N-aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: Design, synthesis, computational studies, and antitumor effect

Jose M. Espejo-Román; Belén Rubio-Ruiz; Meriem Chayah-Ghaddab; Carlos Vega-Gutierrez; Gracia García-García; Arantza Muguruza-Montero; Carmen Domene; Rosario M Sánchez-Martín; Olga Cruz-López; Ana Conejo-García

doi:10.1016/j.ejmech.2023.115570

N-aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: Design, synthesis, computational studies, and antitumor effect

Jose M. Espejo-Román, Belén Rubio-Ruiz, Meriem Chayah-Ghaddab, Carlos Vega-Gutierrez, Gracia García-García, Arantza Muguruza-Montero, Carmen Domene, Rosario M Sánchez-Martín, Olga Cruz-López, Ana Conejo-García

Department of Chemistry

Universidad de Granada

Research output: Contribution to journal › Article › peer-review

4 Citations (SciVal)

Abstract

Hyaluronic acid (HA) plays a crucial role in tumor growth and invasion through its interaction with cluster of differentiation 44 (CD44), a non-kinase transmembrane glycoprotein, among other hyaladherins. CD44 expression is elevated in many solid tumors, and its interaction with HA is associated with cancer and angiogenesis. Despite efforts to inhibit HA-CD44 interaction, there has been limited progress in the development of small molecule inhibitors. As a contribution to this endeavour, we designed and synthesized a series of N-aryltetrahydroisoquinoline derivatives based on existing crystallographic data available for CD44 and HA. Hit 2e was identified within these structures for its antiproliferative effect against two CD44+ cancer cell lines, and two new analogs (5 and 6) were then synthesized and evaluated as CD44-HA inhibitors by applying computational and cell-based CD44 binding studies. Compound 2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-5-ol (5) has an EC50 value of 0.59 μM against MDA-MB-231 cells and is effective to disrupt the integrity of cancer spheroids and reduce the viability of MDA-MB-231 cells in a dose-dependent manner. These results suggest lead 5 as a promising candidate for further investigation in cancer treatment.

Original language	English
Article number	115570
Journal	European Journal of Medicinal Chemistry
Volume	258
Early online date	26 Jun 2023
DOIs	https://doi.org/10.1016/j.ejmech.2023.115570
Publication status	Published - 5 Oct 2023

Bibliographical note

Funding Information:
This research was funded by the Consejería de Universidad, Investigación e Innovación of the Junta de Andalucía and FEDER , Una manera de hacer Europa ( P18-RT-1679 , PT18-TP-4160 , B-FQM-475-UGR18 and PAIDI-TC-PVT-PSETC-2.0. ), the Research Results Transfer Office (OTRI) of the University of Granada ( PR/17/006 ), the Spanish Ministry of Economy and Competitiveness ( PID2019.110987RB.I00 and PID2021.128109OB.I00 ) and the Health Institute Carlos III ( DTS18/00121 ). C.D. thanks HECBioSim, the UK High End Computing Consortium for Biomolecular Simulation (hecbiosim.ac.uk), which is supported by the EPSRC ( EP/L000253/1 ) for awarding computing time in Jade, a UK Tier-2 resource. B.R.-R. gratefully acknowledges funding from the European Union's Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie Grant Agreement no. 754446 and UGR Research and Knowledge Transfer Fund—Athenea3i . J.M.E.-R. thanks the Spanish Ministry of Education for a studentship ( FPU 16/02061 ). A.M.-M. gratefully acknowledges funding from the HPC-Europa3 Transnational Access programme supported by the European Commission H2020 Research & Innovation GA # 730897 (application number HPC17ARM6V ). Funding for open access charge: Universidad de Granada / CBUA .

