Naphthoindole-based analogues of tryptophan and tryptamine: synthesis and cytotoxic properties.
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.
Shchekotikhin
Andrey E
AE
Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia. shchekotikhin@mail.ru
Dezhenkova
Lyubov G
LG
Susova
Olga Yu
OY
Glazunova
Valeria A
VA
Luzikov
Yuri N
YN
Sinkevich
Yuri B
YB
Buyanov
Vladimir N
VN
Shtil
Alexander A
AA
Preobrazhenskaya
Maria N
MN
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
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D007211:Indoles; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014363:Tryptamines; D014364:Tryptophan