Nonprenylated Rotenoids, a New Class of Potent Breast Cancer Resistance Protein Inhibitors

• Published in: Journal of medicinal chemistry 2007-04, Vol.50 (8), p.1933-1938
• Main Authors: Ahmed-Belkacem, Abdelhakim, Macalou, Sira, Borrelli, Francesca, Capasso, Raffaele, Fattorusso, Ernesto, Taglialatela-Scafati, Orazio, Di Pietro, Attilio
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - antagonists & inhibitors; Biochemistry, Molecular Biology; Biological and medical sciences; Cell Line; Drug Resistance, Multiple; Drug Resistance, Neoplasm; General aspects; General pharmacology; Humans; Isoflavones - chemistry; Isoflavones - isolation & purification; Isoflavones - pharmacology; Life Sciences; Medical sciences; Neoplasm Proteins - antagonists & inhibitors; Nyctaginaceae; Nyctaginaceae - chemistry; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Plant Extracts - chemistry; Plant Extracts - isolation & purification; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061450q

Two rotenoids isolated from Boerhaavia diffusa (Nyctaginaceae), boeravinones G (1) and H (2), have been found to potently inhibit the drug efflux activity of breast cancer resistance protein (BCRP/ABCG2), a multidrug transporter responsible for cancer cell resistance to chemotherapy. The isolation of nine additional rotenoid derivatives (3 − 11), including the new boeravinones I (10) and J (11), from the extract of B. diffusa roots allowed us to establish structure−activity relationships toward inhibition of BCRP-mediated drug transport activity. The results show the positive roles of a methoxy group at position 6 of ring B and the absence of a substituent at position 10, and the requirement for a 6a/12a double bond between rings B and C. In contrast, both contraction of ring B, to give a coumaronochromone (11), and tetrasubstitution of ring D appeared to be detrimental for the inhibitory potency. The present study provides the first data on the BCRP-inhibiting activity of rotenoid derivatives, indicating boeravinones as a new class of interesting BCRP inhibitors.