ÐßÐßÊÓƵ

More

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: ÐßÐßÊÓƵ, The Gateway, Leicester, LE1 9BH

T: 0116 2078792

E: abhambra@dmu.ac.uk

W: /alliedhealthsciences

 

Close all sections
Open all sections

Personal profile

Dr Bhambra is an Associate Professor within the Faculty of Health and Life Sciences (HLS) at ÐßÐßÊÓƵ (ÐßÐßÊÓƵ). Throughout his time at ÐßÐßÊÓƵ, 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: Synthesis of Isobenzofuranones and Isoindolinones via Claisen–Schmidt Condensation and Their Antileishmanial Activity dc.contributor.author: Khotsombat, Sireethon; Suddee, Nattanit; Theppitak, Chatphorn; Ruchirawat, Somsak; Kaiser, Marcel; Arroo, R. R. J.; Taylor, Annie; Weaver, George W.; Bhambra, Avninder S.; Thasana, Nopporn dc.description.abstract: In this study, we describe the synthesis of isobenzofuranones and isoindolinones using the Claisen–Schmidt condensation via the formation of a chalcone intermediate, followed by a 5-exo-trig cyclization facilitated by the carboxylate group under basic conditions. The desired products were obtained in good yields. Subsequently, Michael-lactamization reaction of the isobenzofuranones was employed to synthesize isoindolinone derivatives. The three-component Mannich-lactamization reaction was also explored to synthesize isoindolinones from 2–hydroxyacetophenone, phthalaldehydic acid, and amine derivatives. Furthermore, the synthesized compound 5c exhibited low EC50 (μM) values against Leishmania donovani (L. donovani), with no significant cytotoxicity observed against L-6 cells. dc.description: open access article Collaboration between: Chulabhorn Research Institute, Bangkok 10210, Thailand Center of Excellence on Environmental Health and Toxicology (EHT), Bangkok 10400, Thailand Swiss Tropical and Public Health Institute, Basel 4051, Switzerland ÐßÐßÊÓƵ, Leicester LE1 9BH, United Kingdom; Loughborough University, Loughborough LE11 3TU, United Kingdom

  • dc.title: The cytotoxic effect of chrysosplenetin, a natural product from Artemisia annua, investigated with different human cancer cell lines, as well as in vitro CYP450 enzymatic activity in human liver microsomes dc.contributor.author: Neba Ambe, Gael Noel Neh; Bhambra, Avninder S.; Arroo, R. R. J. dc.description.abstract: The polymethoxyflavone Chrysosplenetin [5-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-3’,6,7- trimethoxychromen-4-one] (Fig 1) is one of the many chemical compounds found in the aerial parts of the Artemisia annua plant (Ferreira et al., 2010). A. annua is best known as the source plant for artemisinin, the sesquiterpene precursor for a range of first-line antimalarial drugs (Tu, 2011; Woerdenbag et al., 1990). Our interest is in the polymethoxyflavones which are abundantly present in this medicinal crop plant, and which may find application as drugs in their own right. The cytotoxic effect of chrysosplenetin (1) was tested against the triple negative breast cell line (MDA-MB- 468), a tumorigenic cell line which expresses CYP1, and the normal breast cell line (MCF10A) which is devoid of CYP1 expression. The antiproliferative effect of chrysosplenetin was investigated by MTT assay, and it showed greater toxicity in the CYP1-expressing breast cell line (MDA-MB-468) with a significantly lower IC50 of 0.4 µM as opposed to 20 µM in the normal MCF10A cells. Additionally, the biotransformation of chrysosplenetin by CYP1 microsomes was investigated using High performance Liquid Chromatography (HPLC-DAD) and mass spectrometry (LC-MS). Two metabolite peaks were observed with retention times at 2.8 and 3.3 minutes, both presenting with an average mass of 361.3g in positive ionisation mode. We therefore propose that the polymethoxyflavone chrysosplenetin may act as a prodrug that is selectively activated in hormone- dependent cancer cells. dc.description: Conference Abstract International Congress on Natural Products Research (ICNPR 2024), Krakow, 2024, July 13-17

  • dc.title: Antitrypanosomal quinazolines targeting lysyl-tRNA synthetase show partial efficacy in a mouse model of acute Chagas disease dc.contributor.author: Bhambra, Avninder S.; Tulloch, L. B.; Tawell, H.; Taylor, Annie; Lima, M. L.; Dawson, A.; Carvalho, S.; Wall, R.J .; Corpas-Lopez, V.; Dey, G.; Duggan, J.; Magalhaes, L. G.; Torrie, L. S.; Frame, L.; Robinson, D.; Patterson, S.; Tinti, M.; Weaver, G. W.; Robinson, W. J.; Cal, M dc.description.abstract: The protozoan parasite Trypanosoma cruzi causes Chagas disease, which is among the deadliest parasitic infections in Latin America. Current therapies are toxic and lack efficacy against the chronic stage of infection; thus, new drugs are urgently needed. Here, we describe a previously unidentified series of quinazoline compounds with potential against Trypanosoma cruzi and the related trypanosomatid parasites Trypanosoma brucei and Leishmania donovani. We demonstrated partial efficacy of a lead quinazoline compound in a mouse model of acute Chagas disease. Mechanism of action studies using several orthogonal approaches showed that this quinazoline compound series targeted the ATP-binding pocket of T. cruzi lysyl-tRNA synthetase 1 (KRS1). A high-resolution crystal structure of KRS1 bound to the drug indicated binding interactions that led to KRS1 inhibition. Our study identified KRS1 as a druggable target for treating T. cruzi infection in a mouse model. This quinazoline series shows potential for treating Chagas disease but will require further development to become a future treatment for this neglected disease. dc.description: 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.

