Amaryllidaceae Alkaloids of Belladine-Type from Narcissus pseudonarcissus cv. Carlton as New Selective Inhibitors of Butyrylcholinesterase

Abstract

Thirteen known (1–12 and 16) and three previously undescribed Amaryllidaceae alkaloids of belladine structural type, named carltonine A-C (13–15), were isolated from bulbs of Narcissus pseudonarcissus cv. Carlton (Amaryllidaceae) by standard chromatographic methods. Compounds isolated in sufficient amounts, and not tested previously, were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7), butyrylcholinesterase (BuChE; E.C. 3.1.1.8) and prolyl oligopeptidase (POP; E.C. 3.4.21.26) inhibition activities. Significant human BuChE (hBUChE) inhibitory activity was demonstrated by newly described alkaloids carltonine A (13) and carltonine B (14) with IC50 values of 913 ± 20 nM and 31 ± 1 nM, respectively. Both compounds displayed a selective inhibition pattern for hBuChE with an outstanding selectivity profile over AChE inhibition, higher than 100. The in vitro data were further supported by in silico studies of the active alkaloids 13 and 14 in the active site of hBuChE.

Biosynthesis and Biological Activities of Newly Discovered Amaryllidaceae Alkaloids

“…Several of these novel AAs belong to known structural types, while others harbor new structures. The 91 AAs were classified in this manuscript as I) norbelladine-type (1-6), II) cherylline-type (7, 8), III) galantamine-type (9-16), IV) lycorine-type (17-25), V) homolycorine-type (26)(27)(28)(29)(30), VI) crinine-type (31-50), VII) narciclasine-type (51), VIII) pretazettine-type (52-54), IX) montanine-type (55), and X) other types including AAs related to plicamine (56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67), seco-plicamine (68-70), cripowellin (71)(72)(73)(74)(75)(76), mesembrine (77,78), and various others AAs (79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91). Structures of novel AAs belonging to the I to III scaffold types (norbelladine-, cherylline-, and galantamine-type) are depicted in Figure 3, whereas types IV and V (lycorine-and homolycorine-type) are represented in Figure 4.…”

“…Carlton led to the isolation of thirteen known AAs, and three new norbelladine-type AAs: carltonine A-C (4-6). Their structure was determined using spectroscopic methods including 1D NMR, 2D NMR, and HR-MS [62]. 7-Oxonorpluviine (24), a lycorine-type alkaloid was isolated from fresh bulbs of Narcissus L. cv.…”

“…Molecules 2020, 25, x FOR PEER REVIEW 9 of 28 structure was determined using spectroscopic methods including 1D NMR, 2D NMR, and HR-MS [62]. 7-Oxonorpluviine (24), a lycorine-type alkaloid was isolated from fresh bulbs of Narcissus L. cv.…”

“…Carltonine A–B ( 4 and 5 ) inhibited BChE with IC 50 values of 0.91 ± 0.02 and 0.031 ± 0.001 μM. Computational studies detected a plausible binding site on BChE while SAR suggested that the 1,3-dioxolane ring of carltonine B of ( 5 ) may be responsible of the BChE activity compared to the opening dimethoxybenzene analogue of ( 4 ) [ 62 ].…”

Chemistry and Biological Activity of Alkaloids from the Genus Lycoris (Amaryllidaceae)

“…Three AChE inhibitors, namely donepezil, galanthamine ( 13 ) and rivastigmine, are currently used as the main therapeutic option for AD treatment [ 72 ]. Since the Amaryllidaceae alkaloid galanthamine ( 13 ) has been introduced into clinical practice, other Amaryllidaceae alkaloids have received attention as potential AChE inhibitors [ 5 , 73 , 74 , 75 , 76 ]. Surprisingly, only a few AAs isolated from Lycoris plants have been studied in terms of their AChE inhibition potential.…”