The Noscapine Chronicle: A Pharmaco-Historic Biography of the Opiate Alkaloid Family and its Clinical Applications

Abstract

Given its manifold potential therapeutic applications and amenability to modification, noscapine is a veritable "Renaissance drug" worthy of commemoration. Perhaps the only facet of noscapine's profile more astounding than its versatility is its virtual lack of side effects and addictive properties, which distinguishes it from other denizens of Papaver somniferum. This review intimately chronicles the rich intellectual and pharmacological history behind the noscapine family of compounds, the length of whose arms was revealed over decades of patient scholarship and experimentation. We discuss the intriguing story of this family of nontoxic alkaloids, from noscapine's purification from opium at the turn of the 19th century in Paris to the recent torrent of rationally designed analogs with tremendous anticancer potential. In between, noscapine's unique pharmacology; impact on cellular signaling pathways, the mitotic spindle, and centrosome clustering; use as an antimalarial drug and cough suppressant; and exceptional potential as a treatment for polycystic ovarian syndrome, strokes, and diverse malignancies are catalogued. Seminal experiments involving some of its more promising analogs, such as amino-noscapine, 9-nitronoscapine, 9-bromonoscapine, and reduced bromonoscapine, are also detailed. Finally, the bright future of these oftentimes even more exceptional derivatives is described, rounding out a portrait of a truly remarkable family of compounds.

Keywords: antineoplastic drugs; centrosome declustering drugs; microtubule targeting drugs; noscapine; noscapinoids.

Figure 1

Timeline of noscapine-related discoveries. (A) 1803: Jean-Franҫois Derosne separates a noscapine-containing salt that he calls “narceine” from poppies. (B) 1817: Pierre-Jean Robiquet purifies noscapine from Derosne’s salt. (C) 1895–1930: Noscapine is widely used as an antimalarial based on the recommendations of Sir Robert Williams of the 1893–1895 Royal Commission on Opium. (D) 1930: The antitussive action of noscapine is discovered. (E) 1954: Hans Lettr é describes “narcotine” as a weak mitotic poison whose antimitotic activity synergizes with that of N-methyl-colchicine. (F) 1997: Noscapine’s ability to antagonize dopamine biosynthesis in PC12 cells is discovered. (G) 1998: Mouse models reveal the in vivo anticancer activity of noscapine against various malignancies. (H) 2003: Noscapine’s antistroke activity is discovered. (I) 2003: Brominated noscapine analogs are synthesized that potently inhibit mitosis and proliferation in cancer cells. (J) 2006: A variety of noscapine haloderivatives are synthesized and characterized. (K) 2006: A nitro-derivative of noscapine is synthesized that selectively kills chemotherapy-resistant cancer cells. (L) 2010: Brominated noscapine analogs are found to induce autophagy in macrophages and prostate cancer cells. (M) 2010: Experiments reveal that noscapine may have therapeutic value in polycystic ovarian syndrome. (N) 2011: Amino-noscapine is synthesized and characterized. (O) 2011: Poly(ethylene glycol)-grafted gelatin nanoparticles customized to deliver noscapine intracellularly with long circulating half-lives are synthesized and characterized. (P) 2011: Second-generation benzofuranone ring-substituted derivatives of noscapine analogs are synthesized and characterized. (Q) 2014: Third-generation water-soluble derivatives of noscapine are synthesized and characterized. (R) 2015: Inhalable nanostructured lipid particles containing a brominated noscapine derivative are synthesized and characterized.

Figure 2

Analogs of noscapine. (1a–e) Biaryl derivatives resulting from addition of an aryl unit with a variable R substituent to position-9 in the tetrahydroisoquinoline portion of noscapine. (2a–j) Third-generation analogs resulting from derivatization of the nitrogen (position-6) in noscapine’s isoquinoline ring system. (3a–e) Second-generation analogs resulting from derivatization of position-7 in the benzofuranone ring system. Only a few of the many O-alkylated derivatives are pictured, including two water-soluble analogs (d, e). (4a–c) Substitution of position-9 in a modified noscapine core in which the benzofuranone lactone ring has been reduced to a cyclic ether yields various derivatives, including haloderivatives (b) and a nitro-derivative (c). (5a–l) First-generation analogs resulting from modification of position-9 in noscapine’s isoquinoline ring system.

Figure 3

Molecular mechanisms of noscapine. The mechanisms by which noscapine antagonizes potentially and certainly pathological processes, including cough, ischemic cerebral injury, angiogenesis, fibrosis, and tumor formation (indicated in blue boxes), are depicted.