Synthesis and evaluation of cytotoxic activity derived 2,3-diyne-1,4-naphthoquinones

Abstract

In the present study ten 2,3-diyne-1,4-naphthoquinone derivatives (3a-j) were synthesized by Sonogashira coupling reaction between the 2,3-dibromo-1,4-naphthoquinone (2) and several functionalized terminal alkynes using a catalytic complex of palladium (II) and CuI. Alkynes are among phenylacetylene, 1-ethyl-4-methoxybenzene, 2-methyl-3-butyn-2-ol, 1-ethynyl-1-cyclohexanol, 4-pentyn-2-ol, 4-pentyn-1-ol, 1-pentyne, 1-hexyne, 1-decyne and 1-octyne. The yields of products obtained ranged 15 to 55%. The enediynes having hydroxyl groups, in their structures such as 2,3-di(3-hydroxy-3-methylbut-1-in-1-yl)-, 2,3-di[(1-hydroxycyclohexyl)ethynyl]- and 2,3-di(5-hydroxypent-1-yl)-1,4-naphthoquinone were subjected to acetylation reaction using acetic anhydride and montmorillonite clay K-10 under sonication, thereby obtaining three new enediyne derivatives (3c’, d’ and f’) with yields ranging from 56 to 71%. The compounds were all characterized by 1H NMR and 13C NMR spectra, IR and MS-LC. These compounds containing the 1,4-naphthoquinone nucleus and acetylenic substituents in the quinonoid ring form a enediyne system (Z-3-ene-1,5-diyne) highly reactive, possibly subject to Bergman cycloaromatization, with potential antitumor activity. The enediynes underwent evaluation of the cytotoxic potential against three tumor cell lines, OVCAR-8 (ovarian adenocarcinoma - human), PC-3M (metastatic prostate cancer - human), NCI-H358M (bronchoalveolar lung carcinoma - human), presenting, in general, satisfactory results for inhibition of cell growth. The compound 2,3-di(3-hydroxy-3-methylbut-1-in-yl)-1,4-naphthoquinone (3c) where said among the substances analyzed by presenting a lower IC50 (˂ 2 µg/mL) for three cell lines tested, which is characterized as a potent cytotoxic agent.

Keywords

• 2,3-diyne-1,4-naphthoquinone, antitumor, bergman cycloaromatization