Identification of a new class of proteasome inhibitors based on a naphthyl-azotricyclic-urea-phenyl scaffold

Article


Allardyce, D., Adu Mantey, P., Szalecka, M., Nkwo, R. and Loizidou, E. 2023. Identification of a new class of proteasome inhibitors based on a naphthyl-azotricyclic-urea-phenyl scaffold. RSC Medicinal Chemistry. 14 (3), pp. 573-582. https://doi.org/10.1039/D2MD00404F
TypeArticle
TitleIdentification of a new class of proteasome inhibitors based on a naphthyl-azotricyclic-urea-phenyl scaffold
AuthorsAllardyce, D., Adu Mantey, P., Szalecka, M., Nkwo, R. and Loizidou, E.
Abstract

Proteasomes play an important role in protein degradation and regulation of many cellular pathways by maintaining protein balance. Inhibitors of the proteasome disrupt this balance affecting proteins that are key in malignancies and as such have found applications in the treatment of multiple myeloma and mantle cell lymphoma. However, resistance mechanisms have been reported for these proteasome inhibitors including mutations at the β5 site which necessitates the constant development of new inhibitors. In this work, we report the identification of a new class of proteasome inhibitors, polycyclic molecules bearing a naphtyl-azotricyclic-urea phenyl scaffold, from screening of the ZINC library of natural products. The most potent of these compounds showed evidence of dose dependency though proteasome assays with IC50 values in the low micromolar range and kinetic analysis revealed competitive binding at the β5c site with an estimated inhibition constant, Ki 1.15μΜ. Inhibition was also shown for the β5i site of the immunoproteasome at levels similar to the constitutive proteasome. Structure activity relationship studies identified the naphthyl substituent to be crucial for activity and modelling studies attributed this to enhanced hydrophobic interactions within β5c. Further to this, halogen substitution within the naphthyl ring enhanced activity and allowed for π-π interactions with Y169 in β5c and Y130 and F124 in β5i. Combined these data highlight the importance of hydrophobic and halogen interactions in β5 binding and assist in the design of next generation inhibitors of the proteasome.

Sustainable Development Goals3 Good health and well-being
Middlesex University ThemeHealth & Wellbeing
PublisherRoyal Society of Chemistry
JournalRSC Medicinal Chemistry
ISSN
Electronic2632-8682
Publication dates
Online06 Feb 2023
Print22 Mar 2023
Publication process dates
Deposited07 Feb 2023
Submitted04 Nov 2022
Accepted06 Feb 2023
Output statusPublished
Accepted author manuscript
Copyright Statement

This author's accepted manuscript version is included in this repository in accordance with the publisher's Green open access policy (https://www.rsc.org/journals-books-databases/open-access-publishing/...)

Digital Object Identifier (DOI)https://doi.org/10.1039/D2MD00404F
Web of Science identifierWOS:000934246500001
LanguageEnglish
Permalink -

https://repository.mdx.ac.uk/item/8q433

Download files


Accepted author manuscript
  • 86
    total views
  • 20
    total downloads
  • 0
    views this month
  • 0
    downloads this month

