Lucanthone is a drug used to treat parasitic diseases such as bilharziasis and schistosomiasis It is a prodrug and is converted to the active metabolite hycanthone. |
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InChI=1S/C20H24N2OS/c1- 4- 22(5- 2) 13- 12- 21- 16- 11- 10- 14(3) 20- 18(16) 19(23) 15- 8- 6- 7- 9- 17(15) 24- 20/h6- 11,21H,4- 5,12- 13H2,1- 3H3 |
FBQPGGIHOFZRGH-UHFFFAOYSA-N |
CCN(CC)CCNc1ccc(C)c2sc3ccccc3c(=O)c12 |
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EC 5.99.1.2 (DNA topoisomerase) inhibitor
A topoisomerase inhibitor that inhibits the bacterial enzymes of the DNA topoisomerases, Type I class (EC 5.99.1.2) that catalyze ATP-independent breakage of one of the two strands of DNA, passage of the unbroken strand through the break, and rejoining of the broken strand. These bacterial enzymes reduce the topological stress in the DNA structure by relaxing negatively, but not positively, supercoiled DNA.
EC 5.99.1.3 [DNA topoisomerase (ATP-hydrolysing)] inhibitor
A topoisomerase inhibitor that inhibits DNA topoisomerase (ATP-hydrolysing), EC 5.99.1.3 (also known as topoisomerase II and as DNA gyrase), which catalyses ATP-dependent breakage of both strands of DNA, passage of the unbroken strands through the breaks, and rejoining of the broken strands.
mutagen
An agent that increases the frequency of mutations above the normal background level, usually by interacting directly with DNA and causing it damage, including base substitution.
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schistosomicide drug
Drugs that used to treat infestations by flukes (trematodes) of the genus Schistosoma.
antineoplastic agent
A substance that inhibits or prevents the proliferation of neoplasms.
photosensitizing agent
A chemical compound that can be excited by light of a specific wavelength and subsequently transfer energy to a chosen reactant. This is commonly molecular oxygen within a cancer tissue, which is converted to (highly rective) singlet state oxygen. This rapidly reacts with any nearby biomolecules, ultimately killing the cancer cells.
prodrug
A compound that, on administration, must undergo chemical conversion by metabolic processes before becoming the pharmacologically active drug for which it is a prodrug.
adjuvant
Any pharmacological or immunological agent that modifies the effect of other agents such as drugs or vaccines while having few if any direct effects when given by itself.
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View more via ChEBI Ontology
1-{[2-(diethylamino)ethyl]amino}-4-methyl-9H-thioxanthen-9-one
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lucanthone
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ChemIDplus
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lucanthone
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WHO MedNet
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lucanthonum
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ChemIDplus
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lucantona
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ChemIDplus
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1-((2-(diethylamino)ethyl)amino)-4-methylthioxanthen-9-one
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ChemIDplus
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1-diethylaminoethylethylamino-4-methyl-thioxanthenone
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ChEBI
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1-{[2-(diethylamino)ethyl]amino}-4-methylthioxanthen-9-one
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ChEBI
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Lucanthone
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KEGG COMPOUND
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312369
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Reaxys Registry Number
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Reaxys
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479-50-5
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CAS Registry Number
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ChemIDplus
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Naidu MD, Agarwal R, Pena LA, Cunha L, Mezei M, Shen M, Wilson DM, Liu Y, Sanchez Z, Chaudhary P, Wilson SH, Waring MJ (2011) Lucanthone and its derivative hycanthone inhibit apurinic endonuclease-1 (APE1) by direct protein binding. PloS one 6, e23679 [PubMed:21935361] [show Abstract] Lucanthone and hycanthone are thioxanthenone DNA intercalators used in the 1980s as antitumor agents. Lucanthone is in Phase I clinical trial, whereas hycanthone was pulled out of Phase II trials. Their potential mechanism of action includes DNA intercalation, inhibition of nucleic acid biosyntheses, and inhibition of enzymes like topoisomerases and the dual function base excision repair enzyme apurinic endonuclease 1 (APE1). Lucanthone inhibits the endonuclease activity of APE1, without affecting its redox activity. Our goal was to decipher the precise mechanism of APE1 inhibition as a prerequisite towards development of improved therapeutics that can counteract higher APE1 activity often seen in tumors. The IC(50) values for inhibition of APE1 incision of depurinated plasmid DNA by lucanthone and hycanthone were 5 µM and 80 nM, respectively. The K(D) values (affinity constants) for APE1, as determined by