  • dc.title: Chemopreventive properties of naturally occurring methoxylated resveratrol analogues dc.contributor.author: Brucoli, Federico; Neba Ambe, Gael Noel Neh; Bhambra, Avninder S.; Arroo, R. R. J. dc.description.abstract: Whereas thousands of papers have been published on the cancer chemopreventive properties of resveratrol (3,5,4′-trihydroxy-trans-stilbene) and related monomeric stilbenoids, there still is no consensus on their mechanism of action in a dietary setting. A widely held assumption is that the naturally occurring trans stilbenoids act as phytoestrogens, and thus affect cell metabolism of estrogen sensitive cells. This is known to be the mechanism of action for Tamoxifen, a synthetic drug with a stilbene moiety at its core, which is now approved as a chemopreventive agent. The bioavailability of resveratrol is low, which means that the doses known to inhibit cell proliferation in vitro (IC50 in the range 3–30 µM) are never reached in vivo. The cytotoxic activity of a methoxylated analogue of resveratrol, pterostilbene (3,5-dimethoxy-4’-hydroxy trans stilbene), is in the same range as resveratrol. However, the methoxylated trans stilbenoid appears have better pharmacokinetic properties. Still, its overall bioavailability in vivo seems insufficient to make it have any significant effect on modulation of carcinogenesis. Polymethoxylated cis-stilbenoids (combretastatins), in contrast to the trans-stilbenoids, are too cytotoxic to be considered as chemopreventive agents. Combretastatin A4 has been considered as a cancer therapeutic agent; it inhibits tubulin polymerization by interacting at the colchicine binding site of microtubules, a mechanism of action that is fundamentally different from that of the trans-stilbenoids. It may be speculated that naturally occurring trans stilbenoids selectively accumulate in precancerous cells, thus locally reaching sufficiently high levels. This hypothesis may be difficult to prove experimentally. Further clues on the material properties of stilbenoids will most likely come from synthetic chemistry, where a wide range of analogues can be investigated for structure–activity relationships. dc.description: open access article

  • dc.title: Herbal appetite suppressants used to aid weight loss. dc.contributor.author: Malik, Sonia; Kuntawala, Dhivani H.; Neba Ambe, Gael Noel Neh; Jin, Yannan; Bhambra, Avninder S.; Arroo, R. R. J. dc.description.abstract: Overweight and obesity are global health challenges associated with an increased risk of life-threatening comorbidities. Whereas a healthy diet and a lifestyle with a sufficient amount of exercise is the first recommendation to avert complications arising from overweight, a variety of prescription medicines is recognised as potential aids in weight loss. However, concerns about adverse effects of many prescription weight-loss agents has made that may drugs are now prohibited in some countries, though not in all countries. This has given rise to a clandestine market which has made proper monitoring of safety of products on sale increasingly complex. In addition to pharmaceutical products, a wide range of food substitutes or food supplements that are marketed as aids in weight loss is available. Regulation of food ingredients is considerably less stringent than regulation for pharmaceutical products; whereas pharmaceutical companies need to provide evidence of safety and efficacy before they are allowed marketing of any products, manufacturers of herbal and dietary supplements are just expected to ensure safety of their products. A sustainable reduction in food intake can be a major challenge, and people on weight-loss programmes have to fight cravings and hunger pangs. Appetite suppression-based therapies are the novel and promising treatments to control obesity. Recently, the peptide Semaglutide (Wegovy®, Ozempic®) has emerged as a very popular appetite suppressing prescription drug, which is administered by injection, though oral formulations have been developed too. Appetite suppressing herbal supplements have often been used traditionally since ages and are therefore generally regarded as safe. The aim of present review is to reflect on the most popular herbal supplements that are currently marketed as appetite suppressants, and that are widely promoted as aids in weight loss exercises. Notably, members of the family Apocynaceae, e.g. Caralluma spp. and Hoodia spp. contain pregnane glycosides that have been shown to restore sensitivity to the appetite suppressant hormone leptin in obese mice. The anti-obesity effect of Garcinia spp. (Clusiaceae) has been attributed to the presence of hydroxycitric acid (HCA), which inhibits fatty acid and triglyceride biosynthesis. In addition, HCA administration has been shown to increase serotonin levels, which in turn results in reduced appetite. A similar mechanism of action is seen with extracts of Griffonia simplicifolia (Fabaceae) that are particularly rich in the serotonin precursor 5-hydroxytryptophan. A third mechanism of action is seen in Gymnema sylvestre (Apocynaceae) which contains gymnemic acids that selectively inhibit oral sweet taste sensation in humans, thus lessening the appeal of sweets and pastries. dc.description: This is an extended version of a plenary lecture presented by Randolph Arroo at the conference 'Natural Products in Drug Discovery and Development – Advances and Perspectives', 19-22 September 2022, IaÅŸi, Romania. Full-text access to a view-only version of the paper is available through the following SharedIt link: https://rdcu.be/dZL4e