Keywords

Antiproliferative effect
Cluster of differentiation 44
Hyaluronic acid
Molecular dynamics simulations
Tetrahydroisoquinoline
Three-dimensional cancer model evaluation

ASJC Scopus subject areas

Drug Discovery
Pharmacology
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejmech.2023.115570Licence: CC BY-NC-ND

Cite this

Espejo-Román, J. M., Rubio-Ruiz, B., Chayah-Ghaddab, M., Vega-Gutierrez, C., García-García, G., Muguruza-Montero, A., Domene, C., Sánchez-Martín, R. M., Cruz-López, O., & Conejo-García, A. (2023). N-aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: Design, synthesis, computational studies, and antitumor effect. European Journal of Medicinal Chemistry, 258, Article 115570. https://doi.org/10.1016/j.ejmech.2023.115570

Espejo-Román, JM, Rubio-Ruiz, B, Chayah-Ghaddab, M, Vega-Gutierrez, C, García-García, G, Muguruza-Montero, A, Domene, C, Sánchez-Martín, RM, Cruz-López, O & Conejo-García, A 2023, 'N-aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: Design, synthesis, computational studies, and antitumor effect', European Journal of Medicinal Chemistry, vol. 258, 115570. https://doi.org/10.1016/j.ejmech.2023.115570

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title = "N-aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: Design, synthesis, computational studies, and antitumor effect",

abstract = "Hyaluronic acid (HA) plays a crucial role in tumor growth and invasion through its interaction with cluster of differentiation 44 (CD44), a non-kinase transmembrane glycoprotein, among other hyaladherins. CD44 expression is elevated in many solid tumors, and its interaction with HA is associated with cancer and angiogenesis. Despite efforts to inhibit HA-CD44 interaction, there has been limited progress in the development of small molecule inhibitors. As a contribution to this endeavour, we designed and synthesized a series of N-aryltetrahydroisoquinoline derivatives based on existing crystallographic data available for CD44 and HA. Hit 2e was identified within these structures for its antiproliferative effect against two CD44+ cancer cell lines, and two new analogs (5 and 6) were then synthesized and evaluated as CD44-HA inhibitors by applying computational and cell-based CD44 binding studies. Compound 2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-5-ol (5) has an EC50 value of 0.59 μM against MDA-MB-231 cells and is effective to disrupt the integrity of cancer spheroids and reduce the viability of MDA-MB-231 cells in a dose-dependent manner. These results suggest lead 5 as a promising candidate for further investigation in cancer treatment.",

keywords = "Antiproliferative effect, Cluster of differentiation 44, Hyaluronic acid, Molecular dynamics simulations, Tetrahydroisoquinoline, Three-dimensional cancer model evaluation",

author = "Espejo-Rom{\'a}n, {Jose M.} and Bel{\'e}n Rubio-Ruiz and Meriem Chayah-Ghaddab and Carlos Vega-Gutierrez and Gracia Garc{\'i}a-Garc{\'i}a and Arantza Muguruza-Montero and Carmen Domene and S{\'a}nchez-Mart{\'i}n, {Rosario M} and Olga Cruz-L{\'o}pez and Ana Conejo-Garc{\'i}a",

note = "Funding Information: This research was funded by the Consejer{\'i}a de Universidad, Investigaci{\'o}n e Innovaci{\'o}n of the Junta de Andaluc{\'i}a and FEDER , Una manera de hacer Europa ( P18-RT-1679 , PT18-TP-4160 , B-FQM-475-UGR18 and PAIDI-TC-PVT-PSETC-2.0. ), the Research Results Transfer Office (OTRI) of the University of Granada ( PR/17/006 ), the Spanish Ministry of Economy and Competitiveness ( PID2019.110987RB.I00 and PID2021.128109OB.I00 ) and the Health Institute Carlos III ( DTS18/00121 ). C.D. thanks HECBioSim, the UK High End Computing Consortium for Biomolecular Simulation (hecbiosim.ac.uk), which is supported by the EPSRC ( EP/L000253/1 ) for awarding computing time in Jade, a UK Tier-2 resource. B.R.-R. gratefully acknowledges funding from the European Union's Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie Grant Agreement no. 754446 and UGR Research and Knowledge Transfer Fund—Athenea3i . J.M.E.-R. thanks the Spanish Ministry of Education for a studentship ( FPU 16/02061 ). A.M.-M. gratefully acknowledges funding from the HPC-Europa3 Transnational Access programme supported by the European Commission H2020 Research & Innovation GA # 730897 (application number HPC17ARM6V ). Funding for open access charge: Universidad de Granada / CBUA . ",

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T2 - Design, synthesis, computational studies, and antitumor effect

AU - Espejo-Román, Jose M.

