Direct Semi-Synthesis of the Anticancer Lead-Drug Protoapigenone from Apigenin, and Synthesis of Further New Cytotoxic Protoflavone Derivatives

Abstract

Protoapigenone, a natural flavonoid possessing an unusual p-quinol moiety on its B-ring, is a novel prospective anticancer agent with low toxicity that is currently in development. The first economical, one-step synthesis of protoapigenone from apigenin is described on up to gram scale. 13 new 1′-O-alkylflavone analogs were also synthesized, either from apigenin or β-naphthoflavone. The in vitro cytotoxic activity of each compound was tested on six human cancer cell lines (HepG2, Hep3B, Ca9-22, A549, MCF-7 and MDA-MB-231). In the case of 1′-O-alkyl-protoapigenone derivatives, structure-activity relationships were found depending on the side-chain, and protoapigenone 1′-O-butyl ether was found to exert significantly stronger activity against three of the cell lines (Hep3B, MCF-7 and MDA-MB-231) than its non-substituted analog, protoapigenone itself. In contrast to this, all β-naphthoflavone derivatives bearing the same pharmacophore on their B-ring showed decreased cytotoxic activities when substituted with an O-alkyl side-chain at position 1′, comparing to that of the non-substituted compound.

Synthesis and SAR Study of Anticancer Protoflavone Derivatives: Investigation of Cytotoxicity and Interaction with ABCB1 and ABCG2 Multidrug Efflux Transporters

“…[17] Briefly, an oxidative de-aromatization was performed by a common hypervalent iodine reagent, [bis(trifluoroacetoxy)iodo]benzene (PIFA) in acetonitrile in the presence of water or the alcohol to be coupled at position C-1´. Among these compounds, protoapigenone 1´-O-benzylether (10) and the 6-methoxylated derivatives (25-30) were obtained as new protoflavones; synthesis and structures of the compounds are presented in Scheme 1.…”

“…This, however, did not apply for protogenkwanone and its analogs (11)(12)(13)(14)(15)(16)(17): protogenkwanone 1´-O-methylether (12) exerted a stronger activity on the mouse lymphoma cells than 11. Moreover, an at least two carbons long side-chain was necessary for this series of compounds to be slightly toxic on MCF-7 cells.…”

Inhibition of ATR-Dependent Signaling by Protoapigenone and Its Derivative Sensitizes Cancer Cells to Interstrand Cross-link–Generating Agents In Vitro and In Vivo

“…We did observe that WYC02 treatment caused slight accumulation of the p53 protein, which could have been the result of several posttranslational modifications. However, phosphorylation of the p53 Ser 15 residue did not contribute to this WYC02-induced p53 protein accumulation, suggesting that WYC02 does not directly damage DNA because DNA damage normally stimulates ATM/ATR-dependent p53 Ser 15 phosphorylation. Our result is similar to previous reports that p38 MAPK is activated by WYC02 (19,21,22), as its downstream target MAPKAPK2 was found to be phosphorylated starting as early as 2 hours after WYC02 exposure (Fig.…”

“…For UV irradiation treatment, the cells were irradiated for 10 J/m 2 by a crosslinker (UVP CL-1000) 1 hour before analysis. WYC02 and WYC0209 were isolated and synthesized as described previously (15)(16)(17).…”

“…1A) is a flavonoid that we previously isolated and identified from the whole plant extract of Thelypteris torresiana, a fern species native to Taiwan. This compound was originally screened for cytotoxicity function; using a colorimetric cytotoxicity assay, WYC02 showed therapeutic effects and was a lead compound for potential anticancer drug development (15)(16)(17). In previous studies, WYC02 and its more potent analog WYC0209 (Fig.…”