Kenneth J. M. Beresford

Phytoestrogens as natural prodrugs in cancer prevention: dietary flavonoids

There are many reasons why vegetables and fruits may protect against cancer. As well as containing vitamins and minerals, which help keep the body healthy and strengthen the immune system, they are also good sources of biologically active compounds, which can help to protect cells in the body from damage that can lead to cancer. Notably, dietary flavonoids and other polyphenols are thought to have an important role as chemopreventive agents. Most studies on the possible mechanism of the chemopreventive action of dietary compounds have assumed that free hydroxyl groups of flavonoids and other polyphenols are necessary for their biological effects. However, in the human body dietary polyphenols are rapidly conjugated by glucuronosyltransferases and sulfotransferases, two enzymes that are abundantly present in the small intestine and liver, through which all of the oral dose must pass. Thus, most polyphenols that have been studied, e.g. quercetin, kaempferol, diosmetin, and resveratrol, would not be expected to reach internal organs beyond sites directly along the gastrointestinal tract. When the hydroxyl groups in polyphenols are methylated, the resulting compounds are much less prone to glucuronidation and sulfation. Thus methoxylated compounds are more metabolically stable, increasing their bioavailablity. The peel of various Citrus species can contain high concentrations of polymethoxyflavones, whereas the juice mainly contains hydroxylated flavones. At present, very little is known about the mechanisms by which methoxylated flavones may affect growth and development of tumour cells. Recently, it was shown that tumour specific enzymes can catalyze the O-demethylation of methoxylated flavones, resulting in the formation of flavones with free hydroxyl groups. We propose that demethylation of methoxylated flavones is another example of bioactivation of naturally occurring prodrugs.

Enantioselective addition of diethylzinc to a N-diphenylphosphinoylimine employing cinchona alkaloids as chiral ligands

The use of cinchona alkaloids to promote the addition of diethylzinc to P,P-diphenyl-N-(phenylmethylene)phosphinic amide has been examined. Using cinchonine and cinchonidine as ligands, the S and R enantiomers of N-(1-phenylpropyl)-P,P-diphenylphosphinic amide were prepared in good yield with up to 93% ee. The reaction was shown to proceed with catalytic amounts of ligand.

Phytoestrogens as natural prodrugs in cancer prevention: towards a mechanistic model

It has been widely acknowledged that regular consumption of fresh fruits and vegetables is linked with a relatively low incidence of cancers (e.g. breast, cervix, and colon). Notably, dietary polyphenolic compounds that show some structural similarity to human estrogen, e.g. isoflavones, coumestans, lignans, flavones, have been proposed to play a role in cancer prevention. However, at present there is no satisfactory explanation for the cancer preventative properties of this group of compounds. Whereas polyphenolic compounds have been shown to inhibit proliferation of tumour cells in vitro, the results of in vivo tests have mostly been disappointing in this respect. It seems that mammalian phase II detoxification mechanisms make that dietary polyphenols are rapidly and effectively removed from the body, i.e. their concentration in the blood plasma hardly ever reaches levels high enough to have a possible effect on tumour growth. The polymethoxyflavones nobiletin and tangeretin, common constituents of Citrus peel, are better absorbed than polyhydroxy flavonoids, and maintain their biological activity for a longer period of time. The compounds are known to be substrates for the estrogen-converting cytochrome P450 enzymes CYP1A1 and CYP1B1, which are typically over-expressed in a range of tumour tissues. The enzymes catalyse regioselective hydroxylation and dealkylation of the polymethoxyflavones, resulting in reaction products that appear to inhibit cell proliferation via interference with the MAPK/ERK cell signalling pathway.

Polymer-drug nanoconjugate – an innovative nanomedicine: challenges and recent advancements in rational formulation design for effective delivery of poorly soluble drugs.

The published manuscript is available at EurekaSelect via - See more at: http://dx.doi.org/10.2174/2211738504666160213001714

( E )-3-(3,4,5-Trimethoxyphenyl)-1-(pyridin-4-yl)prop-2-en-1-one, a heterocyclic chalcone is a potent and selective CYP1A1 inhibitor and cancer chemopreventive agent

The overexpression of CYP1 family of enzymes is reported to be associated with development of human carcinomas. It has been well reported that CYP1A1 specific inhibitors prevents carcinogenesis. Herein, thirteen pyridine-4-yl series of chalcones were synthesized and screened for inhibition of CYP1 isoforms 1A1, 1B1 and 1A2 in Sacchrosomes™ and live human HEK293 cells. The structure-activity relationship analysis indicated that chalcones bearing tri-alkoxy groups (8a and 8k) on non-heterocyclic ring displayed selective inhibition of CYP1A1 enzyme, with IC50 values of 58 and 65 nM, respectively. The 3,4,5-trimethoxy substituted derivative 8a have shown >10-fold selectivity towards CYP1A1 with respect to other enzymes of the CYP1 sub-family and >100-fold selectivity with respect to CYP2 and CYP3 family of enzymes. The potent and selective CYP1A1 inhibitor 8a displayed antagonism of B[a]P mediated activation of aromatic hydrocarbon receptor (AhR) in yeast cells, and also protected human cells from CYP1A1-mediated B[a]P toxicity in human cells. This potent and selective inhibitor of CYP1A1 enzyme have a potential for development as cancer chemopreventive agent.

The synthesis of chalcones as anticancer prodrugs and their bioactivation in CYP1 expressing breast cancer cells

BACKGROUND Although the expression levels of many P450s differ between tumour and corresponding normal tissue, CYP1B1 is one of the few CYP subfamilies which is significantly and consistently overexpressed in tumours. CYP1B1 has been shown to be active within tumours and is capable of metabolising a structurally diverse range of anticancer drugs. Because of this, and its role in the activation of procarcinogens, CYP1B1 is seen as an important target for anticancer drug development. OBJECTIVE To synthesise a series of chalcone derivatives based on the chemopreventative agent DMU-135 and investigate their antiproliferative activities in human breast cancer cell lines which express CYP1B1 and CYP1A1. METHOD A series of chalcones were synthesised in yields of 43-94% using the Claisen-Schmidt condensation reaction. These were screened using a MTT assay against a panel of breast cancer cell lines which have been characterised for CYP1 expression. RESULT A number of derivatives showed promising antiproliferative activities in human breast cancer cell lines which express CYP1B1 and CYP1A1, while showing significantly lower toxicity towards a non-tumour breast cell line with no CYP expression. Experiments using the CYP1 inhibitors acacetin and α-naphthoflavone provided supporting evidence for the involvement of CYP1 enzymes in the bioactivation of these compounds. CONCLUSION Chalcones show promise as anticancer agents with evidence suggesting that CYP1 activation of these compounds may be involved.

New resveratrol analogues for potential use in diabetes and cancer.

Resveratrol is a well notorious compound that may play a role in the prevention of diabetes complications and different cancers. Along, resveratrol, a naturally occurring phytoalexin, is known to exert numerous beneficial effects in the organism. Isolation of resveratrol from plants, however, has been proved being difficult. Importantly, the bioavailability in the body is poor therefore capability is reduced and not enough resveratrol reaches the target organ. In this study we generated different methoxylated resveratrol analogues using Wittig reaction. Trans stilbene obtained was 0.08 g and the cis one was 0.01 g. Additionally with the Horner-Witting method a yield of 0.15 g trans stilbene was obtained. By substituting the hydroxyl group with methoxy group at different positions on the aromatic rings, we could increase the efficacy and bioavailability of the Trans form of resveratrol.