Dr Ken Beresford

Job: Senior Lecturer in Pharmaceutical Chemistry

School/department: Leicester School of Pharmacy

Address: De Montfort University, The Gateway, Leicester, LE1 9BH

T: +44 (0)116 250 6356

E: kberesford@dmu.ac.uk

W: dmu.ac.uk/hls

 

Publications and outputs 

  • The synthesis of 4,6-diaryl-2-pyridones and their bioactivation in CYP1 expressing breast cancer cells
    The synthesis of 4,6-diaryl-2-pyridones and their bioactivation in CYP1 expressing breast cancer cells Lodhi, Sabahat; Ankrett, Dyan N.; Wilsher, Nicola E.; Potter, Gerard A.; Beresford, Kenneth J. M.; Arroo, R. R. J.; Ruparelia, K. C. As part of a programme to develop anticancer prodrugs which are activated by cytochrome P450 (CYP)1B1, a library of 4,6-diaryl-2-pyridones was synthesised in yields of 6-60% from the corresponding chalcones. A number of these derivatives showed promising antiproliferative activities in human breast cancer cell lines which express CYP1B1 and CYP1A1, while showing little toxicity towards a non-tumour breast cell line with no CYP expression. Metabolism studies provided evidence supporting the involvement of CYP1 enzymes in the bioactivation of these compounds. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.
  • New resveratrol analogues for potential use in diabetes and cancer.
    New resveratrol analogues for potential use in diabetes and cancer. Zeka, K.; Arroo, R. R. J.; Hasa, Dritan; Beresford, Kenneth J. M.; Ruparelia, K. C. 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. open access journal
  • Effects of novel chalcone derivatives on human endothelial cell proliferation and migration
    Effects of novel chalcone derivatives on human endothelial cell proliferation and migration Hussain, A.; Fretwell, L.; Ruparelia, K. C.; Beresford, Kenneth J. M.; Singh, Harprit Introduction: Angiogenesis is the formation of new blood vessels from the pre-existing vasculature and is essential for some physiological processes including wound healing and menstrual cycles. Unregulated angiogenesis can lead to vascular related diseases such as age related macular degeneration, cancer and rheumatoid arthritis. Chalcones (1,3-diphenylpropenones) are naturally occurring phenolic compounds found in a variety of plants and fruits. Their simple molecular structures have demonstrated an array of pharmacological activity including antioxidant and anti-vascular. Due to Chalcones having an easily modifiable scaffold, they are widely used as parent compounds in drug discovery studies. Endothelial cell proliferation and migration are essential for angiogenic growth, so compounds that possess anti-endothelial activity could be developed further as potential inhibitors of angiogenesis. With this in mind, we report the anti-endothelial activity of two novel analogues (AH1 and AH9) derived from the parent compound 2-chloro-2’5’-dihydroxychalcone. Method: Chalcones were synthesised via the Claisen-Schmidt condensation and verified via nuclear magnetic resonance (NMR) and mass spectrometry (MS). Primary Human umbilical vein endothelial cells (HUVECs) were cultured according to manufactures protocol. Cells were seeding into 96-well plates (3500 cells/well) and, 24 hours later, treated either with AH1, AH9 or Sorafenib, a known anti-angiogenic drug for 72hr at a concentration of 10 µM. Effects of the compounds on cell proliferation was assessed by quantifying the colorimetric conversion of 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) to purple formazan product (measured at 560 nm). Data are expressed as mean % inhibition of cell proliferation ± SEM (n=4). Anti-migratory activity was assessed via the wound healing assay and the effects of the compounds at 3 µM on the width of the scratch across an 8 hour period were compared to untreated control. Analysis was performed by one-way ANOVA with Tukey-Kramer’s multiple comparisons test. Data are expressed as mean % of maximum migration ± SEM (n=3). Results: AH1 and AH9 displayed significant anti-proliferative activity with inhibitory values of 94.94 ± 1.64% and 79.62 ± 4.45% compared to Sorafenib, 69.95 ± 4.12%, respectively. Effects on HUVEC migration showed that AH9 limited migration to 16.19 ± 14.44% (P<0.05 vs. control). AH1 (47.23 ± 6.8%) showed similar anti-migratory activity to Sorafenib (52.68 ± 3.32%). Conclusion: This preliminary data suggests that AH9 has potential antiangiogenic properties and could be developed further as a potential antiangiogenic or vascular remodelling agent. Further studies will elucidate the molecular mechanism of AH9 action in cells stimulated with known angiogenic agent, VEGF.
