Noscapine

Last updated
Noscapine
Noscapine Structure.svg
Noscapine.png
Clinical data
Other namesNarcotine, nectodon, nospen, anarcotine
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • Contraindicated
ATC code
Legal status
Legal status
  • AU: S2 (Pharmacy medicine)
  • EU:BE, SE: OTC
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability ~30%
Elimination half-life 1.5–4 h (mean 2.5 h)
Identifiers
  • (3S)-6,7-Dimethoxy-3-[(5R)-5,6,7,8-tetrahydro-4-methoxy-6-methyl-1,3-dioxolo(4,5-g)isoquinolin-5-yl]-1(3H)-isobenzofuranone
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.004.455 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H23NO7
Molar mass 413.426 g·mol−1
3D model (JSmol)
  • O=C2O[C@@H](c1ccc(OC)c(OC)c12)[C@@H]5N(C)CCc4c5c(OC)c3OCOc3c4
  • InChI=1S/C22H23NO7/c1-23-8-7-11-9-14-20(29-10-28-14)21(27-4)15(11)17(23)18-12-5-6-13(25-2)19(26-3)16(12)22(24)30-18/h5-6,9,17-18H,7-8,10H2,1-4H3/t17-,18+/m1/s1 Yes check.svgY
  • Key:AKNNEGZIBPJZJG-MSOLQXFVSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Noscapine, also known as narcotine, nectodon, nospen, anarcotine and (archaic) opiane, is a benzylisoquinoline alkaloid of the phthalideisoquinoline structural subgroup, which has been isolated from numerous species of the family Papaveraceae (poppy family). It lacks effects associated with opioids such as sedation, euphoria, or analgesia (pain-relief) and lacks addictive potential. [1] Noscapine is primarily used for its antitussive (cough-suppressing) effects.

Contents

Medical uses

Noscapine is often used as an antitussive medication. [2] A 2012 Dutch guideline, however, does not recommend its use for acute coughing. [3]

Side effects

Interactions

Noscapine can increase the effects of centrally sedating substances such as alcohol and hypnotics. [4]

The drug should not be taken with monoamine oxidase inhibitors (MAOIs), as unknown and potentially fatal effects may occur.[ citation needed ]

Noscapine should not be taken in conjunction with warfarin as the anticoagulant effects of warfarin may be increased. [5]

Biosynthesis

Noscapine biosynthesis in P. somniferum Noscapine Biosynthesis.tif
Noscapine biosynthesis in P. somniferum

The biosynthesis of noscapine in P. somniferum begins with chorismic acid, which is synthesized via the shikimate pathway from erythrose 4-phosphate and phosphoenolpyruvate. Chorismic acid is a precursor to the amino acid tyrosine, the source of nitrogen in benzylisoquinoline alkaloids. Tyrosine can undergo a PLP-mediated transamination to form 4-hydroxyphenylpyruvic acid (4-HPP), followed by a TPP-mediated decarboxylation to form 4-hydroxyphenylacetaldehyde (4-HPAA). Tyrosine can also be hydroxylated to form 3,4-dihydroxyphenylalanine (DOPA), followed by a PLP-mediated decarboxylation to form dopamine. Norcoclaurine synthase (NCS) catalyzes a Pictet-Spengler reaction between 4-HPAA and dopamine to synthesize (S)-norcoclaurine, providing the characteristic benzylisoquinoline scaffold. (S)-Norcoclaurine is sequentially 6-O-methylated (6OMT), N-methylated (CNMT), 3-hydroxylated (NMCH), and 4′-O-methylated (4′OMT), with the use of cofactors S-adenosyl-methionine (SAM) and NADP + for methylations and hydroxylations, respectively. These reactions produce (S)-reticuline, a key branchpoint intermediate in the biosynthesis of benzylisoquinoline alkaloids. [6]