Export as

Related outputs

Intentionality for inclusivity - the journey at Middlesex University
Roberts, H., Punev, I., Allardyce, D., Kyprianou, A., Appiah, S., Megeney, A., Calin, A., Gallacher, D. and Mill, R. 2022. Intentionality for inclusivity - the journey at Middlesex University. McGraw Hill.
An experimental FTIR-ATR and computational study of H-bonding in ethanol/water mixtures
Zeinalipour-Yazdi, C. and Loizidou, E. 2021. An experimental FTIR-ATR and computational study of H-bonding in ethanol/water mixtures. Chemical Physics. 550 (1), pp. 1-7. https://doi.org/10.1016/j.chemphys.2021.111295
Nanoparticle-infused-biodegradable-microneedles as drug-delivery systems: Preparation and characterisation
Sully, R., Garelick, H., Loizidou, E., Podoleanu, A. and Gubala, V. 2021. Nanoparticle-infused-biodegradable-microneedles as drug-delivery systems: Preparation and characterisation. Materials Advances. 2 (16), pp. 5432-5442. https://doi.org/10.1039/D1MA00135C
Nanomedicines and microneedles: A guide to their analysis and application
Sully, R., Moore, C., Garelick, H., Loizidou, E., Podoleanu, A. and Gubala, V. 2021. Nanomedicines and microneedles: A guide to their analysis and application. Analytical Methods. 13 (30), pp. 3326-3347. https://doi.org/10.1039/d1ay00954k
Size-dependent bond dissociation enthalpies in single-walled carbon nanotubes
Zenalipour-Yazdi, C., Loizidou, E. and Chutia, A. 2019. Size-dependent bond dissociation enthalpies in single-walled carbon nanotubes. Chemical Physics Letters. 731, pp. 1-6. https://doi.org/10.1016/j.cplett.2019.136628
Argyrin B a non-competitive inhibitor of the human immunoproteasome exhibiting preference for β1i
Allardyce, D., Bell, C. and Loizidou, E. 2019. Argyrin B a non-competitive inhibitor of the human immunoproteasome exhibiting preference for β1i. Chemical Biology and Drug Design. 94 (2), pp. 1556-1567. https://doi.org/10.1111/cbdd.13539
The potential use of microneedles as an alternative method for skin cancer treatment
Loizidou, E., Yagnik, D., Szalecka, M. and Nguyen, D. 2019. The potential use of microneedles as an alternative method for skin cancer treatment. The World Congress on Advanced Treatments and Technologies in Skin Cancer (Skin-Cancer2019). Vienna, Austria 04 - 05 Apr 2019
Analysis of argyrin B binding at constitutive and immunoproteasome active sites using molecular modelling and kinetic assays
Allardyce, D., Bell, C. and Loizidou, E. 2017. Analysis of argyrin B binding at constitutive and immunoproteasome active sites using molecular modelling and kinetic assays. Computational Advances in Drug Discovery (Structure Based Drug Design). Lausanne, Switzerland 05 - 08 Sep 2017
Biochemical and computational studies towards selective inhibition of the immunoproteasome
Allardyce, D. 2018. Biochemical and computational studies towards selective inhibition of the immunoproteasome. Masters thesis Middlesex University Natural Sciences
Teaching atomic structure as a threshold concept in chemistry for biologists
Loizidou, E. and Jones, H. 2016. Teaching atomic structure as a threshold concept in chemistry for biologists. 253rd American Chemical Society National Meeting & Exposition. San Francisco, CA, USA 02 - 06 Apr 2017
Study of the cap structure of (3,3), (4,4) and (5,5)-SWCNTs: application of the sphere-in-contact model
Zeinalipour-Yazdi, C. and Loizidou, E. 2017. Study of the cap structure of (3,3), (4,4) and (5,5)-SWCNTs: application of the sphere-in-contact model. Carbon. 115, pp. 819-827. https://doi.org/10.1016/j.carbon.2017.01.074
Evaluation of geometrical effects of microneedles on skin penetration by CT scan and finite element analysis
Loizidou, E., Inoue, N., Ashton-Barnett, J., Barrow, D. and Allender, C. 2016. Evaluation of geometrical effects of microneedles on skin penetration by CT scan and finite element analysis. European Journal of Pharmaceutics and Biopharmaceutics. 107, pp. 1-6. https://doi.org/10.1016/j.ejpb.2016.06.023
AB diblock and ABC triblock amphiphilic copolymers containing fluorine
Loizidou, E., Haralambous, D., Vamvakaki, M., Patrickios, C., Krasia, T. and Antonietti, M. 2001. AB diblock and ABC triblock amphiphilic copolymers containing fluorine. 221th ACS National Meeting. San Diego, CA, USA 01 Apr 2001