  • The synthesis of chalcones as anticancer prodrugs and their bioactivation in CYP1 expressing breast cancer cells
    The synthesis of chalcones as anticancer prodrugs and their bioactivation in CYP1 expressing breast cancer cells Ruparelia, K. C.; Ljaza, T.; Ankrett, D. N.; Wilsher, Nicola Elizabeth; Lodhia, S.; Beresford, Kenneth J. M.; Bhambra, Avninder S.; Arroo, R. R. J.; Potter, G. A.; Butler, P. C.; Tan, Hoon Leong; Zeka, K. Abstract: 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. Objectives: 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. Results: 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 􀀁-naphthoflavone provided supporting evidence for the involvement of CYP1 enzymes in the bioactivation of these compounds. Conclusions: Chalcones show promise as anticancer agents with evidence suggesting that CYP1 activation of these compounds may be involved. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link
  • (E)-3-(3,4,5-Trimethoxyphenyl)-1-(pyridin-4-yl)prop-2-en-1-one, a heterocyclic chalconeis a potent and selectiveCYP1A1 inhibitor and cancerchemopreventative agent
    (E)-3-(3,4,5-Trimethoxyphenyl)-1-(pyridin-4-yl)prop-2-en-1-one, a heterocyclic chalconeis a potent and selectiveCYP1A1 inhibitor and cancerchemopreventative agent Horley, Neill; Beresford, Kenneth J. M.; Kaduskar, S.; Joshi, Prashant; McCann, Glen J. P.; Ruparelia, K. C.; Williams, Ibidapo Steven; Gatchie, Linda; Sonawane, Vinay; Bharate, Sandip B.; Chaudhuri, Bhabatosh 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 SacchrosomesTM and live human HEK293 cells. The structure-activity relationship analysis indicated that chalcones bearing tri-alkoxy groups (8a and 8k) on nonheterocyclic 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 subfamily 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 file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link
  • Discovery and characterization of novel CYP1B1 inhibitors based on heterocyclic chalcones: Overcoming cisplatin resistance in CYP1B1-overexpressing lines
    Discovery and characterization of novel CYP1B1 inhibitors based on heterocyclic chalcones: Overcoming cisplatin resistance in CYP1B1-overexpressing lines Horley, Neill; Beresford, Kenneth J. M.; Chawla, Tarun; McCann, Glen J. P.; Ruparelia, K. C.; Gatchie, Linda; Sonawane, Vinay; Williams, Vinay R.; Tan, Hoon Leong; Joshi, Prashant; Bharate, Sonali S.; Kumar, Vikas; Bharate, Sandip B.; Chaudhuri, Bhabatosh The structure of alpha-napthoflavone (ANF), a potent inhibitor of CYP1A1 and CYP1B1, mimics the structure of chalcones. Two potent CYP1B1 inhibitors 7k (DMU2105) and 6j (DMU2139) have been identified from two series of synthetic pyridylchalcones. They inhibit human CYP1B1 enzyme bound to yeast-derived microsomes (Sacchrosomes™) with IC50 values of 10 and 9 nM, respectively, and show a very high level of selectivity towards CYP1B1 with respect to the IC50 values obtained with CYP1A1, CYP1A2, CYP3A4, CYP2D6, CYP2C9 and CYP2C19 Sacchrosomes™. Both compounds also potently inhibit CYP1B1 expressed within ‘live’ recombinant yeast and human HEK293 kidney cells with IC50 values of 63, 65, and 4, 4 nM, respectively. Furthermore, the synthesized pyridylchalcones possess better solubility and lipophilicity values than ANF. Both compounds overcome cisplatineresistance in HEK293 and A2780 cells which results from CYP1B1 overexpression. These potent cell-permeable and water-soluble CYP1B1 inhibitors are likely to have useful roles in the treatment of cancer, glaucoma, ischemia and obesity. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.
  • Synthesis and antitrypanosomal activities of novel pyridylchalcones
