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Preferred IUPAC name 3-Hydroxy-2-[(1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl]-5-pentylcyclohexa-2,5-diene-1,4-dione | |
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3D model (JSmol) | |
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CompTox Dashboard (EPA) | |
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Properties | |
C21H28O3 | |
Molar mass | 328.445 g/mol |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
HU-331 is a quinone anticarcinogenic drug synthesized from cannabidiol, a cannabinoid in the Cannabis sativa plant. It showed a great efficacy against oncogenic human cells. HU-331 does not cause arrest in cell cycle, cell apoptosis or caspase activation. HU-331 inhibits DNA topoisomerase II even at nanomolar concentrations, but has shown a negligible effect on the action of DNA topoisomerase I. The cannabinoid quinone HU-331 is a very specific inhibitor of topoisomerase II, compared with most known anticancer quinones. [1] One of the main objectives of these studies is the development of a new quinone derived compound that produces anti-neoplastic activity while maintaining low toxicity at therapeutic doses.
Inhibitors of topoisomerases can act at two different levels. First inhibiting topoisomerase, which stabilize the topoisomerase-DNA complex and thus introduce DNA breaks in the wires that lead to apoptosis, then inhibiting the catalytic activity of topoisomerase, which hinders the activity of these enzymes without introducing breaks into the DNA chains. HU-331 seems to be a catalytic inhibitor of topoisomerase II, probably by enzymatic ligation to the protein. This molecule does not cause damage to DNA, but protects cells from damage, natural, or induced by other inhibitors of topoisomerase II that act as inhibitors of topoisomerase. Even when 60% of the target cells are killed by treatment with HU-331, other cells' nucleic content remains unharmed, with less breakage of DNA chains that control important cellular functions. [2]
Doxorubicin, like other anticancer quinones, was used for chemotherapy in human cancers for many years. The mechanism of action of these drugs has been the subject of considerable controversy since chemotherapeutic drugs exert their cytotoxic effect on target cells by nonspecific mechanisms. The doxorubicin damages DNA by intercalation, the generation of reactive oxygen species and inhibition of DNA topoisomerase I and II. This leads to breaking the chains of DNA single and double strands. The protein associated with these ruptures are the topoisomerase II and DNA damage is catalyzed by this enzyme. [2] Thus, while doxorubicin and other anthraquinones act through many mechanisms such as apoptosis, abrogation of the cell cycle cell, activation of caspases, generation of ROS, inhibition of both topoisomerases, activation of intracellular secondary messengers, etc. Hu-331 is more active and less toxic, since it generates reactive oxygen species in the heart and has a specific activity that gives great potential to develop as a new anticancer drug, according to Kogan et al. [2]
Cannabinoids can act as anticancer compounds killing several oncogenic cells followed by direct interaction with cannabinoid receptors. The growth of glioma is inhibited by a selective activation of the CB2 cannabinoid receptor and endogenous cannabinoids such as anandamide inhibit the proliferation of cells involved in lung cancer. The reason behind the antitumor effect of HU-331 appears unknown as cannabinoid receptor antagonists do not inhibit HU-331, despite being mediated by a cannabinoid receptor. The HU-331 exerts an antiangiogenic effect accompanied by apoptosis of endothelial cells. Although in some studies. HU-331 has not caused the death of cells by oncogenic apoptosis. The conclusion that would lead cells to apoptosis based on treatment with the drug did not increase the proportion of cells containing DNA Lues in the sub-G1 phase and have not found the expression of caspase-3 in cancer cells. [2]
HU-331 is not scheduled at the federal level in the United States. [3]
"HU-331 (3-hydroxy-2-[(1R,6R)-3-methyl-6-(1- methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-2,5-cyclohexadiene-1,4-dione)" is a Schedule I controlled substance in the state of Florida making it illegal to buy, sell, or possess in Florida. [4]
"3-hydroxy-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-2,5-cyclohexadiene-1,4-dione, commonly known as HU-331" is a Schedule I controlled substance in the state of Wisconsin making it illegal to buy, sell, or possess in Wisconsin. [5]
HU-331 is included on the list of novel psychoactive substances (55/2014. [XII. 30.] EMMI rendelet) in Hungary. [6]
Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.
Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used together with other chemotherapy agents. Doxorubicin is given by injection into a vein.
Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from Streptomyces bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder cancer, and lung cancers. The first anthracycline discovered was daunorubicin, which is produced naturally by Streptomyces peucetius, a species of Actinomycetota. Clinically the most important anthracyclines are doxorubicin, daunorubicin, epirubicin and idarubicin.
Genistein (C15H10O5) is a naturally occurring compound that structurally belongs to a class of compounds known as isoflavones. It is described as an angiogenesis inhibitor and a phytoestrogen.
Betulinic acid is a naturally occurring pentacyclic triterpenoid which has antiretroviral, antimalarial, and anti-inflammatory properties, as well as a more recently discovered potential as an anticancer agent, by inhibition of topoisomerase. It is found in the bark of several species of plants, principally the white birch from which it gets its name, but also the ber tree, selfheal, the tropical carnivorous plants Triphyophyllum peltatum and Ancistrocladus heyneanus, Diospyros leucomelas, a member of the persimmon family, Tetracera boiviniana, the jambul, flowering quince, rosemary, and Pulsatilla chinensis.
Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are broken into two broad subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII). Topoisomerase plays important roles in cellular reproduction and DNA organization, as they mediate the cleavage of single and double stranded DNA to relax supercoils, untangle catenanes, and condense chromosomes in eukaryotic cells. Topoisomerase inhibitors influence these essential cellular processes. Some topoisomerase inhibitors prevent topoisomerases from performing DNA strand breaks while others, deemed topoisomerase poisons, associate with topoisomerase-DNA complexes and prevent the re-ligation step of the topoisomerase mechanism. These topoisomerase-DNA-inhibitor complexes are cytotoxic agents, as the un-repaired single- and double stranded DNA breaks they cause can lead to apoptosis and cell death. Because of this ability to induce apoptosis, topoisomerase inhibitors have gained interest as therapeutics against infectious and cancerous cells.
FAS-associated death domain protein, also called MORT1, is encoded by the FADD gene on the 11q13.3 region of chromosome 11 in humans.
Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, is a protein that, in humans, is encoded by the BIRC5 gene.
B-cell lymphoma-extra large (Bcl-xL), encoded by the BCL2-like 1 gene, is a transmembrane molecule in the mitochondria. It is a member of the Bcl-2 family of proteins, and acts as an anti-apoptotic protein by preventing the release of mitochondrial contents such as cytochrome c, which leads to caspase activation and ultimately, programmed cell death.
Gene expression profiling has revealed that diffuse large B-cell lymphoma (DLBCL) is composed of at least 3 different sub-groups, each having distinct oncogenic mechanisms that respond to therapies in different ways. Germinal Center B-Cell like (GCB) DLBCLs appear to arise from normal germinal center B cells, while Activated B-cell like (ABC) DLBCLs are thought to arise from postgerminal center B cells that are arrested during plasmacytic differentiation. The differences in gene expression between GCB DLBCL and ABC DLBCL are as vast as the differences between distinct types of leukemia, but these conditions have historically been grouped together and treated as the same disease.
Edelfosine is a synthetic alkyl-lysophospholipid (ALP). It has antineoplastic (anti-cancer) effects.
An Hsp90 inhibitor is a substance that inhibits that activity of the Hsp90 heat shock protein. Since Hsp90 stabilizes a variety of proteins required for survival of cancer cells, these substances may have therapeutic benefit in the treatment of various types of malignancies. Furthermore, a number of Hsp90 inhibitors are currently undergoing clinical trials for a variety of cancers. Hsp90 inhibitors include the natural products geldanamycin, Retaspimycin hydrochloride and radicicol as well as semisynthetic derivatives 17-N-Allylamino-17-demethoxygeldanamycin (17AAG).
HU-336 is a strongly antiangiogenic compound, significantly inhibiting angiogenesis at concentrations as low as 300 nM. It inhibits angiogenesis by directly inducing apoptosis of vascular endothelial cells without changing the expression of pro- and antiangiogenic cytokines and their receptors. HU-336 is highly effective against tumor xenografts in nude mice. Although it is technically the oxidized quinone of delta-8 THC, it is entirely non psychoactive.
HU-345 is a drug that is able to inhibit aortic ring angiogenesis more potently than its parent compound cannabinol (CBN). It exhibits no psychoactive effects on the body.
Anticancer genes exhibit a preferential ability to kill cancer cells while leaving healthy cells unharmed. This phenomenon is achieved through various processes such as apoptosis following a mitotic catastrophe, necrosis, and autophagy. In the late 1990s, extensive research in the field of cancer cells led to the discovery of anticancer genes. Mutations in these genes due to base substitutions leading to insertions, deletions, or alterations in missense amino acids can cause frameshifts, thereby altering the protein. A change in gene copy number or rearrangements is also essential for deregulating these genes. The loss or alteration of these anticancer genes due to mutations or rearrangements may lead to the development of cancer.
Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding in defence against pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication. In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.
Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anti-cancer therapies. In some cases, cancers can evolve resistance to multiple drugs, called multiple drug resistance.
Immunogenic cell death is any type of cell death eliciting an immune response. Both accidental cell death and regulated cell death can result in immune response. Immunogenic cell death contrasts to forms of cell death that do not elicit any response or even mediate immune tolerance.
Paraptosis is a type of programmed cell death, morphologically distinct from apoptosis and necrosis. The defining features of paraptosis are cytoplasmic vacuolation, independent of caspase activation and inhibition, and lack of apoptotic morphology. Paraptosis lacks several of the hallmark characteristics of apoptosis, such as membrane blebbing, chromatin condensation, and nuclear fragmentation. Like apoptosis and other types of programmed cell death, the cell is involved in causing its own death, and gene expression is required. This is in contrast to necrosis, which is non-programmed cell death that results from injury to the cell.
Vosaroxin is a topoisomerase II inhibitor causing site-selective DNA damage. It is under phase III clinical trial investigation for acute myelogenous leukemia (AML) and ovarian cancer sponsored by Sunesis.