The remainder of the noscapine biosynthetic pathway is largely governed by a single biosynthetic 10-gene cluster. [7] Genes comprising the cluster encode enzymes responsible for nine of the eleven remaining chemical transformations. First, berberine bridge enzyme (BBE), an enzyme not encoded by the cluster, forms the fused four-ring structure in (S)-scoulerine. BBE uses O2 as an oxidant and is aided by cofactor flavin adenine dinucleotide (FAD). Next, an O-methyltransferase (SOMT) methylates the 9-hydroxyl group. Canadine synthase (CAS) catalyzes the formation of a unique C2-C3 methylenedioxy bridge in (S)-canadine. [8] An N-methylation (TNMT) and two hydroxylations (CYP82Y1, CYP82X2) follow, aided by SAM and O2/NADPH, respectively. The C13 alcohol is then acetylated by an acetyltransferase (AT1) using acetyl-CoA. Another cytochrome P450 enzyme (CYP82X1) catalyzes the hydroxylation of C8, and the newly formed hemiaminal spontaneously cleaves, yielding a tertiary amine and aldehyde. A methyltransferase heterodimer (OMT2:OMT3) catalyzes a SAM-mediated O-methylation on C4′. [9] The O-acetyl group is then cleaved by a carboxylesterase (CXE1), yielding an alcohol which immediately reacts with the neighboring C1 aldehyde to form a hemiacetal in a new five-membered ring. The apparent counteractivity between AT1 and CXE1 suggests that acetylation in this context is employed as a protective group, preventing hemiacetal formation until the ester is enzymatically cleaved. [10] Finally, an NAD +-dependent short-chain dehydrogenase (NOS) oxidizes the hemiacetal to a lactone, completing noscapine biosynthesis. [6]

Mechanism of action

Noscapine's antitussive effects appear to be primarily mediated by its σ–receptor agonist activity. Evidence for this mechanism is suggested by experimental evidence in rats. Pretreatment with rimcazole, a σ-specific antagonist, causes a dose-dependent reduction in antitussive activity of noscapine. [11] Noscapine, and its synthetic derivatives called noscapinoids, are known to interact with microtubules and inhibit cancer cell proliferation [12]

Structure analysis

The lactone ring is unstable and opens in basic media. The opposite reaction is presented in acidic media. The bond (C1−C3′) connecting the two optically active carbon atoms is also unstable. In aqueous solution of sulfuric acid and heating it dissociates into cotarnine (4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline) and opic acid (6-formyl-2,3-dimethoxybenzoic acid). When noscapine is reduced with zinc/HCl, the bond C1−C3′ saturates and the molecule dissociates into hydrocotarnine (2-hydroxycotarnine) and meconine (6,7-dimethoxyisobenzofuran-1(3H)-one).

History

Noscapine was first isolated and characterized in chemical breakdown and properties in 1803 under the denomination of "Narcotine" [13] [14] by Jean-Francois Derosne, a French chemist in Paris. Then Pierre-Jean Robiquet, another French chemist, proved narcotine and morphine to be distinct alkaloids in 1831. [15] Finally, Pierre-Jean Robiquet conducted over 20 years between 1815 and 1835 a series of studies in the enhancement of methods for the isolation of morphine, and also isolated in 1832 another very important component of raw opium, that he called codeine, currently a widely used opium-derived compound.

Society and culture

Recreational use

There are anecdotal reports of the recreational use of over-the-counter drugs in several countries, [16] being readily available from local pharmacies without a prescription. The effects, beginning around 45 to 120 minutes after consumption, are similar to dextromethorphan and alcohol intoxication. Unlike dextromethorphan, noscapine is not an NMDA receptor antagonist. [17]

Noscapine in heroin

Noscapine can survive the manufacturing processes of heroin and can be found in street heroin. This is useful for law enforcement agencies, as the amounts of contaminants can identify the source of seized drugs. In 2005 in Liège, Belgium, the average noscapine concentration was around 8%. [18]

Noscapine has also been used to identify drug users who are taking street heroin at the same time as prescribed diamorphine. [19] Since the diamorphine in street heroin is the same as the pharmaceutical diamorphine, examination of the contaminants is the only way to test whether street heroin has been used. Other contaminants used in urine samples alongside noscapine include papaverine and acetylcodeine. Noscapine is metabolised by the body, and is itself rarely found in urine, instead being present as the primary metabolites, cotarnine and meconine. Detection is performed by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry (LCMS) but can also use a variety of other analytical techniques.