    Synthesis and antitrypanosomal activities of novel pyridylchalcones Bhambra, Avninder S.; Ruparelia, K. C.; Tan, Hoon Leong; Tasdemir, D.; Burrell-Saward, H.; Yardley, Vanessa; Beresford, Kenneth J. M.; Arroo, R. R. J. A library of novel pyridylchalcones were synthesised and screened against Trypanosoma brucei rhodesiense. Eight were shown to have good activity with the most potent 8 having an IC50 value of 0.29 M. Cytotoxicity testing with human KB cells showed a good selectivity profile for this compound with a selectivity index of 47. Little activity was seen when the library was tested against Leishmania donovani. In conclusion, pyridylchalcones are promising leads in the development of novel compounds for the treatment of human African trypanosomiasis (HAT). Collaboration with the London School of Hygiene and Tropical Medicine. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.
  • Polymer-drug nanoconjugate – an innovative nanomedicine: challenges and recent advancements in rational formulation design for effective delivery of poorly soluble drugs.
    Polymer-drug nanoconjugate – an innovative nanomedicine: challenges and recent advancements in rational formulation design for effective delivery of poorly soluble drugs. Abioye, A. O.; Chi-Tangyie, George; Kola-Mustapha, A.; Ruparelia, K. C.; Beresford, Kenneth J. M.; Arroo, R. R. J. Abstract Background: Over the last four decades, the use of water soluble polymers in rational formulation design has rapidly evolved into valuable drug delivery strategies to enhance the safety and therapeutic effectiveness of poorly soluble drugs, particularly anticancer drugs. Novel advances in polymer chemistry have provided new generations of well defined polymeric architectures for specific applications in polymer-drug conjugate design. However, total control of crucial parameters such as particle size, molecular weight distribution, polydispersity, localization of charges, hydrophilic-lipophilic balance and non site-specific coupling reactions during conjugation has been a serious challenge. Objective: This review briefly describes the current advances in polymer-drug nanoconjugate design and various challenges hindering their transformation into clinically useful medicines. Method: Existing literature was reviewed. Results: This review provides insights into the significant impact of covalent and non-covalent interactions between drug and polymer on drug loading [or conjugation] efficiency, conjugate stability, mechanism of drug release from the conjugate and biopharmaceutical properties of poorly soluble drugs. The utility values and application of Quality by Design principles in rational design, optimization and control of the Critical Quality Attributes [CQA] and Critical Process Parameters [CPP] that underpin the safety, quality and efficacy of the nanoconjugates are also presented. Conclusion: It was apparent that better understanding of the physicochemical properties of the nanoconjugates as well as the drug-polymer interaction during conjugation process is essential to be able to control the biodistribution, pharmacokinetics, therapeutic activity and toxicity of the nanoconjugates which will in turn enhance the prospect of successful transformation of these promising nanoconjugates into clinically useful nanomedicines. The published manuscript is available at EurekaSelect via - See more at: http://dx.doi.org/10.2174/2211738504666160213001714
  • Effects of Novel Chalcone Derivatives upon H9c2 and MDCK Cell Viability
    Effects of Novel Chalcone Derivatives upon H9c2 and MDCK Cell Viability Hussain, A.; Wright, Jack; Ruparelia, K. C.; Beresford, Kenneth J. M.; Fretwell, L. Many compounds with potential anti-cancer activity fail to reach the latter stages of clinical trials due to adverse effects, often causing cardiac and renal toxicity. Here, we synthesised a group of novel chalcone compounds, thought to have potential anti-cancer activity4 and assessed their effects upon cardiac and renal cell viability. Data revealed that all compounds produced minimal short term toxicity. Further work will be performed to assess the long term effects of these compounds on cell viability, leading to mechanistic studies and structure activity relationship analyses.
