Dr Avninder S Bhambra

Job: Associate Professor and Subject Lead - Biomedical Science

Faculty: Health and Life Sciences

School/department: School of Allied Health Sciences

Research group(s): Leicester Institute for Pharmaceutical Innovation

Address: De 51吃瓜app University, The Gateway, Leicester, LE1 9BH

T: 0116 2078792

E: abhambra@dmu.ac.uk

W: /alliedhealthsciences

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Personal profile

Dr Bhambra is an Associate Professor within the Faculty of Health and Life Sciences (HLS) at De 51吃瓜app University (51吃瓜app). Throughout his time at 51吃瓜app, Dr Bhambra has taught across multiple HLS undergraduate and postgraduate degree programmes using an engaging and adaptive teaching and learning philosophy. He is an experienced Programme Leader where he successfully led the Institute of Biomedical Science (IBMS) accredited BSc Biomedical Science programme. As an experienced academic with an interest in quality assurance, Dr Bhambra is actively involved in quality related events with higher education institutes and accrediting bodies across the health and life science disciplines.

Dr Bhambra’s research interests lie at the interface between biology and chemistry, with particular focus on developing potential drug candidates for cancer and neglected tropical diseases including human African trypanosomiasis, Chagas disease and leishmaniasis. This involves exploring naturally occurring molecules from a range of plant sources and synthetics within various bioassays. The design of synthetic molecules is based on either bioactivity guided structure activity relationship analyses or by implementing in silico drug development techniques against relevant drug targets.

