title: Functional induction of P-glycoprotein efflux pump by phenyl benzenesulfonamides: Synthesis and biological evaluation of T0901317 analogs.
abstract: N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317, 6) is a potent activator of pregnane-X-receptor (PXR), which is a nuclear receptor controlling P-gp expression. Herein, we aimed to investigate P-gp induction activity of T0901317 and establish its structure-activity relationship. T0901317 along with a series of N-triazolyl-methylene-linked benzenesulfonamides were synthesized and screened for P-gp induction activity using a rhodamine-123 based efflux assay in the P-gp overexpressing human adenocarcinoma LS-180 cells, wherein several compounds showed potent P-gp induction activity at 5 μM. Treatment with benzene sulphonamides led to the decrease in intracellular accumulation of a fluorescent P-gp substrate rhodamine-123 up to 48% (control 100%). In the western-blot studies, T0901317 (6) and its triazole linked analog 26e at 5 μM displayed induction of P-gp expression in LS180 cells. These compounds were non-toxic in LS-180 and human neuroblastoma SH-SY5Y cells (IC50 > 50 μM). The compound 26e showed significant P-gp induction even at 0.3 μM, indicating an excellent therapeutic window. These results clearly indicate promise of this class of compounds as potential agents to enhance amyloid-β clearance in Alzheimers patients.
authors: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors: Anil K
authors: AK
authors: Padala
authors: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors: Abubakar
authors: A
authors: Wani
authors: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors: Ram A
authors: RA
authors: Vishwakarma
authors: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India. Electronic address: ajaykmahajan@hotmail.com.
authors: Ajay
authors: A
authors: Kumar
authors: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India. Electronic address: sbharate@iiim.ac.in.
authors: Sandip B
authors: SB
authors: Bharate
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000096926:Benzenesulfonamides; D005466:Fluorocarbons
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D006845:Hydrocarbons, Fluorinated; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C423915:T0901317; D005466:Fluorocarbons
keywords: Alzheimer’s disease; Benzene sulfonamides; LS180; P-gp induction; PXR; T0901317