BIACORE binding studies, were 89 nM for lucanthone/10 nM for hycanthone. APE1 structures reveal a hydrophobic pocket where hydrophobic small molecules like thioxanthenones can bind, and our modeling studies confirmed such docking. Circular dichroism spectra uncovered change in the helical structure of APE1 in the presence of lucanthone/hycanthone, and notably, this effect was decreased (Phe266Ala or Phe266Cys or Trp280Leu) or abolished (Phe266Ala/Trp280Ala) when hydrophobic site mutants were employed. Reduced inhibition by lucanthone of the diminished endonuclease activity of hydrophobic mutant proteins (as compared to wild type APE1) supports that binding of lucanthone to the hydrophobic pocket dictates APE1 inhibition. The DNA binding capacity of APE1 was marginally inhibited by lucanthone, and not at all by hycanthone, supporting our hypothesis that thioxanthenones inhibit APE1, predominantly, by direct interaction. Finally, lucanthone-induced degradation was drastically reduced in the presence of short and long lived free radical scavengers, e.g., TRIS and DMSO, suggesting that the mechanism of APE1 breakdown may involve free radical-induced peptide bond cleavage. | Carew JS, Espitia CM, Esquivel JA, Mahalingam D, Kelly KR, Reddy G, Giles FJ, Nawrocki ST (2011) Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. The Journal of biological chemistry 286, 6602-6613 [PubMed:21148553] [show Abstract] Cellular stress induced by nutrient deprivation, hypoxia, and exposure to many chemotherapeutic agents activates an evolutionarily conserved cell survival pathway termed autophagy. This pathway enables cancer cells to undergo self-digestion to generate ATP and other essential biosynthetic molecules to temporarily avoid cell death. Therefore, disruption of autophagy may sensitize cancer cells to cell death and augment chemotherapy-induced apoptosis. Chloroquine and its analog hydroxychloroquine are the only clinically relevant autophagy inhibitors. Because both of these agents induce ocular toxicity, novel inhibitors of autophagy with a better therapeutic index are needed. Here we demonstrate that the small molecule lucanthone inhibits autophagy, induces lysosomal membrane permeabilization, and possesses significantly more potent activity in breast cancer models compared with chloroquine. Exposure to lucanthone resulted in processing and recruitment of microtubule-associated protein 1 light chain 3 (LC3) to autophagosomes, but impaired autophagic degradation as revealed by transmission electron microscopy and the accumulation of p62/SQSTM1. Microarray analysis, qRT-PCR, and immunoblotting determined that lucanthone stimulated a large induction in cathepsin D, which correlated with cell death. Accordingly, knockdown of cathepsin D reduced lucanthone-mediated apoptosis. Subsequent studies using p53(+/+) and p53(-/-) HCT116 cells established that lucanthone induced cathepsin D expression and reduced cancer cell viability independently of p53 status. In addition, lucanthone enhanced the anticancer activity of the histone deacetylase inhibitor vorinostat. Collectively, our results demonstrate that lucanthone is a novel autophagic inhibitor that induces apoptosis via cathepsin D accumulation and enhances vorinostat-mediated cell death in breast cancer models. | Bases RE, Mendez F (1997) Topoisomerase inhibition by lucanthone, an adjuvant in radiation therapy. International journal of radiation oncology, biology, physics 37, 1133-1137 [PubMed:9169823] [show Abstract]
PurposeTo determine whether lucanthone can inhibit human topoisomerases in vitro.Methods and materialsLucanthone was incubated with human topoisomerases II and I together with their plasmid substrates, to determine if lucanthone interfered with the catalytic activities of topoisomerases and if it enhanced the formation of DNA strand breaks, as determined by agarose gel electrophoresis of the resultant plasmid forms.ResultsIncubation of the enzymes with lucanthone inhibited the catalytic activity of topoisomerases II and I. With topoisomerase II, it increased the abundance of DNA double strand breaks (cleavable complexes).ConclusionLucanthone, like actinomycin D, inhibited topoisomerases II and I. It may act to enhance the yield of DNA double strand breaks in cells through a mechanism of topoisomerase II inhibition. | Archer S, Zayed AH, Rej R, Rugino TA (1983) Analogues of hycanthone and lucanthone as antitumor agents. Journal of medicinal chemistry 26, 1240-1246 [PubMed:6887199] [show Abstract] Hycanthone analogues (5 and 6) containing 7-substituted hydroxyl groups were prepared and evaluated as antitumor agents. These compounds were significantly more active than the corresponding unsubstituted derivatives. The 7-hydroxylated 4-(hydroxymethyl)-9H-xanthen-9-ones, 11 and 12, were also active antitumor agents. However, the 7-hydroxy-9H-xanthen-9-one counterparts of the 7-hydroxylucanthones were totally devoid of antitumor activity. Results obtained thus far are consistent with the hypothesis that 4-hydroxymethyl substituents in the 9H-xanthen-9-one and 9H-thioxanthen-9-one series are required for antitumor activity. | Clive D (1974) Mutagenicity of thioxanthenes (hycanthone, lucanthone and four indazole derivatives) at the TK locus in cultured mammalian cells. Mutation research 26, 307-318 [PubMed:4368942] |
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