Unnatural C-1 homologues of pancratistatin — Synthesis and promising biological activities

Abstract

Several C-1 homologues of pancratistatin and 7-deoxypancratistatin were synthesized by a phenanthrene–phenathridone oxidative recyclization strategy. The key steps involved the enzymatic dihydroxylation of bromobenzene, addition of an aryl alane to an epoxyaziridine, an intramolecular aziridine opening on silica gel in solid phase, and the above-mentioned recylization strategy. Experimental and spectral data are reported for all new compounds. All synthesized C-1 homologues of pancratistatin and 7-deoxypancratistatin were evaluated for antiproliferative activity in a panel of human cancer cell lines. As expected, the 7-hydroxy compounds were found to be more potent and the activity of the C-1 benzoxymethyl analogue exceeded that of narciclasine, which was used as a positive control.

Synthesis and biological evaluation of unnatural derivatives of narciclasine: 7-aza-nornarciclasine and its N-oxide

“…In our previous study it has been shown 2r,t that C-1 analogues 20 and 21 also displayed pronounced activity against pancreatic (BxPC-3), prostate (DU-145), and lung (NCI-H460) cancer cell lines. The respective IC 50 values for these three lines for C-1 acetate 20 were 0.07, 0.06 and 0.07 μM and for C-1 benzoate 21 : 0.01, 0.01.…”

“…1 Many unnatural or truncated derivatives of pancratistatin have been prepared and evaluated for biological activity with the intent to produce more bioavailable agents then the highly water-insoluble natural products. 2 …”

“…Modifications of narciclasine, one of the most potent of Amaryllidaceae constituents, 1d are less common. 2b,3 …”

“…The rationale for this design was based on the assumption that the N -oxide 6 derived from 5 could potentially mimic the donor-acceptor functionality responsible for increased activity in the alkaloids containing the 7-hydroxy-moiety. 2g,l …”

“…Oxidation of 5 to its respective N -oxide 6 was performed, as shown in Scheme 3, and subjected to screening in two cancer cell lines to compare the cytotoxicity results to those of the recently tested pancratistatin C-1 homologues. 2j …”