Research group affiliations

Institute of Allied Health Sciences Research

Publications and outputs

dc.title: A structure-based virtual high-throughput screening, molecular docking, molecular dynamics and MM/PBSA study identified novel putative drug-like dual inhibitors of trypanosomal cruzain and rhodesain cysteine proteases dc.contributor.author: Bhambra, Avninder S.; Eurtivong, Chatchakorn; Zimmer, Collin; Schirmeister, Tanja; Butkinaree, Chutikarn; Saruengkhanphasit, Rungroj; Niwetmarin, Worawat; Ruchirawat, Somsak dc.description.abstract: Virtual screening a collection of鈥墌鈥�25,000 ChemBridge molecule collection identified two nitrogenous heterocyclic molecules, 12 and 15, with potential dual inhibitory properties against trypanosomal cruzain and rhodesain cysteine proteases. Similarity search in DrugBank found the two virtual hits with novel chemical structures with unreported anti-trypanosomal activities. Investigations into the binding mechanism by molecular dynamics simulations for 100 ns revealed the molecules were able to occupy the binding sites and stabilise the protease complexes. Binding affinities calculated using the MM/PBSA method for the last 20 ns showed that the virtual hits have comparable binding affinities to other known inhibitors from literature suggesting both molecules as promising scaffolds with dual cruzain and rhodesain inhibition properties, i.e. 12 has predicted 螖Gbind values of 鈭� 38.1 and 鈭� 38.2 kcal/mol to cruzain and rhodesain, respectively, and 15 has predicted 螖Gbind values of 鈭� 34.4 and 鈭� 25.8 kcal/mol to rhodesain. Per residue binding free energy decomposition studies and visual inspection at 100 ns snapshots revealed hydrogen bonding and non-polar attractions with important amino acid residues that contributed to the 螖Gbind values. The interactions are similar to those previously reported in the literature. The overall ADMET predictions for the two molecules were favourable for drug development with acceptable pharmacokinetic profiles and adequate oral bioavailability.
dc.title: Novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives and their antitrypanosomal activities against T.brucei dc.contributor.author: Bhambra, Avninder S.; Taylor, Annie; Hering, Moritz; Elsegood, Mark R. J.; Teat, Simon J.; Weaver, George W.; Arroo, R. R. J.; Kaiser, Marcel; Maeser, Pascal dc.description.abstract: Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense and is invariably fatal unless treated. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work, informed by previous findings, presents novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives with promising antitrypanosomal activity. In particular, 32 exhibits an in vitro EC50 value of 0.5 碌M against Trypanosoma brucei rhodesiense, and analogues 29, 30 and 33 show antitrypanosomal activities in the <1 碌M range. We have demonstrated that substituted 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidines present promising antitrypanosomal hit molecules with potential for further preclinical development. dc.description: open access article
dc.title: Curriculum design dc.contributor.author: Bhambra, Avninder S. dc.description.abstract: A curriculum is a key academic document, setting out the programme structure and content, also the rationale and vision for a course. It informs stakeholders and assures them a course is fit for purpose as well as demonstrates the level of quality required in the higher education sector. When considering curriculum design for biomedical science, designers must understand the needs of the profession and how to effectively educate those wishing to pursue a career as a Biomedical Scientist. However, not every student has this career aspiration in mind so each programme should be able to prepare students for diverse career paths. Such variation, combined with the already complex nature of the discipline, adds to the challenge of delivering a suitable curriculum which also considers professional development, as well as transferable and practical skills.
dc.title: Effect of the Citrus Flavone Nobiletin on Circadian Rhythms and Metabolic Syndrome dc.contributor.author: Neba Ambe, Gael Noel Neh; Breda, Carlo; Bhambra, Avninder S.; Arroo, R. R. J. dc.description.abstract: The importance of the circadian clock in maintaining human health is now widely acknowledged. Dysregulated and dampened clocks may be a common cause of age-related diseases and metabolic syndrome Thus, circadian clocks should be considered as therapeutic targets to mitigate disease symptoms. This review highlights a number of dietary compounds that positively affect the maintenance of the circadian clock. Notably the polymethoxyflavone nobiletin has shown some encouraging results in pre-clinical experiments. Although many more experiments are needed to fully elucidate its exact mechanism of action, it is a promising candidate with potential as a chronotherapeutic agent. dc.description: Invited review paper for a special issue of Molecules on "Biological Activities of Natural Products III" (Halina Ekiert & Agnieszka Szopa, eds.) open access article
