonists (yohimbine and atipamezole) produced up to 84%, 74%, and 40% drug-lever responding, respectively. In rats discriminating lofexidine (0.032 mg/kg, i.p.) from vehicle, the Aα2R agonists (lofexidine and clonidine), mitragynine, Aα2R antagonists (yohimbine and atipamezole), and morphine produced up to 97%, 95%, 7.1%, and 7.3% drug-lever responding, respectively. In rats discriminating morphine (3.2mg/kg, i.p.) from vehicle, MOR agonists (morphine, fentanyl, and methadone) produced at least 98% drug-lever responding, and mitragynine produced up to 72% drug-lever responding. The Aα2R agonists (lofexidine and clonidine) and antagonists (yohimbine and atipamezole) produced a maximum of 30% drug-lever responding. The full substitution of mitragynine for lofexidine was pharmacologically specific. In rats discriminating the cannabinoid receptor agonist D9-THC (3.2mg/kg, i.p.) from vehicle, another cannabinoid receptor agonist CP55,940, mitragynine, and morphine produced up to 99%, 23%, and 18.4% drug-lever responding, respectively. In the hotplate (52°C) test, the MOR agonists (morphine, fentanyl, and methadone) produced at least 90 % maximum possible effects, whereas MG was ineffective. Aα2R agonists (lofexidine and clonidine) produced up to 63% maximum possible effects, and the Aα2R antagonists (yohimbine and atipamezole) produced up to 85% maximum possible effects. The cannabinoid receptor agonists (D9-THC and CP55,940) produced up to 67% maximum possible effects. Rectal temperature was decreased by 0.3°C for the MOR agonists, 1.0°C for Mitragynine, up to 4.8°C for the Aα2R agonists, up to 3.4°C for the Aα2R antagonists, and up to 3.8°C for the cannabinoid receptor agonists. Atipamezole antagonized the discriminative stimulus effects of mitragynine as well as lofexidine but not the discriminative or antinociceptive effects of morphine. Both lofexidine and clonidine potentiated mitragynine discrimination but not the discriminative or antinociceptive effects of morphine. These results suggest that mitragynine exerts its in vivo effects via dual agonism at µ-opioid and adrenergic-α2 receptors.

Idazoxan

10.1096/fasebj.2021.35.s1.04912

Cite

Citations (1)

Lignans and an abundant flavone glycoside with free-radical scavenging activity from the roots of the endemic species Stachys mialhesi de Noé

S. Laggoune Ignacio Brouard Francisco León Claude-Alain Calliste Jean-luc Duroux Duroux

Scavenging

Source

Cite

Citations (6)

Antinociceptive activity of extracts and secondary metabolites from wild growing and micropropagated plants of Renealmia alpinia

Journal of Ethnopharmacology (2015)

Isabel Gómez-Betancur Natalie Cortés Dora Benjumea Edison Osorio Francisco León

Dichloromethane

Boraginaceae

Alpinia

Zingiberaceae

10.1016/j.jep.2015.02.012

Cite

Citations (11)

Chemotaxonomy of Gonospermum and related genera

Phytochemistry (2010)

Jorge Triana José Luis Eiroa Juan José Ortega Francisco León Ignacio Brouard

Chemotaxonomy

Sesquiterpene lactone

Monophyly

10.1016/j.phytochem.2009.12.013

Cite

Citations (12)

Isolation, Structure Elucidation, Total Synthesis, and Evaluation of New Natural and Synthetic Ceramides on Human SK-MEL-1 Melanoma Cells

Journal of Medicinal Chemistry (2006)

Francisco León Ignacio Brouard Augusto Rivera Fernando Torres Sara Rubio

Two new long-chain ceramides, trametenamides A (1) and B (2), were isolated from the methanolic extract of the fruiting body of the fungus Trametes menziesii. The structures were elucidated by spectroscopic analyses and chemical transformations, and the absolute stereochemistry of trametenamide B (2) was determined by stereoselective total synthesis of four possible diastereomers. The acetyl derivative of the natural ceramide (1a) and synthetic ceramides (24-27) showed cytotoxicity on the human melanoma cell line SK-MEL-1, which was caused by induction of apoptosis as determined by DNA fragmentation, poly(ADP-ribose) polymerase cleavage, and procaspase-9 and -8 processing.

Isolation

10.1021/jm0605334

Cite

Citations (17)

Inhibition of human monoamine oxidase A and B by flavonoids isolated from two Algerian medicinal plants

Phytomedicine (2017)

Farida Larit Khaled M. Elokely Narayan D. Chaurasiya Samira Benyahia Manal A. Nael

Monoamine oxidase A

Monoamine oxidase B

10.1016/j.phymed.2017.12.032

Cite

Citations (75)