6-[(1,4-Naphthoquinone-2-yl)methyl]thio-Glucose Conjugates, a Novel Targeted Approach for Advanced Prostate Cancer.

The Warburg effect is a shift from oxidative phosphorylation to anaerobic glycolysis, accompanied by an enormous increase in glucose uptake into cancer cells. We have utilized this effect to design a new group of targeted 1,4-naphthoquinone-glucose derivatives conjugated with a novel thiomethylene linker that are cytotoxic to prostate cancer cells. Compound PeS-9 revealed the highest efficacy and selectivity, which was conditioned by a GLUT-1-mediated uptake.

Synthesis and Biological Activity of Glycosyl Thiazolyl Disulfides Based on Thiacarpine, an Analogue of the Cytotoxic Alkaloid Polycarpine from the Ascidian .

Polycarpine, a diimidazolyl disulfan alkaloid isolated from the ascidian , showed high cytotoxic activity in vitro. However, in vivo experiments have shown that polycarpine has a high acute toxicity. At the same time, its synthetic thiazolyl analog, thiacarpine, showed less acute toxicity and had a greater therapeutic index, which makes its derivatives promising for further drug development.

Dimeric (Poly)Hydroxynaphthazarins, Metabolites of Echinoderms and Lichens: The History of the Synthesis and Structure Elucidation.

This review provides information on the synthesis and revision of the structures of natural dimeric (poly)hydroxynaphthazarins, metabolites of echinoderms and lichens, and on the refinement of the direction and mechanism of reactions in the synthesis of some of these compounds.

Activity of New Synthetic (2-Chloroethylthio)-1,4-naphthoquinones in Prostate Cancer Cells.

Development of resistance to currently available standard therapies in advanced prostate cancer (PCa) emphasizes the need for novel therapeutic options. Here, we report the synthesis of new hybrid molecules consisting of 2-chloroethylthio and 1,4-naphthoquinone pharmacophores and describe their activity in PCa. In screening analyses, the introduction of one 2-chloroethylthio group improved the anticancer properties of 1,4-naphthoquinones, whereas the introduction of a second 2-chloroethylthio moiety rather decreased activity.

Successful Targeting of the Warburg Effect in Prostate Cancer by Glucose-Conjugated 1,4-Naphthoquinones.

Treatment of castration-resistant prostate cancer (CRPC) remains challenging due to the development of drug resistance. The Warburg effect describes the ability of cancer cells to consume larger amounts of glucose compared to normal tissues. We identified derivatives of natural 1,4-naphthoquinones to be active in CRPC and further synthetically modified them via glucose conjugation to increase selectivity by Warburg effect targeting.

Synthesis, Cytotoxic and Contraceptive Activity of 6,8,9-Trihydroxy-2-methyl-2H-naphtho[2,3-b]pyran-5,10-dione, a Pigment of Echinothrix diadema, and its Analogs.

6,8,9-Trihydroxy-2-methyl-2H-naphtho[2,3-b]pyran-5,10-dion, a pigment of the sea urchin Echinothrix diadema, and six analogs were synthesized. The cytotoxic activity and contraceptive properties of the synthesized pyranonaphthazarins have been investigated using the sperm and eggs of the sea urchin Strongylocentrotus intermedius.

Total synthesis of hybocarpone, a cytotoxic naphthazarin derivative from the lichen Lecanora hybocarpa, and related compounds.

The concise synthesis of the lichen-derived antitumor agent hybocarpone (1) and its analogs is described. A new synthetic approach is based on the direct oxidative dimerization of the available naphthazarin precursors in the formation of the binaphtho[2,3-b; 2,3-d]furantetraone structure. It was shown that the first step to tetrahydrofuran features is the bridging hindered S*,S* and R*,S* carbon-carbon bonds of the molecules, setting the relative configurations of the 5aS*,6aS*,12aS*,12bS* and 5aS*,6aR*,12aR*,12bS* diastereomers.

