IJUP08 - Universidade do Porto

Synthesis, structure elucidation and evaluation of xanthone
derivatives for dual activity: antitumor activity and P-glycoprotein
inhibition
J. Lima 1 , A. Paiva 1 , E. Sousa 1,3 , M. Pinto 1,3 , M. S. J. Nascimento 2,3 and M.
H.Vasconcelos 2,4
1 Department of Organic Chemistry, Faculty of Pharmacy, University of Porto, Portugal.
2 Department of Microbiology, Faculty of Pharmacy, University of Porto, Portugal.
3 Research Centre of Organic Chemistry, Phytochemistry and Pharmacology of the University of
Porto (CEQOFFUP), Faculty of Pharmacy, University of Porto, Portugal.
4 IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Portugal.
Although enormous progress has been achieved in the field of cancer therapy, only
approximately 50 % of all cancers are susceptible to chemotherapy. From these, more than
50 % rapidly develop drug resistance during therapeutical treatment. Most often, this drug
resistance is a multiple drug resistance (MDR) phenotype caused by the overexpression of
P-glycoprotein (P-gp), a membrane-bound efflux pump which transports a wide variety of
anticancer agents out of the tumor cells. Inhibition of P-gp is a powerful approach to
reverse MDR; however, current P-gp inhibitors have demonstrated limited clinical success
[1].
The development of a library of small molecules that will potentially reveal simultaneous
activities, as antitumor and P-gp inhibitor, is in progress, in which the requirements
established for P-gp modulation were applied to antitumor xanthones. Using parallel
synthesis and solid supported
O Cl
O NR2 reagents, several compounds were
Cu2O + NHR2 obtained (Fig. 1).
S
O
O
O
OMe
CHO
OH
CH 3
+
NHR 2
MeOH
r.t. overnight
MP-CNBH3 AcOH
MeOH O
r.t. overnight
Fig. (1). Synthesis of amino(tio)xanthones.
O
S
O
OH
The multiple ligands will be
assessed for their antitumor
activity by testing their capacity to
inhibit the in vitro growth of
several human tumor cell lines.
The in vitro biological evaluation
of MDR modulation will be
conducted by testing the ability of
the molecules to either reduce P-gp protein expression or reduce the efflux of rhodamine
from K562Dox cells (cells from a chronic myeloid leukemia cell line with overexpression
of P-gp, obtained by another group from K562 cells after prolonged drug [2]).
References:
[1] McDevitt, C.A. and Callaghan, R. (2007), How can we best use structural information on Pglycoprotein
to design inhibitors?, Pharmacology & Therapeutics, 113, 429-441.
[2] Lima, R.T., Guimarães, JE and Vasconcelos, M.H. (2007), Overcoming K562Dox resistance to
STI571(Gleevec) by downregulation of P-gp expression using siRNAs,Cancer Therapy, 5, 67-76.
Acknowledgments: FCT (I&D, nº226/94), FEDER, POCI, U. Porto, and Caixa Geral de Depósitos
for financial support.
OMe
CH 3
NR 2
150