Cytotoxic crinane alkaloids of the Amaryllidaceae: in vitro, in vivo and in silico effects, structure–activity relationships and mechanisms of action

Abstract The plant family Amaryllidaceae is recognized for its isoquinoline alkaloid principles, some of which have demonstrated significant potential as anticancer drugs. Its crinane alkaloids have likewise shown much promise, with much having been documented about their anticancer properties prior to 2013. This account summarizes developments between 2013 and 2024 on their in vitro, in vivo and in silico cytotoxic effects, the features of the anticancer pharmacophore, as well as modes of action. The literature survey was carried out on the Scopus, ScienceDirect, SciFinder, PubMed and Google Scholar search engines engaging the names of individual alkaloids together with terms such as ‘anticancer’, ‘cytotoxic’ and ‘antiproliferative’. These returned over 500 hits, of which nearly 130 through relevance were selected to form the basis of the text. Over 150 crinane alkaloids were screened against nearly 60 cancer cell lines. Potent and selective in vitro activities were in instances matched by observations made in vivo, notably for the crinanes haemanthamine and haemanthidine. Structure–activity relationship studies were useful in the refinement of the anticancer pharmacophore. Crinane alkaloids were shown to be capable of inducing apoptosis and inhibiting invasion, adhesion, metastasis and angiogenesis in some cancer cells. In others, they modulated the activities of various cancer-related proteins, such as kinases, reductases, deacetylases, topoisomerases and metalloproteinases. Molecular probes made in silico afforded further insight to their active site interactions with some of these proteins. Imbued with structures that are appealing and activities that are promising, crinane alkaloids afford an abundant resource platform for anticancer drug discovery. Graphical abstract