Synthesis of C3/C1-Substituted Tetrahydroisoquinolines.
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.
Laboratoire de Chimie des Substances Naturelles UR/11-ES-74, Faculté des Sciences de Sfax, Université de Sfax, Route de l'aeroport, BP 1171, 3000 Sfax, Tunisia. mohamed.mihoubi@hotmail.fr.
Mohamed
M
Mihoubi
Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università degli Studi di Messina, Viale Annunziata, 98168 Messina, Italy. nmicale@unime.it.
Nicola
N
Micale
Dipartimento di Scienze Chimiche, Università di Messina, Viale Ferdinando Stagno D'Alcontres 31, 98166 Messina, Italy. ascala@unime.it.
Angela
A
Scala
Laboratoire de Chimie des Substances Naturelles UR/11-ES-74, Faculté des Sciences de Sfax, Université de Sfax, Route de l'aeroport, BP 1171, 3000 Sfax, Tunisia. raoudhajarraya@yahoo.fr.
Raoudha Mezghani
RM
Jarraya
Laboratoire de Chimie des Substances Naturelles UR/11-ES-74, Faculté des Sciences de Sfax, Université de Sfax, Route de l'aeroport, BP 1171, 3000 Sfax, Tunisia. bouaziz.amira@yahoo.fr.
Amira
A
Bouaziz
Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, D 55099 Mainz, Germany. schirmei@uni-mainz.de.
Tanja
T
Schirmeister
Dipartimento di Scienze Chimiche, Università di Messina, Viale Ferdinando Stagno D'Alcontres 31, 98166 Messina, Italy. frisitano@unime.it.
Francesco
F
Risitano
Dipartimento di Scienze Chimiche, Università di Messina, Viale Ferdinando Stagno D'Alcontres 31, 98166 Messina, Italy. apiperno@unime.it.
Anna
A
Piperno
Dipartimento di Scienze Chimiche, Università di Messina, Viale Ferdinando Stagno D'Alcontres 31, 98166 Messina, Italy. ggrassi@unime.it.
Giovanni
G
Grassi
D000818:Animals; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D010271:Parasites / Q000187:drug effects / Q000201:enzymology; D010447:Peptide Hydrolases / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline; D010447:Peptide Hydrolases
Bischler-Napieralski condensation; N-methylisosalsoline; nitroalkene; proteasome; tetrahydroisoquinoline