Antitumoral activity of new polyamine-naphthoquinone conjugates.
Polyamine-naphthoquinone conjugates 5a-c were synthesized by nucleophilic displacement of 2-methoxy-lawsone 3a, 2-methoxylapachol 3b and 2-methoxy-nor-lapachol 3c with the polyamine N1-Boc-N5-Bn-spermidine 4. Unprotected derivatives 6a-c were synthesized to evaluate the effect of the protective Boc group on the activity of compounds 5a-c. The colorimetric MTT assay was used to evaluate their cytotoxic activity. All compounds were active against human lines of promyelocytic leukemia (HL-60), lung cancer (GLC4), Burkitt lymphoma (Daudi) and a mouse breast tumor (Ehrlich carcinoma), but only unprotected 6a-c showed activity against the human line of melanoma (MV-3). IC50 values were obtained from dose response curves by linear regression. DNA fragmentation was measured by quantification of the subG1 peak of the cell cycle. Apoptosis of HL-60 treated with 5c was dose-dependent. The amount of DNA fragmentation observed by exposure of HL-60 to 25 microM of compounds 5a-c and 6a-c is compatible with the decrease in viability induced by the drugs at this concentration. Production of ROS was measured by H2-CFDA. Kinetics of HL-60 DNA fragmentation and ROS formation by 5c indicated that production of ROS precedes cell death. In conclusion, spermidine-1,4-naphthoquinone conjugates exhibited an increase in activity compared with the natural products and induced apoptosis of tumor cell lines by a mechanism that is mediated, at least in part, by ROS production.
Esteves-Souza
Andressa
A
Instituto de Biofísica Carlos Chagas Filho, CCS, Universidade Federal do Rio de Janeiro, 21949-900 Rio de Janeiro, Brazil.
Lucio
Kelly Araújo
KA
Da Cunha
Andréa Sousa
AS
Da Cunha Pinto
Angelo
A
Da Silva Lima
Edson Luiz
EL
Camara
Celso Amorim
CA
Vargas
Maria Domingues
MD
Gattass
Cerli Rocha
CR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D006801:Humans; D051379:Mice; D009285:Naphthoquinones / Q000494:pharmacology*; D011073:Polyamines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D009285:Naphthoquinones; D011073:Polyamines; D017382:Reactive Oxygen Species