Research

Clinical trials

The efficacy of noscapine in the treatment of certain hematological malignancies has been explored in the clinic. [20] [21] Polyploidy induction by noscapine has been observed in vitro in human lymphocytes at high dose levels (>30 μM); however, low-level systemic exposure, e.g. with cough medications, does not appear to present a genotoxic hazard. The mechanism of polyploidy induction by noscapine is suggested to involve either chromosome spindle apparatus damage or cell fusion. [22] [23]

Noscapine biosynthesis reconstitution

Many of the enzymes in the noscapine biosynthetic pathway was elucidated by the discovery of a 10 gene "operon-like cluster" named HN1. [7] In 2016, the biosynthetic pathway of noscapine was reconstituted in yeast cells, [24] allowing the drug to be synthesised without the requirement of harvest and purification from plant material. In 2018, the entire noscapine pathway was reconstituted and produced in yeast from simple molecules. In addition, protein expression was optimised in yeast, allowing production of noscapine to be improved 18,000 fold. [25] It is hoped that this technology could be used to produce pharmaceutical alkaloids such as noscapine which are currently expressed at too low a yield in plantae to be mass-produced, allowing them to become marketable therapeutic drugs. [26]

Anticancer derivatives

Noscapine is itself an antimitotic agent, therefore its analogs have great potential as novel anti-cancer drugs. [27] Analogs having significant cytotoxic effects through modified 1,3-benzodioxole moiety have been developed. [28] Similarly, N-alkyl amine, 1,3-diynyl, 9-vinyl-phenyl and 9-arylimino derivatives of noscapine have also been developed. [29] [30] [31] [32] Their mechanism of action is through tubulin inhibition. [33]

Anti-inflammatory effects

Various studies have indicated that noscapine has anti-inflammatory effects and significantly reduces the levels of proinflammatory factors such as interleukin 1β (IL-1β), IFN-c, and IL-6. In this regard, in another study, Khakpour et al. examined the effect of noscapine against carrageenan-induced inflammation in rats. They found that noscapine at a dose of 5 mg/kg body weight in three hours after the injection has the most anti-inflammatory effects. Moreover, they showed that the amount of inflammation reduction at this dose of noscapine is approximately equal to indomethacin, a standard anti-inflammatory medication. Furthermore, Shiri et al. concluded that noscapine prevented the progression of bradykinin-induced inflammation in the rat's foot by antagonising bradykinin receptors. In addition, Zughaier et al. evaluated the anti-inflammatory effects of brominated noscapine. The brominated form of noscapine has been shown to inhibit the secretion of the cytokine TNF-α and the chemokine CXCL10 from macrophages, thereby reducing inflammation without affecting macrophage survival. Furthermore, the bromated derivative of noscapine has about 5 to 40 times more potent effects than noscapine. Again, this brominated derivative also inhibits toll-like receptors (TLR), TNF-α, and nitric oxide (NO) in human and mouse macrophages without causing toxicity.

See also

Related Research Articles

<span class="mw-page-title-main">Morphine</span> Pain medication of the opiate family

Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies. It is mainly used as an analgesic. There are numerous methods used to administer morphine: orally; administered under the tongue; via inhalation; injection into a vein, injection into a muscle, injection under the skin, or injection into the spinal cord area; transdermal; or via administered into the rectal canal suppository. It acts directly on the central nervous system (CNS) to induce analgesia and alter perception and emotional response to pain. Physical and psychological dependence and tolerance may develop with repeated administration. It can be taken for both acute pain and chronic pain and is frequently used for pain from myocardial infarction, kidney stones, and during labor. Its maximum effect is reached after about 20 minutes when administered intravenously and 60 minutes when administered by mouth, while the duration of its effect is 3–7 hours. Long-acting formulations of morphine are sold under the brand names MS Contin and Kadian, among others. Generic long-acting formulations are also available.

<span class="mw-page-title-main">Opium</span> Dried latex of the opium poppy containing narcotic compounds

Opium is dried latex obtained from the seed capsules of the opium poppy Papaver somniferum. Approximately 12 percent of opium is made up of the analgesic alkaloid morphine, which is processed chemically to produce heroin and other synthetic opioids for medicinal use and for the illegal drug trade. The latex also contains the closely related opiates codeine and thebaine, and non-analgesic alkaloids such as papaverine and noscapine. The traditional, labor-intensive method of obtaining the latex is to scratch ("score") the immature seed pods (fruits) by hand; the latex leaks out and dries to a sticky yellowish residue that is later scraped off and dehydrated.