dc.title: Analysis of plant secondary metabolism using stable isotope鈥恖abelled precursors dc.contributor.author: Arroo, R. R. J.; Bhambra, Avninder S.; Hano, Christophe; Renda, G眉lin; Ruparelia, Ketan C.; Wang, Meng F. dc.description.abstract: Introduction Analysis of biochemical pathways typically involves feeding a labelled precursor to an organism, and then monitoring the metabolic fate of the label. Initial studies used radioisotopes as a label and then monitored radioactivity in the metabolic products. As analytical equipment improved and became more widely available, preference shifted the use stable 鈥榟eavy鈥� isotopes like deuterium (2H)鈥�, carbon鈥�13 (13C)鈥� and nitrogen鈥�15 (15N)鈥恆toms as labels. Incorporation of the labels could be monitored by mass spectrometry (MS), as part of a hyphenated tool kits, e.g. Liquid chromatography (LC)鈥揗S, gas chromatography (GC)鈥揗S, LC鈥揗S/MS. MS offers great sensitivity but the exact location of an isotope label in a given metabolite cannot always be unambiguously established. Nuclear magnetic resonance (NMR) can also be used to pick up signals of stable isotopes, and can give information on the precise location of incorporated label in the metabolites. However, the detection limit for NMR is quite a bit higher than that for MS. Objectives A number of experiments involving feeding stable isotope鈥恖abelled precursors followed by NMR analysis of the metabolites is presented. The aim is to highlight the use of NMR analysis in identifying the precise fate of isotope labels after precursor feeding experiments. As more powerful NMR equipment becomes available, applications as described in this review may become more commonplace in pathway analysis. Conclusion and Prospects NMR is a widely accepted tool for chemical structure elucidation and is now increasingly used in metabolomic studies. In addition, NMR, combined with stable isotope feeding, should be considered as a tool for metabolic flux analyses. dc.description: Special issue of Phytochemical Analysis on NMR-based analytical techniques. open access article
dc.title: The Discovery of Novel Antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines dc.contributor.author: Robinson, W. J.; Taylor, Annie; Lauga-Cami, S.; Weaver, G. W.; Arroo, R. R. J.; Kaiser, M.; Gul, S.; Kuzikov, M.; Ellinger, B.; Singh, K.; Schirmeister, T.; Botana, A.; Eurtivong, C.; Bhambra, Avninder S. dc.description.abstract: Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense which seriously affects human health in Africa. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work herein describes the design and syntheses of novel antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines, with compound 13, the 4-(2-methoxyphenyl)-6-(pyridine-3-yl)pyrimidin-2-amine demonstrating an IC50 value of 0.38 碌M and a promising off-target ADME-Tox profile in vitro. In silico molecular target investigations showed rhodesain to be a putative candidate, supported by STD and WaterLOGSY NMR experiments, however, in vitro evaluation of compound 13 against rhodesain exhibited low experimental inhibition. Therefore, our reported library of drug-like pyrimidines present promising scaffolds for further antikinetoplastid drug development for both phenotypic and target-based drug discovery. dc.description: open access article
dc.title: Chemopreventive Potential of Flavones, Flavonols, and their Glycosides. dc.contributor.author: Arroo, R. R. J.; Wang, Meng F.; Bhambra, Avninder S. dc.description.abstract: Epidemiological studies have long indicated a possible role for dietary flavonoids, notably flavones and flavonols, in the prevention of a range of degenerative diseases, e.g. cancer, diabetes, cardiovascular diseases and neurological disorders like Parkinson鈥檚 and Alzheimer鈥檚 disease. The flavonoids are a large and variable group of compounds, comprising thousands of different structures. The bulk of the dietary flavonoids occur as glycosides. The effect of flavonoid aglycones and their corresponding glycosides on cell metabolism and aetiology of degenerative diseases has been a topic of interest for a number of decades. In contrast, the role of the metabolic products of dietary flavonoid that reach all parts of the human body through systemic circulation, has received much less attention. Studies on animal and human metabolism have shown that the amount flavone and flavonol glycosides is absorbed intact is negligible; the bulk is absorbed only after deglycosylation. Thus, dietary glycosides are not likely to play a direct role in chemoprevention. However, the sugar groups on glycosides can greatly affect the bioavailability of flavones and flavonols. Flavonoids linked with indigestible sugars are not absorbed in the small intestine, but are transported through the digestive tract to be degraded by gut bacteria in the large intestine. The compounds that directly play a tole in the prevention of degenerative diseases are most likely not dietary flavones themselves, but rather their metabolites and conjugation products. dc.description: Collaboration between Leicester Institute for Pharmaceutical Innovation and the Institute for Allied Heath Sciences Research.