  • Resveratrol and Synthetic Analogues: From Cardioprotective Effects to Anticancer Activities
    Resveratrol and Synthetic Analogues: From Cardioprotective Effects to Anticancer Activities Ruparelia, K. C.; Micucci, Matteo; Chiarini, Alberto; Baccherini, Giulia; Budriesi, Roberta; Arroo, R. R. J.; Zeka, K.; Continenza, M. A.; Beresford, Kenneth J. M. 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 have been proposed to play a role in cancer prevention. However, at present there is no satisfactory explanation for the cancer preventative properties of the group of compounds. Whereas polyphenolic compounds have been shown to inhibit proliferation of tumor cells in vitro, the results of in vivo tests have mostly been disappointing in this respect. It seems that mammalian phase I and 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 tumor growth. Despite the experimental evidence regarding the antitumor activity of resveratrol, stilbene found in red grapes, the clinical effectiveness of the natural product is limited because of its low bioavailability. Resveratrol, however, has demonstrated antioxidant and antiproliferative activity in in-vitro models and mice. Although resveratrol exhibits significant anticancer activity, its efficacy in-vivo is limited due to its poor pharmacokinetic properties. In order to improve the pharmacokinetic properties of resveratrol and to increase the chemopreventive activity, several methoxylated resveratrol analogues were designed, synthesized and ested in vitro models. These analogues included a synthetic anticancer prodrug based on the structure of the natural product resveratrol namely DMU-212 or trans 3, 4, 4’ 5 -tetramethoxy stilbene. DMU-212 has considerable potency in submicromolar IC50 in cancer cell lines that renders it an important candidate for further studies, as it deviates from the classical acute toxicity of standard chemotherapeutic drugs. These synthesized analogues have been tested for their antitumor activity and in vitro biological assays have been exerted in order to assess the cardiovascular effects of the compounds. In particular, Structure Activity relationships have been studied in relation to their effects towards cardiovascular parameters. The cardiac activity of these compounds, using in vitro biological assays, on guinea-pig left and right atria, as well as their relaxant activity on guinea-pig vascular (aorta) and nonvascular (ileum) smooth muscle has been studied. The chemical modifications of the resveratrol have been made in order to maintain the stilbene scaffold that is crucial for heart selectivity. All the tested compounds exert a cardiovascular pattern activity similar to that of resveratrol. Heart and smooth muscle activity profile is similar for all tested compounds. The same modifications leading to an antitumor activity increase do not affect cardiovascular parameters. Resveratrol is devoid of relaxing effects towards vascular smooth muscle, while it relaxes non vascular smooth muscle with a low potency (EC50 = 24.34 μM (c.l 16.15-29.87)). All the resveratrol analogues have a similar activity pattern, showing selectivity towards non-vascular smooth muscle. Università degli Studi dell'Aquila, Department of Life, Health, and Environmental Sciences Università di Bologna, Department of Pharmacy and Biotechnology

Click here for a full listing of Ken Beresford's publications and outputs.

Research interests/expertise

  • Medicinal chemistry 
  • Cancer drug discovery
  • Organic synthesis
  • Setreoselective reactions

Membership of professional associations and societies

  • Member of the Royal Society of Chemistry (1999)
  • Chartered chemist (1999)

Current research students

  • Tarun Chawla, PhD, 2nd Supervisor
  • Supriya Shripad Kaduskar, PhD, 2nd Supervisor
  • Saeed Ur-Rashid Nazir, PhD, 2nd Supervisor
  • Ghassan Sonji, PhD, 2nd Supervisor

Internally funded research project information

  • DMU PhD Studentship - Synthesis of CYP1 activated anticancer prodrugs, Avninder Bhambra
  • DMU PhD Studentship - Synthesis of CYP1 activated anticancer prodrugs, Ketan Ruparelia

Published patents

WO/2009/146910, 4, 6-IPHENYLPYRID-2-0NES against cancer.

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