A green multicomponent synthesis of tocopherol analogues with antiproliferative activities

Abstract

A one-pot efficient, practical and eco-friendly synthesis of tocopherol analogues has been developed using water or solvent free conditions via Passerini and Ugi multicomponent reactions. These reactions can be optimized using microwave irradiation or ultrasound as the energy source. Accordingly, a small library of 30 compounds was prepared for biological tests. The evaluation of the antiproliferative activity in the human solid tumor cell lines A549 (lung), HBL-100 (breast), HeLa (cervix), SW1573 (lung), T-47D (breast), and WiDr (colon) provided lead compounds with GI values between 1 and 5 μM. A structure-activity relationship is also discussed. One of the studied compounds comes up as a future candidate for the development of potent tocopherol-mimetic therapeutic agents for cancer.

Electrophilic nitroalkene-tocopherol derivatives: synthesis, physicochemical characterization and evaluation of anti-inflammatory signaling responses

“…1B . The phenolic group of 1b was protected by treatment with di- tert -butyl dicarbonate to produce the ester 5 33 . Then, the methyl ester was reduced to a primary alcohol 34 and subsequently oxidized to produce the aldehyde derivative 7 .…”

A Focused Library of NO‐Donor Compounds with Potent Antiproliferative Activity Based on Green Multicomponent Reactions

“…As part of an ongoing research project aimed at the design and synthesis of novel active NO‐donor compounds, we report herein the construction of a small focused library of these structures using green‐oriented iMCRs (i.e., performed under ′on water′ or solvent‐free conditions and continued microwave or ultrasound irradiation), and the study of their cytotoxicity against six human solid tumor cell lines. Some tocopherol–NO‐donor hybrids previously obtained showed similar GI 50 values when compared with the standard anticancer drugs cisplatin and etoposide (Figure ) . Compounds from Pass‐1 and Ugi‐1 reactions (Figure B) incorporate a furoxan system (1,2,5‐oxadiazole N ‐oxide) as NO‐donor, while Ugi‐2 products contain an organic nitrate.…”

“…The in vitro antiproliferative activity of the synthesized compounds was determined against six human solid tumor cells, A549 (lung), HBL‐100 (breast), HeLa (cervix), SW1573 (lung), T‐47D (breast) and WiDr (colon), using the sulforhodamine B assay . The results were expressed as GI 50 , which is the drug concentration resulting in a 50 % decrease in cellular net growth relative to values of untreated control cells.…”

“…The in vitro antiproliferative activity of the synthesized compoundsw as determined against six human solidt umor cells, A549 (lung), HBL-100( breast), HeLa (cervix), SW1573 (lung), T-47D (breast) and WiDr (colon), using the sulforhodamine B assay. [25] The results were expressed as GI 50 ,w hich is the drug concentration resulting in a5 0% decrease in cellular net growth relativet ov alues of untreated control cells. Standard anticancer drugs cisplatin ande toposide were used as positive controls.R esults are summarized in Ta ble 3f or the 4a-o, 7a-e Passerini and 6a-g, 8a-c Ugi products as well as the starting components 1a, 2a and 2b.…”

“…Some tocopherol-NO-donor hybrids previously obtained showeds imilarG I 50 values when compared with the standard anticancer drugs cisplatin and etoposide ( Figure 1). [25] Compounds from Pass-1 and Ugi-1 reactions ( Figure 1B)i ncorporate af uroxan system (1,2,5-oxadiazole N-oxide) as NO-donor,w hile Ugi-2 products contain an organic nitrate. Particularly,i nT -47D (breast) and WiDr (colon)d rug-resistantc ell lines, tocopherol analogue Pass-1 was four to six times more activet han cisplatin and etoposide, respectively.…”