A Convenient Synthesis of Aryl-Substituted N-Carbamoyl/N-Thiocarbamoyl Narcotine and Related Compounds

Abstract

The reaction of nornarcotine and 5-bromonornarcotine, synthesized from noscapine, with suitable aromatic isocyanates or isothiocyanates provides a general method for the synthesis of aryl-substituted N-carbamoyl or N-thiocarbamoylnarcotine and related compounds. Similarly, 15a has been prepared via the reduction of the lactone ring moiety of noscapine. Also, an improved procedure, which utilizes narcotine N-oxide ¥ HCl for generation of nornarcotine, is described.Introduction. ± Alkaloids and their analogs are important targets in chemical synthesis mainly because a large number of these compounds possess pronounced biological and pharmacological activities [1]. The basic isoquinoline-skeletal structure of various aporphine alkaloids, namely, (AE)-thaliporphine, (AE)-N-methylaurotetanine, and (AE)-isoboldine have been found to be of significant biological and biogenetic interest [2]. Noscapine, for example, a phthalide-isoquinoline alkaloid derived from opium, known for its antitussive action [3] [4] has recently been described as a prospective antineoplastic agent [5]. Ye et al. reported that noscapine has potent antitumor activity against solid lymphoid tumors induced in mice and, hence, exhibits outstanding therapeutic potential. In our earlier communication, we focussed on structural modulations of papaverine, a naturally occurring isoquinoline-based alkaloid isolated from Papaver somniferum [6], and reported the synthesis of urea/thiourea derivatives of papaverine, which were found to be more efficacious in terms of specificity and action in their antispasmodic effect. On similar lines of thought, we have also synthesized N-carbamoyl/N-thiocarbamoyl analogs of noscapine and other related compounds, which might prove as well to be more efficacious and less cytotoxic. Hence, new synthetic methodologies leading to novel antitumor agents are highly desired. In a recent publication from our laboratory [7], we have discussed the structure and the fragmentation patterns of narcotine and N-carbamoyl/N-thiocarbamoyl analogs of narcotine-related compounds. In the present paper, our interest circumscribes the synthetic procedures of N-demethylation and preparation of N-carbamoyl/N-thiocarbamoyl analogs of narcotine. It is the purpose of this communication to show how the target compound nornarcotine (3a) and other similar N-demethylated narcotine derivatives can be prepared in a few straightforward steps starting from noscapine (1a) and their further derivatization with aryl isocyanates and aryl isothiocyanates yielded the desired title compunds (Scheme 1).

Progress Toward the Development of Noscapine and Derivatives as Anticancer Agents

“…122 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 Braun reaction, however these were unsuccessful in the synthesis of the secondary amine scaffold. 105,124 It is reported that these conditions resulted in cleavage of 6 at the benzylic and tertiary centers adjacent to the amine functionality. 105 Non-classical Polonovski reaction conditions 125 successfully delivered the desired secondary amine core for further functionalization.…”

“…105 Non-classical Polonovski reaction conditions 125 successfully delivered the desired secondary amine core for further functionalization. 105 The reaction procedure began with the synthesis of the tertiary amine oxide using m-CPBA in chloroform followed by the acidification of tertiary amine oxide with hydrochloric acid to form the tertiary amine oxide as the hydrochloride salt. 126 Noscapine-N-oxide hydrochloride was then dissolved in a citric acid buffer solution containing Fe (III) -citrate which gave 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 the desired secondary amine core for further derivatisation.…”

“…126 Noscapine-N-oxide hydrochloride was then dissolved in a citric acid buffer solution containing Fe (III) -citrate which gave 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 the desired secondary amine core for further derivatisation. 105,126 Aggarwal et al synthesized a small series of N-substituted phenyl ureas and thioureas. 105 The bioactivity data for these analogs however has not been reported.…”

“…105,126 Aggarwal et al synthesized a small series of N-substituted phenyl ureas and thioureas. 105 The bioactivity data for these analogs however has not been reported. Research by our group was directed to the understanding of the SAR of noscapine related analogs.…”

Rational Design of Novel Anti-microtubule Agent (9-Azido-Noscapine) from Quantitative Structure Activity Relationship (QSAR) Evaluation of Noscapinoids

“…indeed, our initial efforts have been quite encouraging in that we have some more effective derivatives of the lead compound noscapine. [6][7][8][9] this led us to build a reasonable quantitative structure activity relationship (qsaR) model. the qsaR model guided us in rationally designing the azido derivatives of noscapine with superior activity.…”