Synthesis and Biological Evaluation of N‐Substituted Noscapine Analogues

Abstract

Noscapine is a phthalideisoquinoline alkaloid isolated from the opium poppy Papaver somniferum. It has long been used as an antitussive agent, but has more recently been found to possess microtubule-modulating properties and anticancer activity. Herein we report the synthesis and pharmacological evaluation of a series of 6'-substituted noscapine derivatives. To underpin this structure-activity study, an efficient synthesis of N-nornoscapine and its subsequent reduction to the cyclic ether derivative of N-nornoscapine was developed. Reaction of the latter with a range of alkyl halides, acid chlorides, isocyanates, thioisocyanates, and chloroformate reagents resulted in the formation of the corresponding N-alkyl, N-acyl, N-carbamoyl, N-thiocarbamoyl, and N-carbamate derivatives, respectively. The ability of these compounds to inhibit cell proliferation was assessed in cell-cycle cytotoxicity assays using prostate cancer (PC3), breast cancer (MCF-7), and colon cancer (Caco-2) cell lines. Compounds that showed activity in the cell-cycle assay were further evaluated in cell viability assays using PC3 and MCF-7 cells.

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.…”

“…131 The cyclic ether N-ethyl urea analog 22 was shown to be the most active compound within the series with EC 50 values of 6.7 and 3.58 µM (PC3 and MCF-7, respectively) and became a lead core for further development. 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 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 In silico molecular modeling calculations were conducted for each compound to investigate their binding affinity based on a reasonable predictive model prior to chemical synthesis.…”

“…morphine, thebaine, codeine) 127 using FeSO 4 •7H 2 O in methanol provided the best conditions for the N-demethylation of noscapine-N-oxide hydrochloride in good yield 131. The pre-existing literature yield of N-nornoscapine (42) using a ferric citrate…”

In vitro radical scavenging and cytotoxic activities of novel hybrid selenocarbamates

“…22 Taking into account our previous experience in selenocyanate and diselenide chemistry [23][24][25] and the fact that we have recently reported some carbamates as potential antiproliferative drugs, 26 we decided to further extend our research by synthesising thirty new hybrid compounds in which selenocyanate or diselenide and carbamate moieties were combined. In these compounds the carbamate function, a group commonly found in antitumour active http compounds [27][28][29][30][31][32] acts as a link between the central and ending scaffolds, thus enabling their chemical accessibility and increasing polarity in this area as compared to our previously described structures. 23,[33][34][35] Besides, this group might facilitate the hydrolysis of the compounds towards anionic species that could act as prodrugs (Fig.…”

Synthesis of Densely Functionalised 5‐Halogen‐1,3‐oxazin‐2‐ones by Halogen‐Mediated Regioselective Cyclisation of N‐Cbz‐Protected Propargylic Amines: A Combined Experimental and Theoretical Study

“…[17] On the basis of early reported results in the synthesis of halo derivatives of heterocycles by halocyclisation of conveniently functionalised alkynes we envisioned that the N-Cbz-protected propargylic amines must be suitable substrates to investigate a novel route for preparing densely-functionalised 1,3-oxazin-2-ones or oxazolidin-2-ones (cyclic carbamates) through an O-halocyclisation process. Carbamates represent an important class of compounds with interesting properties and have found wide utility in several areas, such as pharmaceuticals [18] or agrochemicals. [19] Cyclic carbamates are less known, although they have been used as chiral auxiliaries [20] and, besides, present interesting biological activity.…”