Synthesis of the flavonoid 3′,4′,5′-trimethoxyflavonol and its determination in plasma and tissues of mice by HPLC with fluorescence detection

Britton, Robert G.; Fong, Isabel Lim; Saad, Shaban E. A.; Brown, Karen; Steward, William P.; Gescher, Andreas J.; Sale, Stewart

doi:10.1016/j.jchromb.2009.02.043

Cited by 5 publications

(6 citation statements)

References 9 publications

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“…This tissue specificity could arguably be the consequence of differences in levels of TMFol between intestinal sections, with TMFol concentrations inadequate for activity in the intestine beyond the proximal section. We have reported previously that the concentration of TMFol in the gastrointestinal mucosa of C57BL6/J mice, the Apc Min background strain, which received TMFol for a week at the same dietary dose as that used in the Apc Min mice described here, was 220 ± 68 nmoles/g tissue, 220 μmol/L in concentration terms (32). This value is 169-fold the IC 50 for growth inhibition by TMFol in APC10.1 cells as described here.…”

Section: Ability In the Apcsupporting

confidence: 67%

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Preclinical Colorectal Cancer Chemopreventive Efficacy and p53-Modulating Activity of 3′,4′,5′-Trimethoxyflavonol, a Quercetin Analogue

Howells

Britton

Mazzoletti

et al. 2010

Cancer Prevention Research

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Some naturally occurring flavonols, exemplified by quercetin, seem to possess experimental cancer chemopreventive efficacy. Modulation of p53 is a mechanism thought to contribute to their activity. The hypothesis was tested that a synthetic flavonol, 3′,4′,5′-trimethoxyflavonol (TMFol), can interfere with tumor development and p53 expression in two models of colorectal carcinogenesis, Apc Min mice and human-derived HCT116 adenocarcinoma-bearing nude mice. Mice received TMFol with their diet (0.2%) from weaning to week 16 in the case of Apc Min or from either day 7 before ("TMFol early") or day 7 after ("TMFol late") tumor inoculation in HCT116 mice. The ability of TMFol to affect tumor proliferation or apoptosis, as reflected by staining for Ki-67 or cleaved caspase-3, respectively, was studied in HCT116 tumors. TMFol tumor levels were measured by high-performance liquid chromatography. Consumption of TMFol reduced small intestinal adenoma burden in Apc Min mice by 47%, compared with control mice (P < 0.002). The TMFol early regimen approximately halved HCT116 tumor size (P < 0.05), decreased tumor proliferation, and increased apoptosis, whereas the TMFol late regimen had no significant effect when compared with controls. In tumor tissues from mice, in which TMFol reduced tumor development, p53 expression was increased 3-fold in Apc Min and 1.5-fold in HCT116 tumor-bearing mice (P = 0.02). TMFol increased p53 also in cells derived from these tumors. TMFol was detected in HCT116 tumors, but levels did not correlate with tumor burden. TMFol was not mutagenic in the Ames test. The results suggest that chemical modification of the flavonol structure may generate safe and efficacious cancer chemopreventive agents. Cancer Prev Res; 3(8); 929-39. ©2010 AACR.

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Section: Ability In the Apcsupporting

confidence: 67%

“…TMFol, synthesized as previously described (32), was >99% pure as determined by high-performance liquid chromatography (HPLC) analysis. 2′,5′,5,6,7,8-Hexamethoxyflavone used as an internal standard in the HPLC analysis was supplied by the National Cancer Institute Developmental Therapeutic Programme Open Compound Repository.…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

Preclinical Colorectal Cancer Chemopreventive Efficacy and p53-Modulating Activity of 3′,4′,5′-Trimethoxyflavonol, a Quercetin Analogue

Howells

Britton

Mazzoletti

et al. 2010

Cancer Prevention Research

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“…TMFol was synthesised as described previously [6]. Cleaved caspase-3 antibody was sourced from Cell Signaling Technology (Hitchin, UK) while the Novolink polymer detection system was obtained from Leica Biosystems (Newcastle, UK).…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

Inhibition of prostate cancer cell growth by 3′,4′,5′-trimethoxyflavonol (TMFol)