<i>Papaver somniferum</i> Species of flowering plant in the family Papaveraceae

Papaver somniferum, commonly known as the opium poppy or breadseed poppy, is a species of flowering plant in the family Papaveraceae. It is the species of plant from which both opium and poppy seeds are derived and is also a valuable ornamental plant grown in gardens. Its native range was east of the Mediterranean Sea, but has since been obscured and vastly expanded by introduction and cultivation from ancient times to the present day, being naturalized across much of Europe and Asia.

<span class="mw-page-title-main">Papaverine</span> Chemical compound

Papaverine is an opium alkaloid antispasmodic drug, used primarily in the treatment of visceral spasms and vasospasms, occasionally in the treatment of erectile dysfunction and acute mesenteric ischemia. While it is found in the opium poppy, papaverine differs in both structure and pharmacological action from the analgesic morphine and its derivatives.

<span class="mw-page-title-main">Natural product</span> Chemical compound or substance produced by a living organism, found in nature

A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical synthesis and have played a central role in the development of the field of organic chemistry by providing challenging synthetic targets. The term natural product has also been extended for commercial purposes to refer to cosmetics, dietary supplements, and foods produced from natural sources without added artificial ingredients.

<span class="mw-page-title-main">Berberine</span> Quaternary ammonium cation

Berberine is a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids, occurring naturally as a secondary metabolite in some plants including species of Berberis, from which its name is derived.

<span class="mw-page-title-main">NMDA receptor antagonist</span> Class of anesthetics

NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for humans and animals; the state of anesthesia they induce is referred to as dissociative anesthesia.

<span class="mw-page-title-main">Narcotoline</span> Chemical compound

Narcotoline is an opiate alkaloid chemically related to noscapine. It binds to the same receptors in the brain as noscapine to act as an antitussive, and has also been used in tissue culture media.

<span class="mw-page-title-main">Mitotic inhibitor</span> Cell division inhibitor

A mitotic inhibitor, microtubule inhibitor, or tubulin inhibitor, is a drug that inhibits mitosis, or cell division, and is used in treating cancer, gout, and nail fungus. These drugs disrupt microtubules, which are structures that pull the chromosomes apart when a cell divides. Mitotic inhibitors are used in cancer treatment, because cancer cells are able to grow through continuous division that eventually spread through the body (metastasize). Thus, cancer cells are more sensitive to inhibition of mitosis than normal cells. Mitotic inhibitors are also used in cytogenetics, where they stop cell division at a stage where chromosomes can be easily examined.

<span class="mw-page-title-main">Butamirate</span> Cough suppressant

Butamirate is a cough suppressant. It has been marketed in Europe and Mexico, but not in the United States.

<span class="mw-page-title-main">Dimemorfan</span> Cough suppressant

Dimemorfan (INN), or dimemorfan phosphate (JAN), also known as 3,17-dimethylmorphinan, is an antitussive of the morphinan family that is widely used in Japan and is also marketed in Spain and Italy. It was developed by Yamanouchi Pharmaceutical and introduced in Japan in 1975. It was later introduced in Spain in 1981 and Japan in 1985.

The enzyme (S)-norcoclaurine synthase (EC 4.2.1.78) catalyzes the chemical reaction

<span class="mw-page-title-main">Higenamine</span> Chemical compound

Higenamine (norcoclaurine) is a chemical compound found in a variety of plants including Nandina domestica (fruit), Aconitum carmichaelii (root), Asarum heterotropioides, Galium divaricatum, Annona squamosa, and Nelumbo nucifera.

<span class="mw-page-title-main">Benzylisoquinoline</span> Chemical compound

Substitution of the heterocycle isoquinoline at the C1 position by a benzyl group provides 1‑benzylisoquinoline, the most widely examined of the numerous benzylisoquinoline structural isomers. The 1-benzylisoquinoline moiety can be identified within numerous compounds of pharmaceutical interest, such as moxaverine; but most notably it is found within the structures of a wide variety of plant natural products, collectively referred to as benzylisoquinoline alkaloids. This class is exemplified in part by the following compounds: papaverine, noscapine, codeine, morphine, apomorphine, berberine, tubocurarine.

