Synthesis and Structure–Activity Relationships of Lapacho Analogues. 1. Suppression of Human Keratinocyte Hyperproliferation by 2-Substituted Naphtho[2,3-b]furan-4,9-diones, Activation by Enzymatic One- and Two-Electron Reduction, and Intracellular Generation of Superoxide

Abstract

A series of linearly anellated lapacho quinone analogues substituted at the 2-position of the tricyclic naphtho[2,3-b]furan-4,9-dione system were synthesized and evaluated for their ability to suppress keratinocyte hyperproliferation using HaCaT cells as the primary test system. While very good in vitro potency with IC(50) values in the submicromolar range was attained with electron-withdrawing substituents, some compounds were found to induce plasma membrane damage, as evidenced by the release of LDH activity from cytoplasm of the keratinocytes. The most potent analogue against keratinocyte hyperproliferation was the 1,2,4-oxadiazole 18, the potency of which was combined with comparably low cytotoxic membrane damaging effects. Structure-activity relationship studies with either metabolically stable or labile analogues revealed that the quinone moiety was required for activity. Selected compounds were studied in detail for their capability to generate superoxide radicals both in isolated enzymatic one- and two-electron reduction assays as well as in a HaCaT cell-based assay.

Synthesis, Anti-Proliferative Activity Evaluation and 3D-QSAR Study of Naphthoquinone Derivatives as Potential Anti-Colorectal Cancer Agents

“…Final oxidation and ether cleavage using diammonium cerium(IV) nitrate provided the target structure 5c ( Scheme 5 ). Finally, following previously reported procedures, the compound N , N -diethyl-4,9-dioxo-4,9-dihydronaphtho[2,3- b ]furan-2-carboxamide ( 6 ) [ 19 ], as well as the naphthothiophene derivatives 8-hydroxy-2-(thiophen-2-ylcarbonyl)naphtho[2,3- b ]thiophene-4,9-dione ( 7 ) [ 20 ], 8-chloro- N , N -diethyl-4,9-dioxo-4,9-dihydronaphtho[2,3- b ]thiophene-2-carboxamide ( 8 ) [ 21 ], and 2-(3-ethyl-1,2,4-oxadiazol-5-yl)naphtho[2,3- b ]thiophene-4,9-dione ( 9 ) [ 22 ] were synthesized.…”

“…Similarly, Inagaki et al [ 24 ], evaluated the cytotoxic activity of furanonaphthoquinone analogs against two cancer cell lines, observing stronger cytotoxicity in compounds with a 2-acetyl substituted furan ring. Likewise, a series of analogs substituted at the 2-position of the tricyclic naphtho-[2,3- b ]furan-4,9-dione system, including the compounds 4d , 4e , 4j and 6 , were evaluated to determine the ability to suppress keratinocyte hyperproliferation, showing the importance of 2-electron withdrawing substituents [ 19 ]. Furthermore, it was observed that quinone derivatives with a tricyclic system in an angular conformation (4,5-diones) showed higher activity than those with a linear conformation (4,9-diones), suggesting that the spatial configuration is important for the cytotoxic activity; which agrees with the report of Kongkathip et al [ 25 ].…”

Overcoming naphthoquinone deactivation: rhodium-catalyzed C-5 selective C–H iodination as a gateway to functionalized derivatives

“…2 f Because of their biological importance, significant efforts are devoted to the synthesis and evaluation of a wide range of naphthoquinone derivatives. 3 While methods for the modification of the quinone B-ring are reasonably well established, 4 flexible protocols that allow the direct functionalization of the benzenoid A-ring are rare ( Scheme 1B ). 5 This situation is exacerbated by the limitations associated with de novo naphthoquinone construction.…”

Naphthoquinone-based chalcone hybrids and derivatives: synthesis and potent activity against cancer cell lines

“…1 In a four-year period, the estimated number increased from 12.7 million new cancer cases with 7.6 million cancerrelated deaths in 2008, to 14.1 million new cancer cases and 8.2 million cancer-related deaths in 2012. 4 Among these, naphthoquinoidal compounds obtained from natural products, such as lapachol and lawsone (2-hydroxy-1,4-naphthoquinone), have received considerable attention because of their antitumor potential. 2,3 Naphthoquinone containing natural products belong to an important class of naturally occurring secondary metabolites found in the bignoniaceae family.…”