(±)-trans-Dihydronarciclasine and (±)-trans-dihydrolycoricidine analogues modified in their ring A: Evaluation of their anticancer activity and a SAR study

• Published in: European journal of medicinal chemistry 2019-07, Vol.173, p.76-89
• Main Authors: Varró, Gábor, Pálchuber, Péter, Pogrányi, Balázs, Simon, András, Hegedűs, László, Kádas, István
• Format: Article
• Language: English
• Subjects: (±)-trans-Dihydronarciclasine; Alkaloids; Anticancer activity; Structure–activity relationship (SAR)
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.04.010

A series of (±)-trans-dihydronarciclasine and (±)-trans-dihydrolycoricidine derivatives with variously substituted ring A was synthesised and evaluated for their antiproliferative activity against 60 human tumour cell lines (NCI60), representing leukemia, melanoma, and cancers of the lung, colon, brain, ovary, breast, prostate, as well as kidney in vitro. Among the 13 alkaloids screened, (±)-trans-dihydronarciclasine showed the highest potency as a cytotoxic molecule. A structure–activity relationship (SAR) study indicated that the presence of a hydroxy group at position 7 and a rigid, 1,3-benzodioxole scaffold were essential for the antiproliferative activity. [Display omitted] •(±)-trans-Dihydronarciclasines and (±)-trans-dihydrolycoricidines modified in ring A were synthesised.•Their antiproliferative activity was evaluated against 60 tumour cell lines (NCI60).•(±)-trans-Dihydronarciclasine showed the highest cytotoxic potency (mean GI50 = 88 nM).•A SAR study indicated that the 7-OH group and 1,3-benzodioxole scaffold are essential for the anticancer activity.