Characterization of amphiphilic polymers covalently attached with Pirkle-concept chiral selectors for chiral seperations by Merck
Loizidou, E., Zhang, K. and Sun, L. 2002. Characterization of amphiphilic polymers covalently attached with Pirkle-concept chiral selectors for chiral seperations by Merck. 224th ACS National Meeting. 18 Aug 2002
Molecular recognition of barbiturate artificial receptor covalently bound to an amphiphilic copolymer
Loizidou, E. and Sun, L. 2003. Molecular recognition of barbiturate artificial receptor covalently bound to an amphiphilic copolymer. International Symposium on the Synthesis and Characterization of Macromolecules. Amsterdam, Netherlands 07 - 11 Feb 2003
Structure-based computational analysis of the implications of subtype specific polymorphisms on the efficacy of integrase inhibitors
Loizidou, E., Kousiappa, I., Zeinalipour-Yazdi, C., Van De Vijver, D. and Kostrikis, L. 2009. Structure-based computational analysis of the implications of subtype specific polymorphisms on the efficacy of integrase inhibitors. 7th European HIV Drug Resistance Workshop. Stockholm, Sweden
Rational design of argyrin analogues as selective inhibitors of the proteasome
Loizidou, E. and Zeinalipour-Yazdi, C. 2012. Rational design of argyrin analogues as selective inhibitors of the proteasome. COST Conference on Personalised Medicine. Larnaca, Cyprus 17 - 22 Jun 2012
Design of argyrin analogues as proteasome inhibitors with subunit specicificity
Loizidou, E. and Zeinalipour-Yazdi, C. 2014. Design of argyrin analogues as proteasome inhibitors with subunit specicificity. 247th ACS National Meeting. Dallas, TX, USA 16 - 20 Mar 2014
Simulating the effect of geometry on the structural properties of microneedles
Loizidou, E., Ashton-Barnett, J., Barrow, D. and Allender, C. 2014. Simulating the effect of geometry on the structural properties of microneedles. Perspectives in Percutaneous Penetration Fourteenth International Conference including FP7 HIPODERM Symposium on High Potency Dermatologicals. La Grande Motte, France 23 - 25 Apr 2014
Structural properties of sugar microneedles: a finite element analysis
Loizidou, E., Barrow, D. and Allender, C. 2014. Structural properties of sugar microneedles: a finite element analysis. Perspectives in Percutaneous Penetration Fourteenth International Conference including FP7 HIPODERM Symposium on High Potency Dermatologicals. La Grande Motte, France 23 - 25 Apr 2014
Implications of HIV-1 M group polymorphisms on intergase inhibitor efficacy and resistance: genetic and structural in-silico analyses
Loizidou, E., Kousiappa, I., Zeinalipour-Yazdi, C., Van De Vijver, D. and Kostrikis, L. 2009. Implications of HIV-1 M group polymorphisms on intergase inhibitor efficacy and resistance: genetic and structural in-silico analyses. Biochemistry. 48 (1), pp. 4-6. https://doi.org/10.1021/bi8019349
Molecular recognition of barbiturate artificial receptor covalently bound to an amphiphilic copolymer
Loizidou, E. and Sun, L. 2003. Molecular recognition of barbiturate artificial receptor covalently bound to an amphiphilic copolymer. 226th ACS National Meeting. New York, New York, USA 07 - 11 Sep 2003
Part I: total synthesis of azaspiracid-3 Part II: molecular recognition studies in aqueous solutions facilitated by a receptor-modified polymer
Loizidou, E. 2006. Part I: total synthesis of azaspiracid-3 Part II: molecular recognition studies in aqueous solutions facilitated by a receptor-modified polymer. PhD thesis University of California San Diego / San Diego State University Chemistry
HIV-1 integrase inhibitors: from biology to chemotherapeutics
Loizidou, E., Nicolaou, C., Nicolaides, A. and Kostrikis, L. 2007. HIV-1 integrase inhibitors: from biology to chemotherapeutics. Current HIV Research. 5 (4), pp. 365-388. https://doi.org/10.2174/157016207781023965
Multi-objective optimization methods in de novo drug design
Nicolaou, C., Kannas, C. and Loizidou, E. 2012. Multi-objective optimization methods in de novo drug design. Mini Reviews in Medicinal Chemistry. 12 (10), pp. 979-987. https://doi.org/10.2174/138955712802762284
Structural assignment and total synthesis of azaspiracid-1