dc.title: Bioproduction of Anticancer Podophyllotoxin and Related Aryltretralin-Lignans in Hairy Root Cultures of Linum Flavum L. dc.contributor.author: Mikac, Sara; Markulin, Lucija; Drouet, Samantha; Corbin, Cyrielle; Tungmunnithum, Duangjai; Kiani, Reza; Kabra, Atul; Abassi, Bilal Haider; Renouard, Sullivan; Fuss, Elisabeth; Hano, Christophe; Arroo, R. R. J.; Bhambra, Avninder S.; Laine, Eric dc.description.abstract: Podophyllotoxin (PPT) is the unique natural precursor of Etoposide, a topoisomerase II inhibitor drug, used in more than a dozen anticancer chemotherapy treatments. Etoposide is appearing on the list of essential medicines of the World Health Organization. PPT is still exclusively extracted from the rhizome of Podophyllum species, its main natural source. The supply of Podophyllum hexandrum plants is limited, since the occurrence of these plant species is scarce, collection is destructive, and the plants need a long regeneration period. As a consequence, this species is now endangered and listed on Appendix II of the Convention on International Trading of Endangered Species. Chemical synthesis of PPT is difficult due to the presence of four contiguous chiral centers and the presence of a base sensitive trans-lactone moiety. Alternatives are being actively searched, but so far, no wild plants have been described with similar PPT production capacity as compared to Podophyllum. However, several plants producing PPT or other related aryltetralin lignans (ATL) have been identified in recent decades, including the Linaceae. Given its high lignan accumulation capacity, Linum flavum is considered a promising alternative source of PPT and other related ATL. However, unlike the common flax L. usitatissimum, L. flavum has a low agricultural potential (e.g., slow growth and dehiscence of fruits). Therefore, in vitro cultures of plant cells and/or tissues provide an interesting alternative to whole L. flavum plants for the production of these valuable ATL. In particular, L. flavum hairy roots (HRs) accumulate high levels of ATL and it is also possible to further increase this ATL accumulation by the selection of the best genotype, optimization of cultures media and conditions and choice of carbon sources, use of plant growth regulators, elicitor treatments, or precursors鈥� addition. To date, the ATL accumulation levels can still be perceived insufficient for L. flavum HRs before being used as a commercially viable biotechnological production system. To reach this goal, a better knowledge of the mechanisms that regulate the metabolic flux of intermediates in the different branches of the ATL metabolic pathway will be an important prerequisite to direct the biosynthesis toward the production of a high amount of the desired PPT. In the future, metabolic engineering aiming at constructing the PPT pathway in a heterologous host is very appealing, but for that approach in-depth knowledge of the biosynthetic pathway toward PPT and other related ATL is necessary.
dc.title: Synthesis of Novel CYP1 Activated Heterocyclic Anticancer Prodrugs dc.contributor.author: Bhambra, Avninder S. dc.description.abstract: The cytochrome P450 superfamily of enzymes are critical in the metabolism of endogenous and exogenous substrates. CYP1A1 and CYP1B1 have been found to be over-expressed in tumour cells whilst undetected or present in very low levels in corresponding normal tissue. This presented a novel target for the development of anti-cancer prodrugs, which would remain non-toxic until undergoing metabolism to toxic species by CYP1 enzymes over-expressed at tumour sites. The chalcones have been shown to exhibit effective anti-cancer prodrug activity, but are labile to photoisomerisation reactions converting the potent trans isomer to the less toxic cis isomer. Several heterocyclic ring systems were incorporated across the 伪,尾-unsaturated moiety of the chalcones to produce rigid structures, eliminating the possibility of photoisomerisation occurring whilst maintaining the substituted phenyl groups in a trans like geometry. Lead compounds were identified using an in vitro MTT screening assay against a panel of tumour cell lines characterised for their constitutive or inducible CYP1 expression. These were the MDA 468, MCF7 and MDA 231 cell lines. The non-tumour MCF10A cell line which has no basal CYP1 expression was used as the control. A library of eighteen 3,5-diarylpyrazoles were synthesised. The lead pyrazole 51吃瓜app 10107 (3-(2,3,4-trimethoxyphenyl)-5-(3,4-methylenedioxyphenyl)pyrazole) gave an IC50 value of 8渭M towards the MDA 468 cell line. The MCF7 cells, TCDD induced and non-induced gave IC50 values of 10渭M each. Although the pyrazoles showed plausible tumour toxicity, an investigation into six membered pyrimidine heterocycles was undertaken in an attempt to obtain enhanced cytotoxicities than those observed from the five membered pyrazoles. Therefore, a library of fifteen 2-amino-4,6-diarylpyrimidines was synthesised. The lead amino-pyrimidine 51吃瓜app 10212 (2-amino-4-(2,4-dimethoxyphenyl)-6-(3,4-methylenedioxyphenyl)pyrimidine) showed significant cytotoxicity towards the MDA 468 cell line with an IC50 value of 0.01渭M. Notable IC50 values of 0.3渭M and 0.07渭M were also observed towards the MCF7 and MCF7 cells induced with TCDD. The important toxicity seen from the 2-amino-4,6-diarylpyrimidines prompted the investigation of the 2-position of the pyrimidine ring, and to assess the tumour toxicities of the synthesised compounds. The 2-amino-4,6-diarylpyrimidines were converted to produce 4,6-diarylpyrimidones by a one-step conversion reaction using sodium nitrate. The pyrimidone 51吃瓜app 10313 (4-(2-methoxyphenyl)-6-(3,4-methylenedioxyphenyl)pyrimidin-2-one) showed high toxicity with an IC50 value of 0.07渭M towards the MDA 468 cells and IC50 values of 1.8渭M and 0.5渭M 3 towards the MCF7 and MCF7 cells induced with TCDD. A library of nine 2-morpholino-4,6-diarylpyrimidines was synthesised. The lead compound 51吃瓜app 10405 (4-(2,4-dimethoxyphenyl)-6-(4-methoxyphenyl)-2-morpholinopyrimidine) gave an IC50 value of 10渭M towards the MDA 468 cells. 