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Novel unit B cryptophycin analogues as payloads for targeted therapy

Cryptophycins are naturally occurring cytotoxins with great potential for chemotherapy. Since targeted therapy provides new perspectives for treatment of cancer, new potent analogues of cytotoxic agents containing functional groups for conjugation to homing devices are required. We describe the desi...

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Detalles Bibliográficos
Autores principales: Figueras, Eduard, Borbély, Adina, Ismail, Mohamed, Frese, Marcel, Sewald, Norbert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Beilstein-Institut 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009196/
https://www.ncbi.nlm.nih.gov/pubmed/29977395
http://dx.doi.org/10.3762/bjoc.14.109
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author Figueras, Eduard
Borbély, Adina
Ismail, Mohamed
Frese, Marcel
Sewald, Norbert
author_facet Figueras, Eduard
Borbély, Adina
Ismail, Mohamed
Frese, Marcel
Sewald, Norbert
author_sort Figueras, Eduard
collection PubMed
description Cryptophycins are naturally occurring cytotoxins with great potential for chemotherapy. Since targeted therapy provides new perspectives for treatment of cancer, new potent analogues of cytotoxic agents containing functional groups for conjugation to homing devices are required. We describe the design, synthesis and biological evaluation of three new unit B cryptophycin analogues. The O-methyl group of the unit B D-tyrosine analogue was replaced by an O-(allyloxyethyl) moiety, an O-(hydroxyethyl) group, or an O-(((azidoethoxy)ethoxy)ethoyxethyl) substituent. While the former two maintain cytotoxicity in the subnanomolar range, the attachment of the triethylene glycol spacer with a terminal azide results in a complete loss of activity. Docking studies of the novel cryptophycin analogues to β-tubulin provided a rationale for the observed cytotoxicities.
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spelling pubmed-60091962018-07-05 Novel unit B cryptophycin analogues as payloads for targeted therapy Figueras, Eduard Borbély, Adina Ismail, Mohamed Frese, Marcel Sewald, Norbert Beilstein J Org Chem Full Research Paper Cryptophycins are naturally occurring cytotoxins with great potential for chemotherapy. Since targeted therapy provides new perspectives for treatment of cancer, new potent analogues of cytotoxic agents containing functional groups for conjugation to homing devices are required. We describe the design, synthesis and biological evaluation of three new unit B cryptophycin analogues. The O-methyl group of the unit B D-tyrosine analogue was replaced by an O-(allyloxyethyl) moiety, an O-(hydroxyethyl) group, or an O-(((azidoethoxy)ethoxy)ethoyxethyl) substituent. While the former two maintain cytotoxicity in the subnanomolar range, the attachment of the triethylene glycol spacer with a terminal azide results in a complete loss of activity. Docking studies of the novel cryptophycin analogues to β-tubulin provided a rationale for the observed cytotoxicities. Beilstein-Institut 2018-06-01 /pmc/articles/PMC6009196/ /pubmed/29977395 http://dx.doi.org/10.3762/bjoc.14.109 Text en Copyright © 2018, Figueras et al. https://creativecommons.org/licenses/by/4.0https://www.beilstein-journals.org/bjoc/termsThis is an Open Access article under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (https://www.beilstein-journals.org/bjoc/terms)
spellingShingle Full Research Paper
Figueras, Eduard
Borbély, Adina
Ismail, Mohamed
Frese, Marcel
Sewald, Norbert
Novel unit B cryptophycin analogues as payloads for targeted therapy
title Novel unit B cryptophycin analogues as payloads for targeted therapy
title_full Novel unit B cryptophycin analogues as payloads for targeted therapy
title_fullStr Novel unit B cryptophycin analogues as payloads for targeted therapy
title_full_unstemmed Novel unit B cryptophycin analogues as payloads for targeted therapy
title_short Novel unit B cryptophycin analogues as payloads for targeted therapy
title_sort novel unit b cryptophycin analogues as payloads for targeted therapy
topic Full Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009196/
https://www.ncbi.nlm.nih.gov/pubmed/29977395
http://dx.doi.org/10.3762/bjoc.14.109
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