Frederick, M., Cole, K., Petrovic, G., Loizidou, E. and Nicolaou, K. 2007. Structural assignment and total synthesis of azaspiracid-1. in: Botana, L. (ed.) Phycotoxins: chemistry and biochemistry Ames, Iowa WileyBlackwell. pp. 297-309
Computational inhibition studies of the human proteasome by argyrin-based analogues with subunit specificity
Loizidou, E. and Zeinalipour-Yazdi, C. 2014. Computational inhibition studies of the human proteasome by argyrin-based analogues with subunit specificity. Chemical Biology and Drug Design. 84 (1), pp. 99-107. https://doi.org/10.1111/cbdd.12298
Receptor-attached amphiphilic terpolymer for selective drug recognition in aqueous solutions
Loizidou, E., Sun, L. and Zeinalipour-Yazdi, C. 2011. Receptor-attached amphiphilic terpolymer for selective drug recognition in aqueous solutions. Journal of Molecular Recognition. 24 (4), pp. 678-686. https://doi.org/10.1002/jmr.1098
Analysis of binding parameters of HIV-1 integrase inhibitors: correlates of drug inhibition and resistance
Loizidou, E., Zeinalipour-Yazdi, C., Christofides, T. and Kostrikis, L. 2009. Analysis of binding parameters of HIV-1 integrase inhibitors: correlates of drug inhibition and resistance. Bioorganic & Medicinal Chemistry. 17 (13), pp. 4806-4818. https://doi.org/10.1016/j.bmc.2009.04.058
Second generation total synthesis of azaspiracids-1, -2 and -3
Nicolaou, K., Frederick, M., Loizidou, E., Petrovic, G., Cole, K., Koftis, T. and Yamada, Y. 2006. Second generation total synthesis of azaspiracids-1, -2 and -3. Chemistry: an Asian Journal. 1 (1-2), pp. 245-263. https://doi.org/10.1002/asia.200600059
Structural characterization and transdermal delivery studies on sugar microneedles: experimental and finite element modelling analyses
Loizidou, E., Williams, N., Barrow, D., Eaton, M., McCrory, J., Evans, S. and Allender, C. 2015. Structural characterization and transdermal delivery studies on sugar microneedles: experimental and finite element modelling analyses. European Journal of Pharmaceutics and Biopharmaceutics. 89, pp. 224-231. https://doi.org/10.1016/j.ejpb.2014.11.023
Total synthesis and confirmation of the revised structures of azaspiracid-2 and azaspiracid-3
Nicolaou, K., Frederick, M., Petrovic, G., Cole, K. and Loizidou, E. 2006. Total synthesis and confirmation of the revised structures of azaspiracid-2 and azaspiracid-3. Angewandte Chemie International Edition. 45 (16), pp. 2609-2615. https://doi.org/10.1002/anie.200600295
Total synthesis and structural elucidation of azaspiracid-1 : construction of key building blocks for originally proposed structure
Nicolaou, K., Pihko, P., Bernal, F., Frederick, M., Qian, W., Uesaka, N., Diedrichs, N., Hinrichs, J., Koftis, T., Loizidou, E., Petrovic, G., Rodriquez, M., Sarlah, D. and Zou, N. 2006. Total synthesis and structural elucidation of azaspiracid-1 : construction of key building blocks for originally proposed structure. Journal of the American Chemical Society. 128 (7), pp. 2244-2257. https://doi.org/10.1021/ja0547477
Studies toward the synthesis of azadirachtin, part 2 : construction of fully functionalized ABCD ring frameworks and unusual intramolecular reactions induced by close-proximity effects
Nicolaou, K., Sasmal, P., Koftis, T., Converso, A., Loizidou, E., Kaiser, F., Roecker, A., Dellios, C., Sun, X. and Petrovic, G. 2005. Studies toward the synthesis of azadirachtin, part 2 : construction of fully functionalized ABCD ring frameworks and unusual intramolecular reactions induced by close-proximity effects. Angewandte Chemie International Edition. 44 (22), pp. 3447-3452. https://doi.org/10.1002/anie.200500217
Artificial receptor-attached amphiphilic copolymer for barbiturate binding in aqueous media
Loizidou, E., Zeinalipour-Yazdi, C. and Sun, L. 2004. Artificial receptor-attached amphiphilic copolymer for barbiturate binding in aqueous media. Biomacromolecules. 5 (5), pp. 1647-1652. https://doi.org/10.1021/bm0497320
Synthesis and characterization of novel networks with nano-engineered structures: cross-linked star homopolymers
Vamvakaki, M., Hadjiyiannakou, S., Loizidou, E. and Patrickios, C. 2001. Synthesis and characterization of novel networks with nano-engineered structures: cross-linked star homopolymers. Chemistry of Materials. 13 (12), pp. 4738-4744. https://doi.org/10.1021/cm010569e