51吃瓜app 10600 (4-(2,4-dimethoxyphenyl)-6-(3,4-methylenedioxyphenyl)-2-dimethylethylenediaminopyrimidine), showed an IC50 value of 7渭M towards the MDA 468 cells and an identical IC50 value of 10渭M towards the MCF7 and MCF7 cells treated with TCDD. 51吃瓜app 10700 (2-methyl-4-(2,4-dimethoxyphenyl)-6-(3,4-methylenedioxyphenyl)pyrimidine), a substituted pyrimidine based on the phenyl substitutions of 51吃瓜app 10212 gave an IC50 value of 2.5渭M towards the MDA 468 cells. 51吃瓜app 10800 (4-(2,4-dimethoxyphenyl)-6-(3,4-methylenedioxyphenyl)pyrimidine), also based on the phenyl substitutions of 51吃瓜app 10212 showed an IC50 value of 0.08渭M towards the MDA 468 cells and equal IC50 values of 0.2渭M against the MCF7 and MCF7 cells induced with TCDD. All lead compounds did not show toxicity towards the non-tumour MCF10A cell line. 51吃瓜app 10212 was selected as the overall lead compound due to the significant tumour toxicities recorded, and for the non-toxicity observed towards the MCF10A cells. Inhibition studies using the known CYP1 inhibitor 伪-naphthoflavone (伪-NF) were conducted to show that 51吃瓜app 10212 was a substrate of the CYP1 enzymes. The resulting data showed that the cytotoxicity of 51吃瓜app 10212 was completely eliminated suggesting CYP1 enzymes play an activating role in the cytotoxic effect of 51吃瓜app 10212. LCMS metabolism studies using isolated CYP1 isoforms were performed showing that 51吃瓜app 10212 is metabolised to produce four metabolites (M1, M2, M3 and M4), determined from their individual retention times and molecular masses. The metabolites of 51吃瓜app 10212 were also found to be generated at a greater rate with CYP1A1 than CYP1B1. Metabolite structures were proposed as CYP1 enzyme reactions are known. The metabolite M2 was synthesised and was identified to be an authentic metabolite of 51吃瓜app 10212 via LCMS and co-elution studies. Screening of M2 against the tumour cells gave an IC50 value of 0.6渭M towards the MDA 468 cells, and IC50 values of 0.6渭M and 1渭M against the MCF7 and MCF7 cells induced with TCDD. In conclusion, 51吃瓜app 10212, a novel CYP1 activated anticancer prodrug with selective high toxicity towards tumour cells has been identified.
dc.title: Investigation of Linum flavum (L.) Hairy Root Cultures for the Production of Anticancer Aryltetralin Lignans. dc.contributor.author: Arroo, R. R. J.; Hano, C.; Renouard, S.; Corbin, C.; Drouet, S.; Medvedec, B.; Doussot, J.; Colas, C.; Maunit, B.; Bhambra, Avninder S.; Gontier, E.; Jullian, N.; Mesnard, F.; Boitel, M.; Abbasi, B. H.; Lain茅, E. dc.description.abstract: Linum flavum hairy root lines were established from hypocotyl pieces using Agrobacterium rhizogenes strains LBA 9402 and ATCC 15834. Both strains were effective for transformation but induction of hairy root phenotype was more stable with strain ATCC 15834. Whereas similar accumulation patterns were observed in podophyllotoxin-related compounds (6-methoxy-podophyllotoxin, podophyllotoxin and deoxypodophyllotoxin), significant quantitative variations were noted between root lines. The influence of culture medium and various treatments (hormone, elicitation and precursor feeding) were evaluated. The highest accumulation was obtained in Gamborg B5 medium. Treatment with methyl jasmonate, and feeding using ferulic acid increased the accumulation of aryltetralin lignans. These results point to the use of hairy root culture lines of Linum flavum as potential sources for these valuable metabolites as an alternative, or as a complement to Podophyllum collected from wild stands. dc.description: Collaboration with: Universit茅 d鈥橭rl茅ans, 28000 Chartres, France, Universit茅 de Picardie Jules Verne, F-80037 Amiens, France De 51吃瓜app University Open access article

Research interests/expertise

Structure and ligand based drug design

Natural products chemistry

In vitro drug screening

Pedagogy

Qualifications

BSc (Hons)
PhD
PGCert
MRSC
CChem
FIBMS

Courses taught

BSc Biomedical Science
BMedSci Medical Science
MSc Advanced Biomedical Science

Membership of professional associations and societies

Member of the Royal Society of Chemistry
Chartered Chemistt (CChem)
Member of the Phytochemical Society of Europe
Fellow of the Higher Education Academy
Fellow of the Institute of Biomedical Science
Editorial Board member for Cogent Chemistry

Current research students

Currently supervising PhD students internally and externally.

Please contact for Master's by Research or PhD opportunities.