title: Synthesis and P-glycoprotein induction activity of colupulone analogs.
abstract: Brain amyloid-beta (Aβ) plaques are one of the primary hallmarks associated with Alzheimer's disease (AD) pathology. Efflux pump proteins located at the blood-brain barrier (BBB) have been reported to play an important role in the clearance of brain Aβ, among which the P-glycoprotein (P-gp) efflux transporter pump has been shown to play a crucial role. Thus, P-gp has been considered as a potential therapeutic target for treatment of AD. Colupulone, a prenylated phloroglucinol isolated from Humulus lupulus, is known to activate pregnane-X-receptor (PXR), which is a nuclear receptor controlling P-gp expression. In the present work, we aimed to synthesize and identify analogs of colupulone that are potent P-gp inducer(s) with an ability to enhance Aβ transport across the BBB. A series of colupulone analogs were synthesized by modifications at both prenyl as well as acyl domains. All compounds were screened for P-gp induction activity using a rhodamine 123 based efflux assay in the P-gp overexpressing human adenocarcinoma LS-180 cells, wherein all compounds showed significant P-gp induction activity at 5 μM. In the western blot studies in LS-180 cells, compounds 3k and 5f were able to induce P-gp as well as LRP1 at 1 μM. The effect of compounds on the Aβ uptake and transport was then evaluated. Among all tested compounds, diprenylated acyl phloroglucinol displayed a significant increase (29%) in Aβ transport across bEnd3 cells grown on inserts as a BBB model. The results presented here suggest the potential of this scaffold to enhance clearance of brain Aβ across the BBB and thus its promise for development as a potential anti-Alzheimer agent.
authors: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu-180001, India. sbharate@iiim.ac.in.
authors: Jaideep B
authors: JB
authors: Bharate
authors: Yazan S
authors: YS
authors: Batarseh
authors: Abubakar
authors: A
authors: Wani
authors: Sadhana
authors: S
authors: Sharma
authors: Ram A
authors: RA
authors: Vishwakarma
authors: Amal
authors: A
authors: Kaddoumi
authors: Ajay
authors: A
authors: Kumar
authors: Sandip B
authors: SB
authors: Bharate
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003512:Cyclohexanones / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D027582:Humulus / Q000737:chemistry; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D010696:Phloroglucinol / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D016229:Amyloid beta-Peptides; D003512:Cyclohexanones; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C075356:colupulone; D010696:Phloroglucinol