Preparative production of spinochrome E, a pigment of different sea urchin species.

A concise route to spinochrome E (1) (2,3,5,6,7,8-hexahydroxy-1,4-naphthoquinone), a pigment isolated from sea urchins of different species, has been developed starting from either commercially available 5,8-dihydroxy-1,4-naphthoquinone (11) or 2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone (12). The protocol involves 3 steps, the chlorination of either 11 or 12 to tetrachloronaphthazarin (13), the total nucleophilic substitution of the chlorine atoms in 13 by methoxy groups, and hydrolysis of tetramethyl ether14; this makes possible the preparation of the target compound in overall yields from 41 to 46%.

Concerning the structure of islandoquinone isolated from the lichen Cetraria islandica.

An investigation of the oxidative coupling products of some substituted hydroxynaphthazarins led to a revision of the proposed structure of islandoquinone, previously isolated from the lichen Cetraria islandica, and yielding (7aS*, 13aS*)-6,7a-diethyl-2,5,9,11,12,13a-hexahydroxy-7, 4-dioxabenzo[a]tetracene-1,4,8,13(7aH, 13aH)-tetraone through X-ray diffraction analysis of its 2,11-dimethyl ether.

Quinone-carbohydrate nonglucoside conjugates as a new type of cytotoxic agents: synthesis and determination of in vitro activity.

We have found that 2-methoxy-1,4-naphthoquinones easily react with primary alcohols to produce the corresponding 2-alkoxyderivatives. Using this reaction, we synthesized methyl-6-O-(naphthalene-1,4-dione-2-yl)-α-D-glucopyranosides, a new type of water soluble quinone-carbohydrate nonglucoside conjugates. The resulting conjugates induced apoptosis in human cancer HeLa and normal mouse JB6 P(+) Cl41 cells with simultaneous inhibition of p53-dependant transcriptional activity, suggesting that the observed cell death was p53-independent.

Synthesis of echinamines A and B, the first aminated hydroxynaphthazarins produced by the sea urchin Scaphechinus mirabilis and its analogues.

The first total synthesis of two marine aminated hydroxynaphthazarins, echinamines A (3-amino-7-ethyl-2,5,6,8-tetrahydroxy-1,4-naphthoquinone) and B (2-amino-7-ethyl-3,5,6,8-tetrahydroxy-1,4-naphthoquinone), produced by the sea urchin Scaphechinus mirabilis is described. This was achieved from 1,2,4-triacetoxybenzene (13) through a sequence involving double Fries rearrangement of 13, reduction of 3,5-diacetyl-1,2,4-trihydroxybenzene (14), methylation of 3,5-diethyl-1,2,4-trihydroxybenzene (15), simultaneous double acylation of 3,5-diethyl-1,2,4-trimethoxybenzene (16) with a dichloromaleic anhydride-ethyl radical elimination process, methylation of 6,7-dichloro-3-ethyl-2-hydroxynaphthazarin (17), nucleophilic substitution of a chlorine atom by the methoxy group in 6,7-dichloro-3-ethyl-2-methoxynaphthazarin (18), introduction of an amino group via direct substitution of a chlorine atom in 7-chloro-3-ethyl-2,6-dimethoxy- (11) and 7-chloro-2-ethyl-3,6-dimethoxynaphthazarins (12) by an azido group, and functional group deprotection. The synthesis of amino analogues of spinazarin and spinochrome D is also described.

Echinamines A and B, first aminated hydroxynaphthazarins from the sea urchin Scaphechinus mirabilis.

Two new spinochromes, echinamines A (1) and B (2), were isolated from the sea urchin Scaphechinus mirabilis. Compounds 1 and 2 represent the first examples of natural polyhydroxynaphthazarins with a primary amine group. The structures of 1 and 2 were established by analysis of spectroscopic data and synthesis of their dimethyl ethers.