AU - Rubio-Ruiz, Belén

AU - Chayah-Ghaddab, Meriem

AU - Vega-Gutierrez, Carlos

AU - García-García, Gracia

AU - Muguruza-Montero, Arantza

AU - Domene, Carmen

AU - Sánchez-Martín, Rosario M

AU - Cruz-López, Olga

AU - Conejo-García, Ana

N1 - Funding Information: This research was funded by the Consejería de Universidad, Investigación e Innovación of the Junta de Andalucía and FEDER , Una manera de hacer Europa ( P18-RT-1679 , PT18-TP-4160 , B-FQM-475-UGR18 and PAIDI-TC-PVT-PSETC-2.0. ), the Research Results Transfer Office (OTRI) of the University of Granada ( PR/17/006 ), the Spanish Ministry of Economy and Competitiveness ( PID2019.110987RB.I00 and PID2021.128109OB.I00 ) and the Health Institute Carlos III ( DTS18/00121 ). C.D. thanks HECBioSim, the UK High End Computing Consortium for Biomolecular Simulation (hecbiosim.ac.uk), which is supported by the EPSRC ( EP/L000253/1 ) for awarding computing time in Jade, a UK Tier-2 resource. B.R.-R. gratefully acknowledges funding from the European Union's Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie Grant Agreement no. 754446 and UGR Research and Knowledge Transfer Fund—Athenea3i . J.M.E.-R. thanks the Spanish Ministry of Education for a studentship ( FPU 16/02061 ). A.M.-M. gratefully acknowledges funding from the HPC-Europa3 Transnational Access programme supported by the European Commission H2020 Research & Innovation GA # 730897 (application number HPC17ARM6V ). Funding for open access charge: Universidad de Granada / CBUA .

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N2 - Hyaluronic acid (HA) plays a crucial role in tumor growth and invasion through its interaction with cluster of differentiation 44 (CD44), a non-kinase transmembrane glycoprotein, among other hyaladherins. CD44 expression is elevated in many solid tumors, and its interaction with HA is associated with cancer and angiogenesis. Despite efforts to inhibit HA-CD44 interaction, there has been limited progress in the development of small molecule inhibitors. As a contribution to this endeavour, we designed and synthesized a series of N-aryltetrahydroisoquinoline derivatives based on existing crystallographic data available for CD44 and HA. Hit 2e was identified within these structures for its antiproliferative effect against two CD44+ cancer cell lines, and two new analogs (5 and 6) were then synthesized and evaluated as CD44-HA inhibitors by applying computational and cell-based CD44 binding studies. Compound 2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-5-ol (5) has an EC50 value of 0.59 μM against MDA-MB-231 cells and is effective to disrupt the integrity of cancer spheroids and reduce the viability of MDA-MB-231 cells in a dose-dependent manner. These results suggest lead 5 as a promising candidate for further investigation in cancer treatment.

AB - Hyaluronic acid (HA) plays a crucial role in tumor growth and invasion through its interaction with cluster of differentiation 44 (CD44), a non-kinase transmembrane glycoprotein, among other hyaladherins. CD44 expression is elevated in many solid tumors, and its interaction with HA is associated with cancer and angiogenesis. Despite efforts to inhibit HA-CD44 interaction, there has been limited progress in the development of small molecule inhibitors. As a contribution to this endeavour, we designed and synthesized a series of N-aryltetrahydroisoquinoline derivatives based on existing crystallographic data available for CD44 and HA. Hit 2e was identified within these structures for its antiproliferative effect against two CD44+ cancer cell lines, and two new analogs (5 and 6) were then synthesized and evaluated as CD44-HA inhibitors by applying computational and cell-based CD44 binding studies. Compound 2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-5-ol (5) has an EC50 value of 0.59 μM against MDA-MB-231 cells and is effective to disrupt the integrity of cancer spheroids and reduce the viability of MDA-MB-231 cells in a dose-dependent manner. These results suggest lead 5 as a promising candidate for further investigation in cancer treatment.

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KW - Cluster of differentiation 44

KW - Hyaluronic acid

KW - Molecular dynamics simulations

KW - Tetrahydroisoquinoline

KW - Three-dimensional cancer model evaluation

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JO - European Journal of Medicinal Chemistry

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N-aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: Design, synthesis, computational studies, and antitumor effect

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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