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Conjugation with polyamines enhances the antitumor activity of naphthoquinones against human glioblastoma cells

Romão, Lucianaa,b; do Canto, Vanessa, P.c; Netz, Paulo, A.c; Moura-Neto, Vivaldob; Pinto, Ângelo, C.d,✠; Follmer, Cristiane

doi: 10.1097/CAD.0000000000000619

Glioblastoma multiform (GBM) is the most common and devastating type of primary brain tumor, being considered the deadliest of human cancers. In this context, extensive efforts have been undertaken to develop new drugs that exhibit both antiproliferation and antimetastasis effects on GBM. 1,4-Naphthoquinone (1,4-NQ) scaffold has been found in compounds able to inhibit important biological targets associated with cancer, which includes DNA topoisomerase, Hsp90 and monoamine oxidase. Among potential antineoplastic 1,4-NQs is the plant-derived lapachol (2-hydroxy-3-prenyl-1,4-naphthoquinone) that was found to be active against the Walker-256 carcinoma and Yoshida sarcoma. In the present study, we examined the effect of polyamine (PA)-conjugated derivatives of lapachol, nor-lapachol and lawsone on the growth and invasion of the human GBM cells. The conjugation with PA (a spermidine analog) resulted in dose-dependent and time-dependent increase of cytotoxicity of the 1,4-NQs. In addition, in-vitro inhibition of GBM cell invasion by lapachol was increased upon PA conjugation. Previous biochemical experiments indicated that these PA-1,4-NQs are capable of inhibiting DNA human topoisomerase II-α (topo2α), a major enzyme involved in maintaining DNA topology. Herein, we applied molecular docking to investigate the binding of PA-1,4-NQs to the ATPase site of topo2α. The most active molecules preferentially bind at the ATP-binding site of topo2α, which is energetically favored by the conjugation with PA. Taken together, these findings suggested that the PA-1,4-NQ conjugates might represent potential molecules in the development of new drugs in chemotherapy for malignant brain tumors.

aCampus Xerém

bInstitute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

cInstitute of Chemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil

dDepartment of Organic Chemistry

eDepartment of Physical Chemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

✠ Deceased.

Correspondence to Cristian Follmer, PhD, Department of Physical Chemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil Tel: +55 21 2562 7752; fax: +55 21 2562 7265; e-mail:

Received November 6, 2017

Accepted February 23, 2018

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