<span class="mw-page-title-main">Canadine</span> Chemical compound

(S)-Canadine, also known as (S)-tetrahydroberberine and xanthopuccine, is a benzylisoquinoline alkaloid (BIA), of the protoberberine structural subgroup, and is present in many plants from the family Papaveraceae, such as Corydalis yanhusuo and C. turtschaninovii.

<span class="mw-page-title-main">Opiate</span> Substance derived from opium

An opiate is an alkaloid substance derived from opium. It differs from the similar term opioid in that the latter is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain. Opiates are alkaloid compounds naturally found in the opium poppy plant Papaver somniferum. The psychoactive compounds found in the opium plant include morphine, codeine, and thebaine. Opiates have long been used for a variety of medical conditions, with evidence of opiate trade and use for pain relief as early as the eighth century AD. Most opiates are considered drugs with moderate to high abuse potential and are listed on various "Substance-Control Schedules" under the Uniform Controlled Substances Act of the United States of America.

<span class="mw-page-title-main">Chelidonine</span> Chemical compound

Chelidonine is an isolate of Papaveraceae with acetylcholinesterase and butyrylcholinesterase inhibitory activity.

<span class="mw-page-title-main">Magnoflorine</span> Chemical compound

(S)-Magnoflorine is a quaternary benzylisoquinoline alkaloid (BIA) of the aporphine structural subgroup which has been isolated from various species of the family Menispermaceae, such as Pachygone ovata,Sinomenium acutum, and Cissampelos pareira. 

Morphinone reductase is an enzyme which catalyzes the NADH-dependent saturation of the carbon-carbon double bond of morphinone and codeinone, yielding hydromorphone and hydrocodone respectively. This saturation reaction is assisted by a FMN cofactor and the enzyme is a member of the α/β-barrel flavoprotein family. The sequence of the enzyme has been obtained from bacteria Pseudomonas putida M10 and has been successfully expressed in yeast and other bacterial species. The enzyme is reported to harbor high sequence and structural similarity to the Old Yellow Enzyme, a large group of flavin-dependent redox biocatalysts of yeast species, and an oestrogen-binding protein of Candida albicans. The enzyme has demonstrated value in biosynthesis of semi-opiate drugs in microorganisms, expanding the chemical diversity of BIA biosynthesis.

<span class="mw-page-title-main">Jean-François Derosne</span>

Jean-François Derosne was a French pharmacist and chemist. Along with his brother Louis-Charles he ran the family pharmacy in Paris while also conducting research. He is known for his extraction of noscapine from opium.

