Geiparvarin analogs. 2. Synthesis and cytostatic activity of 5-(4-arylbutadienyl)-3(2H)-furanones and of N-substituted 3-(4-oxo-2-furanyl)-2-buten-2-yl carbamates

Abstract

In an attempt to determine some of the structural features of geiparvarin (1) that account for its cytostatic activity in vitro, a series of geiparvarin analogues (10a-i, 1, 12, and 14-16) which contain novel modifications in the region of the olefinic double bond and of the coumarin moiety have been designed and synthesized. Among the derivatives containing a carbamate moiety, only the analogues containing a carbamate group linked to an alkyl moiety 10b-i were endowed with potent cytostatic activity, whereas the corresponding benzene derivative 10a was devoid of any antiproliferative activity. 6-Methoxygeiparvarin 101 proved equally effective as geiparvin (1), while compounds containing an additional double bond at the side chain (12 and 14-16) were invariably 5-100-fold less effective than geiparvarin. Diene derivative 15, bearing a coumarin moiety, was essentially inactive against murine (L1210, FM3A) tumor cells but exhibited good activity against human (Molt/4F, MT-4) tumor cells.

Synthesis, Cytotoxicity, and Apoptosis Induction in Human Tumor Cells by Geiparvarin Analogues

“…Molecular modification at the level of the furanone moiety as in compound 18, in which a Me group was replaced by a Ph group, does not show significant activity variation when compared to 14. Compound 21, in which only the conjugated double-bond pattern was conserved, lacking both the bulky 2,2-dimethylfuranone and the cycle constraint, shows a decrease in activity, thus confirming that this part of the molecule is necessary for the activity as postulated in [8] [9].…”

“…The structural modifications in compound 14, represented by compounds 18 and 21, indicate that the introduction of a Ph group in the furanone ring induces an activity increase. On the contrary, compound 21 that can be considered an open analogue of 14 is less active confirming the importance of the integrity of the furan-3(2H)-one ring for the cytotoxic activity as postulated in [8] [9].…”

“…The introduction of a Me group in the coumarin (2H-1-benzofuran) moiety of compounds 14, 15, and 16, or two Me groups, as in 17, further increases the activity, resulting to be ca. 5 ± 10 times higher than that of geiparvarin (8). Contrarily, introduction of a Me group (compounds 10 and 12) on the geiparvarin molecule leads to a decrease in the activity.…”

“…These compounds demonstrated a stronger increase in growth inhibitory activity when compared to the parent compound geiparvarin (8). In particular, the activity increased even further in the series of demethylated compounds when a Me substituent in the coumarin moiety is introduced.…”

“…Thus, the relative importance of moieties appearing in the geiparvarine structure as the furan-3(2H)-one ring, the coumarin group, and the alkenyloxy bridge have been extensively studied but without conclusive results. In particular, the allyloxy bridge of geiparvarin was changed to buta-1,3-diene [8] or is spaced from the furanone ring by a terpenoidal unit [9], but none of these modifications gave rise to compounds as active as geiparvarin.…”