Hill

Saad

Britton

et al. 2015

Cancer Chemother Pharmacol

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Purpose TMFol (3ʹ, 4ʹ, 5ʹ-trimethoxyflavonol) is a synthetic analogue of the naturally occurring flavonols fisetin and quercetin, which have been considered of potential usefulness in the management of prostate cancer. We investigated whether TMFol may have preclinical features superior to those of its two flavonol congeners.Methods The ability of the three flavonols to compromise prostate cancer cell survival was tested in four prostate cancer cell types 22Rv1, TRAMP C2, PC-3 and LNCaP. The effect of TMFol on prostate cancer development in vivo was investigated in nude mice bearing the 22Rv1 or TRAMP C2 tumours.Results TMFol inhibited cell growth in vitro in all four prostate cancer cell types more potently than fisetin and quercetin. It also interfered with TRAMP C2 tumour development in vivo, whilst fisetin and quercetin at equivalent doses were without activity in this model. Likewise, TMFol slowed the growth of the 22Rv1 tumour in vivo. Efficacy in either model was accompanied by induction of apoptosis, although in vitro only TRAMP C2 cells, but not 22Rv1, underwent apoptosis when exposed to TMFol. ConclusionsThe results support the notion that among the three congeneric flavonols, quercetin, fisetin and TMFol the latter may be the most suitable candidate agent for potential development in prostate cancer management.

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“…TMFol was synthesized using a procedure described previously (Britton et al, 2009). 2′,5′,5,6,7,8-Hexamethoxyflavone, supplied by the NCI Developmental Therapeutic Program's Open Compound Repository (NCI, Bethesda, MD, USA), was used as internal standard (IS).…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

“…Frozen samples of plasma or tissues were thawed to room temperature and prepared as described previously (Britton et al, 2009).…”

Section: Sample Preparationmentioning

confidence: 99%

Tissue distribution and metabolism of the putative cancer chemopreventive agent 3′,4′,5′‐trimethoxyflavonol (TMFol) in mice

Saad

Jones

Norris

et al. 2012

Biomedical Chromatography

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3',4',5'-Trimethoxyflavonol (TMFol) is a synthetic flavonol with preclinical cancer chemopreventive properties. The hypothesis was tested that, in mice, p.o. administration of TMFol results in measureable levels of the parent in target tissues. A single oral dose (240 mg/kg) was administered to mice (n = 4 per time point) with time points ranging from 5 to 1440 min. TMFol and its metabolites were identified and quantitated in all tissues by high-performance liquid chromatography (HPLC). Plasma levels of TMFol were at the limit of quantification or below, although metabolites were identified. Peak levels of TMFol in the gastrointestinal tract and the prostate averaged 1671 ± 265 µg/g (5.3 µmol/g) and 6.0 ± 1.6 µg/g (18.4 nmol/g), and occurred 20 and 360 min post-dose, respectively. The area under the tissue concentration-time curve (AUC) for TMFol was greater than those of the metabolites, indicating that TMFol is relatively metabolically stable. Micromolar TMFol levels are easily achieved in the prostate and gastrointestinal tract, suggesting that TMFol might exert chemopreventive efficacy at these tissue sites. Further investigations are warranted to elucidate the potential chemopreventive potency of TMFol.

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Synthesis of the flavonoid 3′,4′,5′-trimethoxyflavonol and its determination in plasma and tissues of mice by HPLC with fluorescence detection

Cited by 5 publications

References 9 publications

Preclinical Colorectal Cancer Chemopreventive Efficacy and p53-Modulating Activity of 3′,4′,5′-Trimethoxyflavonol, a Quercetin Analogue

Preclinical Colorectal Cancer Chemopreventive Efficacy and p53-Modulating Activity of 3′,4′,5′-Trimethoxyflavonol, a Quercetin Analogue

Inhibition of prostate cancer cell growth by 3′,4′,5′-trimethoxyflavonol (TMFol)

Tissue distribution and metabolism of the putative cancer chemopreventive agent 3′,4′,5′‐trimethoxyflavonol (TMFol) in mice

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