References

  1. ↑ Altinoz MA, Topcu G, Hacimuftuoglu A, Ozpinar A, Ozpinar A, Hacker E, Elmaci İ (August 2019). "Noscapine, a Non-addictive Opioid and Microtubule-Inhibitor in Potential Treatment of Glioblastoma". Neurochemical Research. 44 (8): 1796–1806. doi:10.1007/s11064-019-02837-x. PMID   31292803. S2CID   195873326.
  2. ↑ Singh H, Singh P, Kumari K, Chandra A, Dass SK, Chandra R (March 2013). "A review on noscapine, and its impact on heme metabolism". Current Drug Metabolism. 14 (3): 351–360. doi:10.2174/1389200211314030010. PMID   22935070.
  3. ↑ Verlee L, Verheij TJ, Hopstaken RM, Prins JM, Salomé PL, Bindels PJ (2012). "[Summary of NHG practice guideline 'Acute cough']". Nederlands Tijdschrift voor Geneeskunde. 156: A4188. PMID   22917039.
  4. ↑ Jasek, W, ed. (2007). Austria-Codex (in German) (2007/2008 ed.). Vienna: Österreichischer Apothekerverlag. ISBN   978-3-85200-181-4.
  5. ↑ Ohlsson S, Holm L, Myrberg O, Sundström A, Yue QY (February 2008). "Noscapine may increase the effect of warfarin". British Journal of Clinical Pharmacology. 65 (2): 277–278. doi:10.1111/j.1365-2125.2007.03018.x. PMC   2291222 . PMID   17875192.
  6. 1 2 Singh A, Menéndez-Perdomo IM, Facchini PJ (2019). "Benzylisoquinoline alkaloid biosynthesis in opium poppy: an update". Phytochemistry Reviews. 18 (6): 1457–1482. Bibcode:2019PChRv..18.1457S. doi:10.1007/s11101-019-09644-w. S2CID   208301912.
  7. 1 2 Winzer T, Gazda V, He Z, Kaminski F, Kern M, Larson TR, et al. (June 2012). "A Papaver somniferum 10-gene cluster for synthesis of the anticancer alkaloid noscapine". Science. 336 (6089): 1704–1708. Bibcode:2012Sci...336.1704W. doi: 10.1126/science.1220757 . PMID   22653730. S2CID   41420733.
  8. ↑ Dang TT, Facchini PJ (January 2014). "Cloning and characterization of canadine synthase involved in noscapine biosynthesis in opium poppy". FEBS Letters. 588 (1): 198–204. doi:10.1016/j.febslet.2013.11.037. PMID   24316226. S2CID   26504234.
  9. ↑ Park MR, Chen X, Lang DE, Ng KK, Facchini PJ (July 2018). "Heterodimeric O-methyltransferases involved in the biosynthesis of noscapine in opium poppy". The Plant Journal. 95 (2): 252–267. doi: 10.1111/tpj.13947 . PMID   29723437. S2CID   19237801.
  10. ↑ Dang TT, Chen X, Facchini PJ (February 2015). "Acetylation serves as a protective group in noscapine biosynthesis in opium poppy". Nature Chemical Biology. 11 (2): 104–106. doi:10.1038/nchembio.1717. PMID   25485687.
  11. ↑ Kamei J (1996). "Role of opioidergic and serotonergic mechanisms in cough and antitussives". Pulmonary Pharmacology. 9 (5–6): 349–356. doi:10.1006/pulp.1996.0046. PMID   9232674.
  12. ↑ Lopus M, Naik PK (February 2015). "Taking aim at a dynamic target: Noscapinoids as microtubule-targeted cancer therapeutics". Pharmacological Reports. 67 (1): 56–62. doi:10.1016/j.pharep.2014.09.003. PMID   25560576. S2CID   19622488.
  13. ↑ Derosne JF (1803). "Mémoire sur l'opium". Annales de chimie. 11: 257–285.
  14. ↑ Drobnik J, Drobnik E (December 2016). "Timeline and bibliography of early isolations of plant metabolites (1770-1820) and their impact to pharmacy: A critical study". Fitoterapia. 115: 155–164. doi:10.1016/j.fitote.2016.10.009. PMID   27984164.
  15. ↑ Wisniak J (March 2013). "Pierre-Jean Robiquet". Educación Química. 24 (Supplement 1): 139–149. doi: 10.1016/S0187-893X(13)72507-2 .
  16. ↑ Bhatia M, Vaid L (August 2004). "Type of drug abuse in patients with psychogenic cough". The Journal of Laryngology and Otology. 118 (8): 659–660. doi: 10.1258/0022215041917844 . PMID   15453951.
  17. ↑ Church J, Jones MG, Davies SN, Lodge D (June 1989). "Antitussive agents as N-methylaspartate antagonists: further studies". Canadian Journal of Physiology and Pharmacology. 67 (6): 561–567. doi:10.1139/y89-090. PMID   2673498.
  18. ↑ Denooz R, Dubois N, Charlier C (September 2005). "[Analysis of two year heroin seizures in the Liege area]". Revue Médicale de Liège (in French). 60 (9): 724–728. PMID   16265967.
  19. ↑ Paterson S, Lintzeris N, Mitchell TB, Cordero R, Nestor L, Strang J (December 2005). "Validation of techniques to detect illicit heroin use in patients prescribed pharmaceutical heroin for the management of opioid dependence". Addiction. 100 (12): 1832–1839. doi: 10.1111/j.1360-0443.2005.01225.x . PMID   16367984.
