Abstract
A broad biological screening of the natural alkaloid N-methylisosalsoline (2) extracted from Hammada scoparia leaves against a panel of human and parasitic proteases revealed an interesting activity profile of 2 towards human 20S proteasome. This outcome suggests that the 1,2,3,4-tetrahydroisoquinoline skeleton may be exploited as a template for the development of novel anticancer agents. In this article, we report the synthesis and chemical characterization of a new series of isosalsoline-type alkaloids (10–11) with variations at N2 and C3 positions with respect to the natural Compound 2, obtained by a synthetic strategy that involves the Bischler-Napieralski cyclization. The substrate for the condensation to the tetrahydroisoquinoline system, i.e., a functionalized β-arylethyl amine, was obtained through an original double reduction of nitroalkene. The synthetic strategy can be directed to the construction of highly substituted and functionalized 1,2,3,4-tetrahydroisoquinolines.
Highlights
The 1,2,3,4-tetrahydroisoquinoline (THIQ) skeleton is an important structural motif commonly encountered in naturally-occurring alkaloids of vegetal origin with interesting biological/pharmacological properties, including inhibition of cell proliferation/anticancer activity [1], multiple cardiovascular activities related to different mechanisms of action [2,3,4], anti-inflammatory [5], antimicrobial [6,7], antiplasmodial activities [8,9] and acetylcholinesterase inhibitory effects [10,11]
The majority of the natural THIQ alkaloids endowed with drug-like properties have been isolated from plants of the genus Corydalis (Papaveraceae), and traditionally, some Corydalis species have long been used for the treatment of different aliments in Eastern Asian countries [23]
Compound 2 did not show any inhibitory activity in most cases, with the exception of recombinant Leishmania mexicana cysteine protease CPB2.8 (~14%) and of the already discussed β5-subunits of human 20S proteasome (~40%)
Summary
The 1,2,3,4-tetrahydroisoquinoline (THIQ) skeleton is an important structural motif commonly encountered in naturally-occurring alkaloids of vegetal origin with interesting biological/pharmacological properties, including inhibition of cell proliferation/anticancer activity [1], multiple cardiovascular activities related to different mechanisms of action [2,3,4], anti-inflammatory [5], antimicrobial [6,7], antiplasmodial activities [8,9] and acetylcholinesterase inhibitory effects [10,11]. As part of an ongoing program of targeting small molecules of natural and synthetic origin, 2 was tested against a panel of human and parasitic proteases at our disposal, including cathepsin-B and -L, human 20S proteasome, recombinant Leishmania mexicana cysteine protease CPB2.8, Rhodesain and Dengue virus NS2B/NS3 protease From this screening, Compound 2 turned out to be active against human 20S proteasome, suggesting a potential as a lead structure for the development of anticancer agents. 2 did not show any inhibitory activity in the cross-reactivity test against bovine pancreatic α-chymotrypsin This interesting outcome prompted us to devise a new synthetic method to obtain THIQ derivatives with variations at 2–3 positions compared to 2 in the attempt to optimize the biological profile of our lead structure toward 20S proteasome and to provide at the same time a simple and alternative strategy for the construction of the THIQ ring system.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
