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

Abstract

A series of geiparvarin analogues modified on the unsaturated alkenyloxy bridge, where a H-atom replaced the 3'-Me group, were synthesized and evaluated against a panel of human tumor cell lines in vitro. 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. On the contrary, the same modifications exerted on the parent compound led to an activity reduction. Interestingly, the new derivatives proved to be fully inhibitory to drug-resistant cell lines, thus suggesting that they are not subject to the pump-mediating efflux of antitumor drugs. On the basis of their cytotoxic profiles, the most-active compounds were selected for further biological evaluation. The extracellular acidification rate by the new geiparvarin analogues was measured with the Cytosensor microphysiometer. The new derivatives significantly increased the acidification rate during the 24-48 h of incubation in a concentration-dependent manner. Cell-cycle analysis, evaluated by flow cytometry, revealed a strong apoptotic induction by these compounds confirmed by DNA laddering and observation by electron microscopy. Interestingly, the apoptotic pathway did not appear to be mediated by the activation of caspase-3.

Synthesis and Biological Evaluation of New Geiparvarin Derivatives

“…Thus MCF7-MDR cells are known to possess both efflux pumps as well as increased levels of glutathione peroxidase activity. [17] In agreement with our previous results [8] in which we showed that 1 and 2 a retain activity in multidrug-resistant cells, the new compounds also proved to be fully inhibitory to these resistant cell lines, as shown in Table 2, suggesting that they are not subject to the pump-mediated efflux of antitumor drugs.…”

“…Optical activity was measured with a Jasco DIP-370 digital polarimeter (l = 589 nm). Compounds (R,S)-12, [8] 17, [31] 18, [31] and 19 [32] were obtained as reported. Silica gel plates (Merck F 254 ) and silica gel 60 (Merck 230-400 mesh) were used for analytical TLC and column chromatography, respectively.…”

“…As previously demonstrated, demethylation of the lead compound 1 led to compound 2 a, which exhibits a significant increase in antiproliferative activity. [7,8] The introduction of a methyl group at position 1' of 2 a gives two enantiomers, (R)-4 and (S)-4, which exhibited a slight increase in activity. Interestingly, antiproliferative activity does not depend on the configuration at the 1' carbon atom.…”

“…[7,8] In pursuing our interest in the synthesis and biological evaluation of geiparvarin derivatives and on the basis of our previous results, we report herein the synthesis of some new geiparvarin analogues. Moreover, we describe their evaluation against a panel of human tumor cell lines in vitro together with detailed experiments designed to elucidate the mechanism(s) of their antiproliferative effect.…”

Synthesis of purine homo-N-nucleosides modified with coumarins as free radicals scavengers*

“…Coumarin derivatives, naturally occurring or synthetic, exhibit a broad range of biological activities [14][15][16][17][18][19] including anticoagulant, antibiotic, antifungal, antipsoriasis, cytotoxic, anti-HIV, anti-inflammatory, antioxidant, antithrombin etc. The geiparvarin (VIII) and their derivatives exhibit antitumorial activity 20,21 and they also appeared as MAO-B inhibitors 22 . The auraptene (IX) is a chemopreventative agent against different kinds of cancer and an antiiflammatory agent 23 .…”