Semisynthesis and Biological Activity of Stemofoline Alkaloids

Abstract

The semisynthesis of the Stemona alkaloids (3'R)-stemofolenol (1), (3'S)-stemofolenol (2), methylstemofoline (3), and (3'S)-hydroxystemofoline (5) and the unnatural analogues (11E)-methylstemofoline (15) and 3'R-hydroxystemofoline (11) has been achieved starting from (11Z)-1',2'-didehydrostemofoline (4). This synthesis allowed, for the first time, access to diastereomerically enriched samples of 1 and 2 and the assignment of their absolute configurations at C-3'. These compounds were obtained in sufficient quantities to allow for their biological testing. In a quantitative assay as AChE inhibitors, (11Z)-1',2'-didehydrostemofoline (4) and (3'S)-hydroxystemofoline (5) were found to be the most active.

Natural Products and Their Mimics as Targets of Opportunity for Discovery

“…131 Although many Stemona alkaloids exhibit insect acetylcholinesterase activity, didehydrostemofoline is among the most potent. 155 It also has in vivo antioxytocin activity and antitumor activity against gastric carcinoma. 156 We first established the underlying viability of intermolecular dipolar cycloadditions of substrates related to 298 to give the tricyclic framework characteristic of the stemofoline alkaloids in a series of preliminary studies.…”

Asymmetric formal total synthesis of the stemofoline alkaloids: the evolution, development, and application of a catalytic dipolar cycloaddition cascade

“…8 In a recent screen for AChE inhibitory activity, didehydrostemofoline ( 1 ) was found to be among the most potent of the stemofoline alkaloids. 9 Didehydrostemofoline also exhibits in vivo anti-oxytocin activity and antitumor activity against gastric carcinoma, 4,10 whereas stemofoline ( 2 ) has been shown to be effective at increasing the sensitivity of clinically-used anticancer drugs such as paclitaxel, vinblastine, and doxorubicin by reversing P-glycoprotein mediated multi-drug resistance. 11 Continued interest in these alkaloids is reflected in more recent work in which a number of semisynthetic analogs were prepared and found to possess potent AChE inhibitory activity.…”

“…11 Continued interest in these alkaloids is reflected in more recent work in which a number of semisynthetic analogs were prepared and found to possess potent AChE inhibitory activity. 9,12 …”

Enantioselective Formal Total Syntheses of Didehydrostemofoline and Isodidehydrostemofoline through a Catalytic Dipolar Cycloaddition Cascade

“…These alkaloids, which were first reported by Irie and coworkers in 1970 [ 3 ] and later isolated from other Stemona species, [4,5,6] exhibit strong insecticidal activity because they act as insect acetylcholine receptor antagonists. [7] Didehydrostemofoline ( 1 ) is not only the most potent acetylcholine receptor antagonist, [8] but it also exhibits in vivo anti-oxytocin activity as well as antitumor activity against gastric carcinoma. [4,9] A recent study has shown that stemofoline ( 2 ) increases the sensitivity of anticancer drugs such as vinblastine, paclitaxel, and doxorubicin by reversal of P-glycoprotein mediated multi-drug resistance.…”

“…[ 10 ] A number of semisynthetic analogs of these alkaloids have been prepared and found to exhibit acetylcholinesterase inhibitory activity. [8,11] …”