Synthesis and Structure–Activity Relationships of Lapacho Analogues. 2. Modification of the Basic Naphtho[2,3-b]furan-4,9-dione, Redox Activation, and Suppression of Human Keratinocyte Hyperproliferation by 8-Hydroxynaphtho[2,3-b]thiophene-4,9-diones

Abstract

The basic structure of linearly anellated lapacho quinones, naphtho[2,3-b]furan-4,9-dione (7), was modified in the search for novel agents against keratinocyte hyperproliferation. The synthesis and structure-activity relationships of several heterocycle-fused naphthoquinones as well as a full range of 2- and 7-substituted derivatives of one of these, 8-hydroxynaphtho[2,3-b]thiophene-4,9-dione (8a), are described. Out of a total of 71 analogues, particularly 2-thenoyl-substituted 26l, 2-nicotinoyl-substituted 26m, and 2-oxadiazole-substituted 35a compared favorably with the antipsoriatic agent anthralin. Their potency for suppression of keratinocyte hyperproliferation, which was evaluated using HaCaT cells as a model, was combined with comparably low membrane-damaging effects toward keratinocytes, as established by the release of lactate dehydrogenase activity from the cytoplasm of the cells. With respect to the mechanism of action, redox activation of lapacho quinones by one- and two-electron reduction in isolated enzymatic assays was studied, and their potential to generate superoxide was confirmed in the keratinocyte-based hyperproliferation 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.…”

Redox Center Modification of Lapachones towards the Synthesis of Nitrogen Heterocycles as Selective Fluorescent Mitochondrial Imaging Probes

“…Inspiration from nature for chemical transformations and the synthesis of new compounds is virtually unlimited Versatile synthons and intermediates may be directly accessed and, in many cases, multigram access is not a drawback for fine chemical transformations. β‐Lapachone ( 4 ; see Scheme ) and its derivatives are among these classes of natural substrates, and are widely used in a plethora of applications, such as in organic chemistry transformations and as anticancer and trypanocidal agents among many others . Lapachol ( 1 ) is a naturally occurring naphthoquinone prone to several chemical modifications and therefore attracts interest for its possible structural diversity and applications…”

QSAR Model of Indeno[1,2-b]indole Derivatives and Identification of N-isopentyl-2-methyl-4,9-dioxo-4,9-Dihydronaphtho[2,3-b]furan-3-carboxamide as a Potent CK2 Inhibitor

“…These results indicate that the tested compounds showed a good effect on cell viability. It is important to note that some compounds with a naphtho [2,3-b]furan-4,9dione backbone are known to have anticancer effects and are highly cytotoxic [38,39], and other natural naphtho [2,3-b]furan-4,9-dione derivatives, which are found in the lapacho (Tabebuia) tree, are known to have different biological activities, such as antibacterial, antifungal, anti-inflammatory, and antitumor activities [40]. All naphtho [2,3-b]furan-4,9-dione compounds in this study were docked in the ATP binding site of the crystal structure of CK2, as mentioned above using PDB ID: 3C13 from the Protein Data Bank (PDB) [41], having a resolution of 1.95 Å.…”