title: Design, synthesis, and in vitro activity of catamphiphilic reverters of multidrug resistance: discovery of a selective, highly efficacious chemosensitizer with potency in the nanomolar range.
abstract: On the basis of the results obtained in previous research, three series of compounds (A-C), derived from verapamil, were designed and synthesized to obtain drugs able to revert multidrug resistance (MDR), an acquired resistance that frequently impairs cancer chemotherapy. The ability of the obtained compounds to revert MDR was evaluated on anthracycline-resistant erythroleukemia K 562 cells, measuring the uptake of THP-adriamycin (pirarubicin) by continuous spectrofluorometric monitoring of the decrease of the fluorescence signal of the anthracycline at 590 nm (lambdaex = 480 nm), after incubation with cells. Cardiovascular activity, which is responsible for unwanted side effects, was also evaluated. The results obtained show that many of the compounds studied are potent reverters of MDR and are endowed with reduced cardiovascular activity. One of the compounds (7, MM36) presents a pharmacological profile (unprecedented nanomolar potency, high reversal of MDR, low cardiovascular activity) that makes it a promising drug candidate to treat MDR and a useful tool for studying P-glycoprotein.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Universita' di Firenze, via G. Capponi 9, 50121 Firenze, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Teodori
authors.forename: S
authors.initials: S
authors.lastname: Dei
authors.forename: P
authors.initials: P
authors.lastname: Quidu
authors.forename: R
authors.initials: R
authors.lastname: Budriesi
authors.forename: A
authors.initials: A
authors.lastname: Chiarini
authors.forename: A
authors.initials: A
authors.lastname: Garnier-Suillerot
authors.forename: F
authors.initials: F
authors.lastname: Gualtieri
authors.forename: D
authors.initials: D
authors.lastname: Manetti
authors.forename: M N
authors.initials: MN
authors.lastname: Romanelli
authors.forename: S
authors.initials: S
authors.lastname: Scapecchi
mesh_terms: D000818:Animals; D000840:Anisoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D015195:Drug Design; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D011817:Rabbits; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000840:Anisoles; D000970:Antineoplastic Agents; C119208:MM 36; D009570:Nitriles