Selective Electrophile-Promoted Cyclization Reactions of Lapachol and Evaluation of Bioactive Naphthoquinones Against Cancer Cell Lines

Abstract

Cyclic ether-fused tricyclic naphthoquinones are major pharmacophores because of their biological activities. The methodology of construction is either by inter or intra-molecular cyclization of functionalized naphthoquinones. This reaction includes a wide range of reagents from classical Brønsted to Lewis acids. The choice of appropriate reagent and reaction conditions against the substrate is the key to accomplishing the regio- and/or stereo-selective synthesis of these compounds, though it seems difficult at first glance to decide how because numerous numbers of actual examples have been presented. To have a deeper insight into the mechanism of cyclization under acid conditions, lapachol 1 was subjected to electrophilic entities: Brønsted acids (H₂SO₄, HCl, H₃PO₄, HNO₃, HCOOH, CH₃COOH, HOOCCH₂COOH), Lewis acids (AlCl₃, FeCl₃, ZnCl₂) nitrogenous cations (NO⁺, NO²⁺), carbocation (CH₃CO⁺), neutral polarized molecules (CH₃COCl, CH₃COOCH₃), neutral polarizable molecules (Br₂, I₂), oxidant promoted cyclization (DDQ, CAN, Peroxides), and reaction conditions. A series of Naphthoquinones based on the Isoprenyl-1,4-naphthoquinone (Lapachol), naphtho[1,2-b]furan-4,5-dione (nor β-lapachone), naphtho[2,3-b]pyran-5,10-dione (α-lapachone), naphtho[1,2-b]pyran-5,6-dione (β-lapachone), and naphtho[2,3-b]furan-4,9-dione (2-acetyl furonaphthoquinone) skeletons were selectively synthesized. By looking at our result, there are characteristic trends of cyclized adducts depending on which reagents were used. The synthesized compounds were evaluated for their biological activity against the MDA-MB-231 breast cancer, HT-29 MTX colon cancer, and non-transformed mammary epithelial cell lines at concentrations of 1 μM, 10 μM, and 100 μM. The result indicated that lapachol and β-lapachone skeletons were the most active at 10 μM and 100 μM especially 3-hydroxy-β-lapachone 8 with interesting growth stimulatory effect on cancer cell lines, but not the non-transformed cells.