Article J. Braz. Chem. Soc., Vol. 21, No. 1, 169-178, 2010. Printed in Brazil - ©2010 Sociedade Brasileira de Química 0103 - 5053 $6.00+0.00 *e-mail: mdvargas@vm.uff.br #Present address: Instituto de Química, Universidade Federal do Rio de Janeiro, 22640-000 Rio de Janeiro-RJ, Brazil Novel 2-(R-phenyl)amino-3-(2-methylpropenyl)-[1,4]-naphthoquinones: Synthesis, Characterization, Electrochemical Behavior and Antitumor Activity Acácio I. Francisco, a Annelise Casellato, a,# Amanda P. Neves, a J. Walkimar de M. Carneiro, a Maria D. Vargas,* ,a Lorenzo do C. Visentin, b Alviclér Magalhães, c Celso A. Câmara, d Claudia Pessoa, e Letícia V. Costa-Lotufo, e José D. B. Marinho Filho e and Manoel O. de Moraes e a Instituto de Química, Universidade Federal Fluminense, 24020-141 Niterói-RJ, Brazil b Instituto de Química, Universidade Federal do Rio de Janeiro, 22640-000 Rio de Janeiro-RJ, Brazil c Instituto de Química, Universidade Estadual de Campinas, 13083-970 Campinas-SP, Brazil d Instituto de Química, Universidade Federal Rural de Pernambuco, 52171-900 Recife-PE, Brazil e Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, 60430-270 Fortaleza-CE, Brazil Novas 2-(R-fenil)amino-3-(2-metilpropenil)-[1,4]-naftoquinonas (R = H, 4-OMe, 4-Ferrocenil, 4-Me, 3-Me, 4-I, 3-I, 4-CN, 3-CN, 4-NO 2 e 3-NO 2 ) derivadas do nor-lapachol [2-hidroxi-3-(2- metilpropenil)-1,4-naftoquinona] foram obtidas em bons rendimentos. A estrutura dos compostos foi proposta com base em estudos de difração de raios-X (R = OMe, 2b), dados de RMN de 1 H e 13 C e cálculos teóricos utilizando o funcional B3LYP e a base 6-311+G(2d,p). Os potenciais de meia-onda das aminonaftoquinonas e o deslocamento químico do hidrogênio da cadeia 3-propenil dos compostos 2a-k mostraram boa correlação com as constantes de Hammett dos substituintes presentes no anel fenileno. A avaliação da citotoxicidade evidenciou atividade antitumoral promissora para o substrato metóxi-nor-lapachol 1 e o derivado 4-ferrocenil 2c. Novel 2-(R-phenyl)amino-3-(2-methyl-propenyl)-[1,4]-naphthoquinones (R = H, 4-OMe, 4-Ferrocenyl, 4-Me, 3-Me, 4-I, 3-I, 4-CN, 3-CN, 4-NO 2 and 3-NO 2 ) derived from nor-lapachol [2-hydroxy-3-(2-methylpropenyl)-1,4-naphthoquinone] were obtained in good yields. Their structures were proposed on the basis of a single crystal X-ray diffraction study (R = OMe, 2b), 1 H and 13 C NMR studies and calculations using the B3LYP functional and the 6-311+G(2d,p) basis set. The half-wave potentials of the aminonaphthoquinones and 1 H NMR chemical shifts of the 3-propenyl hydrogen in 2a-k show good correlation with the substituent Hammett constants on the phenylamino ring. The antitumor assays showed promising activity for substrate methoxy- nor-lapachol 1 and the 4-ferrocenyl derivative 2c. Keywords: Nor-lapachol, arylamine, aminonaphthoquinone, electrochemistry, B3LYP, antitumor activity Introduction Naphthoquinones are widely distributed in nature and some of these molecules have an important role in the biochemistry of microbial energy production, by means of photosynthesis and respiratory chain. 1 Compounds containing the quinone group are known for exhibiting antitumor, 2 trypanocide, 3 moluscicide, 4 fungicide 5 and antimalarial 6 activities. The presence of an amino group in quinones has led to interesting biologically active compounds. 7-12 Biological activity of quinones is often related to their electrochemical behavior. 13 The ability to accept one or two electrons to form the corresponding radical anion (Q •- ) or dianion (Q 2- ) species is believed to induce formation of reactive oxygen species, responsible for the oxidative stress in cells. 14 The electron-accepting capacity of naphthoquinones may be tuned by carbonyl position changes (1,2- x 1,4-naphthoquinones) 15 or different substituents or functions attached to the naphthoquinone moiety, and the use of electrochemical methods to study