  • 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 ~ 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 ΔGbind values of − 38.1 and − 38.2 kcal/mol to cruzain and rhodesain, respectively, and 15 has predicted ΔGbind values of − 34.4 and − 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 ΔGbind 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 µM against Trypanosoma brucei rhodesiense, and analogues 29, 30 and 33 show antitrypanosomal activities in the <1 µM 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: 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 chaicones 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 a,p-unsaturated moiety of the chaicones 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 CYPI expression was used as the control. A library of eighteen 3,5-diarylpyrazoles were synthesised. The lead pyrazole ÐßÐßÊÓƵ 10107 (3-(2,3,4-trimethoxyphenyl)-5-(3,4-methylenedioxyphenyl)pyrazole) gave an IC50 value of 8pM towards the MDA 468 cell line. The MCF7 cells, TCDD induced and non-induced gave IC50 values of 10|iM 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 ÐßÐßÊÓƵ 10212 (2-amino-4-(2,4-dimethoxyphenyI)-6-(3,4- methylenedioxyphenyl)pyrimidine) showed significant cytotoxicity towards the MDA 468 cell line with an IC50 value of 0.01 pM. Notable IC50 values of 0.3pM and 0.07pM 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 ÐßÐßÊÓƵ 10313 (4-(2- methoxyphenyl)-6-(3,4-methylenedioxyphenyl)pyrimidin-2-one) showed high toxicity with an IC50 value of 0.07,uM towards the MDA 468 cells and IC50 values of I.811M and 0.5uM towards the MCF7 and MCF7 cells induced with TCDD. A library of nine 2-morpholino-4,6- diarylpyrimidines was synthesised. The lead compound ÐßÐßÊÓƵ 10405 (4-(2,4- dimethoxyphenyl)-6-(4-methoxyphenyl)-2-morphoIinopyrimidine) gave an IC50 value of lOpM towards the MDA 468 cells. ÐßÐßÊÓƵ 10600 (4-(2,4-dimethoxyphenyl)-6-(3,4- methylenedioxyphenyl)-2-dimethylethylenediaminopyrimidine), showed an IC5o value of 7pM towards the MDA 468 cells and an identical IC50 value of 10pM towards the MCF7 and MCF7 cells treated with TCDD. ÐßÐßÊÓƵ 10700 (2-methyl-4-(2,4-dimethoxyphenyl)-6-(3,4- methylenedioxyphenyl)pyrimidine), a substituted pyrimidine based on the phenyl substitutions of ÐßÐßÊÓƵ 10212 gave an IC50 value of 2.5p.M towards the MDA 468 cells. ÐßÐßÊÓƵ 10800 (4-(2,4-dimethoxyphenyl)-6-(3,4-methylenedioxyphenyl)pyrimidine), also based on the phenyl substitutions of ÐßÐßÊÓƵ 10212 showed an IC50 value of 0.08pM towards the MDA 468 cells and equal IC50 values of 0.2pM against the MCF7 and MCF7 cells induced with TCDD. All lead compounds did not show toxicity towards the non-tumour MCF10A cell line. ÐßÐßÊÓƵ 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 a-naphthoflavone (a-NF) were conducted to show that ÐßÐßÊÓƵ 10212 was a substrate of the CYP1 enzymes. The resulting data showed that the cytotoxicity of ÐßÐßÊÓƵ 10212 was completely eliminated suggesting CYP1 enzymes play an activating role in the cytotoxic effect of ÐßÐßÊÓƵ 10212. LCMS metabolism studies using isolated CYP1 isoforms were performed showing that ÐßÐßÊÓƵ 10212 is metabolised to produce four metabolites (Ml, M2, M3 and M4), determined from their individual retention times and molecular masses. The metabolites of ÐßÐßÊÓƵ 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 ÐßÐßÊÓƵ 10212 via LCMS and co-elution studies. Screening of M2 against the tumour cells gave an IC50 value of 0.6pM towards the MDA 468 cells, and IC50 values of 0.6pM and IpM against the MCF7 and MCF7 cells induced with TCDD. In conclusion, ÐßÐßÊÓƵ 10212, a novel CYP1 activated anticancer prodrug with selective high toxicity towards tumour cells has been identified.

  • 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

. 

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.