title: Naphthoindole-based analogues of tryptophan and tryptamine: synthesis and cytotoxic properties.
abstract: The efficacy of anthracycline based anticancer drugs is limited by pleiotropic drug resistance of tumor cells. Aiming at the design of anthracyclinone congeners capable of circumventing drug resistance, we synthesized naphthoindole containing derivatives of tryptophan and tryptamine. In doing so we adapted the traditional, gramine based approach for tryptophan and tryptamine synthesis. The most potent new compound, 3-(2-aminoethyl)-4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione (16), was equally cytotoxic (IC(50) within low micromolar concentrations) for human K562 leukemia and HCT116 colon carcinoma cell lines and their isogenic sublines with genetically defined determinants of altered drug response, that is, the expression of the multidrug transporter P-glycoprotein and loss of pro-apoptotic p53. Each of these mechanisms conferred resistance to the reference drug adriamycin. In contrast, naphthotryptamine 16, although less potent than adriamycin, was equally toxic for wild type cell lines and drug resistant counterparts. Moreover, at 3-5 microM 16 inhibited topoisomerase I in vitro. Thus, our novel naphthoindole based derivative of tryptamine gained new activities important for anticancer therapy, namely, suppression of topoisomerase I and the ability to overcome resistance mediated by P-glycoprotein expression and p53 dysfunction.
authors.affiliation: Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia. shchekotikhin@mail.ru
authors.forename: Andrey E
authors.initials: AE
authors.lastname: Shchekotikhin
authors.forename: Lyubov G
authors.initials: LG
authors.lastname: Dezhenkova
authors.forename: Olga Yu
authors.initials: OY
authors.lastname: Susova
authors.forename: Valeria A
authors.initials: VA
authors.lastname: Glazunova
authors.forename: Yuri N
authors.initials: YN
authors.lastname: Luzikov
authors.forename: Yuri B
authors.initials: YB
authors.lastname: Sinkevich
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Buyanov
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Shtil
authors.forename: Maria N
authors.initials: MN
authors.lastname: Preobrazhenskaya
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D007211:Indoles / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014363:Tryptamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D007211:Indoles; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014363:Tryptamines; D014364:Tryptophan