Multifactorial neurodegenerative disorders such as Alzheimer's disease (AD) are considered a growing public health problem due the rising incidence and low effectiveness of current treatments [6]. Since pharmacotherapy based on a single target has been insufficient for drug development in complex diseases, the emerging multi-target approach is a promising strategy for the search of new anti-AD drug candidates. Herein described natural isoquinoline alkaloids were investigated for multi-target activity on key mechanisms associated with the AD's pathogenesis, i.e. cholinergic depletion, beta amyloid (Aβ) aggregation and oxidative stress. Alkaloid isolation from root extract of Zanthoxylum rigidum was carried out using multi-step chromatography and TLC-bioautography against acetylcholinesterase (AChE) giving eight purified isoquinoline alkaloids. Isolated compounds were tested for inhibitory activity against cholinesterase (AChE and BChE), monoamine oxidase (MAO-A and B) and Aβ aggregation. Our study revealed two benzophenanthridine alkaloids, nitidine (5) and avicine (7), as the most potent multi-target candidates. Both showed dual cholinesterase inhibition, being more active against AChE over BChE, with IC₅₀ values in sub-micromolar range in AChE. Kinetic analysis with cholinesterase showed, that both compounds are reversible-mixed inhibitors, where avicine (7) presented highest potency with K_i values of 0.063 µM (EeAChE), 0.511 µM (HrAChE) and 0.123 µM (EqBChE). In addition, these alkaloids presented moderate Aβ_1-42 anti-aggregation activity and MAO-A inhibition with IC₅₀ values between 0.5 and 2 µM. Our findings suggest that avicine (7) is a promising natural compound and multifunctional candidate representing a suitable starting point for the development of new therapeutic agents for Alzheimer's disease.

01 Jan 2011·Organic & Biomolecular ChemistryQ3 · CHEMISTRY

Palladium-catalyzed tandem reaction to construct benzo[c]phenanthridine: application to the total synthesis of benzo[c]phenanthridine alkaloids

Q3 · CHEMISTRY

Article

Author: Longguan Xie ; Xiaohua Xu ; Pei Lv ; Kanglun Huang

A concise and efficient synthesis of benzo[c]phenanthridines was accomplished by the palladium-catalyzed ring-opening coupling of azabicyclic alkene with o-iodobenzoates, followed by tandem cyclization. The strategy was successfully applied in the total synthesis of benzo[c]phenanthridine alkaloids such as sanguinarine, chelerythrine, nitidine and avicine.

01 Jul 2006·Journal of EthnopharmacologyQ2 · MEDICINE

Validation of use of a traditional antimalarial remedy from French Guiana, Zanthoxylum rhoifolium Lam

Q2 · MEDICINE

Article

Author: Séverine Maurel ; Geneviève Bourdy ; Michel Sauvain ; S. Georges ; Valérie Jullian

Zanthoxylum rhoifolium bark (Rutaceae) is a medicinal plant, traditionally used in French Guiana to treat and prevent malaria. Bioassay-guided extractions of Zanthoxylum rhoifolium bark have shown that antiplasmodial activity is concentrated in the alkaloid fraction. Further fractionation of this extract has yielded seven benzophenanthridine alkaloids, dihydroavicine 1, dihydronitidine 2, oxyavicine 3, oxynitidine 4, fagaridine 5, avicine 6 and nitidine 7. Antimalarial activity of the last five compounds has been evaluated, and nitidine was the most potent, displaying an IC(50)<0.27microM against Plasmodium falciparum. Investigation of the traditional remedy, a trunk bark decoction in water, has shown that fagaridine 5, avicine 6 and nitidine 7 are also present in the decoction, therefore justifying the traditional use of Zanthoxylumrhoifolium bark as antimalarial.

100 Deals associated with Cancer vaccine(Sarepta Therapeutics, Inc.)

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Indication	Highest Phase	Country/Location	Organization	Date
Colorectal Cancer	Phase 3	-	Supergen Bioenergy Hub	-
Colorectal Cancer	Phase 3	-	Sarepta Therapeutics, Inc.	-
Pancreatic Cancer	Phase 3	-	Supergen Bioenergy Hub	-
Pancreatic Cancer	Phase 3	-	Sarepta Therapeutics, Inc.	-
Prostatic Cancer	Phase 3	-	Supergen Bioenergy Hub	-
Prostatic Cancer	Preclinical	-	Sarepta Therapeutics, Inc.	-

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