  20. ↑ "Study of Noscapine for Patients With Low Grade Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia Refractory to Chemotherapy". ClinicalTrials.gov. May 22, 2014.
  21. ↑ "A Study of Noscapine HCl (CB3304) in Patients with Relapsed or Refractory Multiple Myeloma". ClinicalTrials.gov. October 7, 2016.
  22. ↑ Mitchell ID, Carlton JB, Chan MY, Robinson A, Sunderland J (November 1991). "Noscapine-induced polyploidy in vitro". Mutagenesis. 6 (6): 479–486. doi:10.1093/mutage/6.6.479. PMID   1800895.
  23. ↑ Schuler M, Muehlbauer P, Guzzie P, Eastmond DA (January 1999). "Noscapine hydrochloride disrupts the mitotic spindle in mammalian cells and induces aneuploidy as well as polyploidy in cultured human lymphocytes". Mutagenesis. 14 (1): 51–56. doi: 10.1093/mutage/14.1.51 . PMID   10474821.
  24. ↑ Li Y, Smolke CD (July 2016). "Engineering biosynthesis of the anticancer alkaloid noscapine in yeast". Nature Communications. 7: 12137. Bibcode:2016NatCo...712137L. doi:10.1038/ncomms12137. PMC   4935968 . PMID   27378283.
  25. ↑ Li Y, Li S, Thodey K, Trenchard I, Cravens A, Smolke CD (April 2018). "Complete biosynthesis of noscapine and halogenated alkaloids in yeast". Proceedings of the National Academy of Sciences of the United States of America. 115 (17): E3922–E3931. Bibcode:2018PNAS..115E3922L. doi: 10.1073/pnas.1721469115 . PMC   5924921 . PMID   29610307.
  26. ↑ Kries H, O'Connor SE (April 2016). "Biocatalysts from alkaloid producing plants". Current Opinion in Chemical Biology. 31: 22–30. doi: 10.1016/j.cbpa.2015.12.006 . hdl: 21.11116/0000-0002-B92F-A . PMID   26773811.
  27. ↑ Mahmoudian M, Rahimi-Moghaddam P (January 2009). "The anti-cancer activity of noscapine: a review". Recent Patents on Anti-Cancer Drug Discovery. 4 (1): 92–97. doi:10.2174/157489209787002524. PMID   19149691.
  28. ↑ Yong C, Devine SM, Abel AC, Tomlins SD, Muthiah D, Gao X, et al. (September 2021). "1,3-Benzodioxole-Modified Noscapine Analogues: Synthesis, Antiproliferative Activity, and Tubulin-Bound Structure". ChemMedChem. 16 (18): 2882–2894. doi:10.1002/cmdc.202100363. PMID   34159741. S2CID   235610355.
  29. ↑ Dash SG, Suri C, Nagireddy PK, Kantevari S, Naik PK (September 2021). "Rational design of 9-vinyl-phenyl noscapine as potent tubulin binding anticancer agent and evaluation of the effects of its combination on Docetaxel". Journal of Biomolecular Structure & Dynamics. 39 (14): 5276–5289. doi:10.1080/07391102.2020.1785945. PMID   32608323. S2CID   220283865.
  30. ↑ Meher RK, Pragyandipta P, Pedapati RK, Nagireddy PK, Kantevari S, Nayek AK, Naik PK (September 2021). "Rational design of novel N-alkyl amine analogues of noscapine, their chemical synthesis and cellular activity as potent anticancer agents". Chemical Biology & Drug Design. 98 (3): 445–465. doi:10.1111/cbdd.13901. PMID   34051055. S2CID   235243148.
  31. ↑ Patel AK, Meher RK, Reddy PK, Pedapati RK, Pragyandipta P, Kantevari S, et al. (July 2021). "Rational design, chemical synthesis and cellular evaluation of novel 1,3-diynyl derivatives of noscapine as potent tubulin binding anticancer agents". Journal of Molecular Graphics & Modelling. 106: 107933. doi:10.1016/j.jmgm.2021.107933. PMID   33991960. S2CID   234683080.
  32. ↑ Patel AK, Meher RK, Nagireddy PK, Pragyandipta P, Pedapati RK, Kantevari S, Naik PK (April 2021). "9-Arylimino noscapinoids as potent tubulin binding anticancer agent: chemical synthesis and cellular evaluation against breast tumour cells". SAR and QSAR in Environmental Research. 32 (4): 269–291. doi:10.1080/1062936X.2021.1891567. PMID   33687299. S2CID   232161419.
  33. ↑ Mandavi S, Verma SK, Banjare L, Dubey A, Bhatt R, Thareja S, Jain AK (2021). "A Comprehension into Target Binding and Spatial Fingerprints of Noscapinoid Analogues as Inhibitors of Tubulin". Medicinal Chemistry. 17 (6): 611–622. doi:10.2174/1573406416666200117120348. PMID   31951171. S2CID   210701250.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.