Discovery of S-Phase Arresting Agents Derived from Noscapine

Abstract

Analogues of the natural product noscapine were synthesized, and their potential as antitumor agents were examined. The discovery of a novel regio- and stereoselective O-demethylation led to the synthesis of several O-alkylated analogues that induced an unexpected S-phase arrest of mammalian cells. Compound 4a was the most potent analogue inhibiting cell proliferation at an EC(50) of 1.9 microM.

Anticancer Activity of Papaver Somniferum

“…Our findings showed that opium extracts caused high antiproliferative and low cytotoxic activities towards cell lines at IC50 concentrations; indicating they have significant potential as a useful medicine. Previous studies reported that these extracts have a similar effect with current chemotherapeutics in various cell lines [20,21]. These extracts induced decrease in cell growth in culture through causing cell shrinkage and changing their astrocyte-like and fibroblast-like structures to globular shape.…”

Progress Toward the Development of Noscapine and Derivatives as Anticancer Agents

“…6,105,[109][110][111][112]117,118,131,135,145,146 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 68 noscapine. 109,110,117,118,131 Recently our group has shown the introduction of multiple modifications in the 1-, 7-, 6′ and 9′-positions on noscapine could lead to analogs with improved activity and reduced cell line variability. 135 can infer drug resistance after exposure to any drug and is not specific for chemotherapeutics.…”

Synthesis of microtubule-interfering halogenated noscapine analogs that perturb mitosis in cancer cells followed by cell death

“…Among the various antimitotic agents that perturb microtubule dynamics, noscapinoids constitute an emerging class of compounds receiving considerable attention [9][10][11][12][13][14][15][16]. A key structure for the cytotoxic activity of this class of compounds is the presence of two chiral centers forcing the two aromatic rings to be non-coplanar and in half-chair conformation [17].…”

“…The water solubility and feasibility for oral administration also represent valuable advantages of noscapine over many other antimicrotubule drugs [25][26][27]. Recently, several noscapine analogs have been reported by us and others that have much better therapeutic indices and improved pharmacological profiles [9][10][11][12][13][14][15][16].…”