Synthesis of novel purpurealidin analogs and evaluation of their effect on the cancer-relevant potassium channel KV10.1

Lien Moreels, Chinmaya Bhat, Manuela Voráčová, Steve Peigneur, Hannah Goovaerts, Eero Mäki-Lohiluoma, Farrah Zahed, Luis A. Pardo, Jari Tapani Yli-Kauhaluoma, Paula Sinikka Kiuru, Jan Tytgat

Research output: Contribution to journalArticleScientificpeer-review

Abstract

In the search for novel anticancer drugs, the potassium channel K(V)10.1 has emerged as an interesting cancer target. Here, we report a new group of K(V)10.1 inhibitors, namely the purpurealidin analogs. These alkaloids are produced by the Verongida sponges and are known for their wide variety of bioactivities. In this study, we describe the synthesis and characterization of 27 purpurealidin analogs. Structurally, bromine substituents at the central phenyl ring and a methoxy group at the distal phenyl ring seem to enhance the activity on K(V)10.1. The mechanism of action of the most potent analog 5 was investigated. A shift of the activation curve to more negative potentials and an apparent inactivation was observed. Since K(V)10.1 inhibitors can be interesting anticancer drug lead compounds, the effect of 5 was evaluated on cancerous and non-cancerous cell lines. Compound 5 showed to be cytotoxic and appeared to induce apoptosis in all the evaluated cell lines.
Original languageEnglish
Article number0188811
JournalPLoS One
Volume12
Issue number12
Number of pages18
ISSN1932-6203
DOIs
Publication statusPublished - 8 Dec 2017
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 317 Pharmacy
  • SPONGE PSAMMAPLYSILLA-PURPU REA
  • MARINE SPONGE
  • BROMOTYROSINE ALKALOIDS
  • CANCER
  • METABOLITES
  • APOPTOSIS
  • CELLS

Cite this

Moreels, L., Bhat, C., Voráčová, M., Peigneur, S., Goovaerts, H., Mäki-Lohiluoma, E., ... Tytgat, J. (2017). Synthesis of novel purpurealidin analogs and evaluation of their effect on the cancer-relevant potassium channel KV10.1. PLoS One, 12(12), [0188811]. https://doi.org/10.1371/journal.pone.0188811
Moreels, Lien ; Bhat, Chinmaya ; Voráčová, Manuela ; Peigneur, Steve ; Goovaerts, Hannah ; Mäki-Lohiluoma, Eero ; Zahed, Farrah ; Pardo, Luis A. ; Yli-Kauhaluoma, Jari Tapani ; Kiuru, Paula Sinikka ; Tytgat, Jan. / Synthesis of novel purpurealidin analogs and evaluation of their effect on the cancer-relevant potassium channel KV10.1. In: PLoS One. 2017 ; Vol. 12, No. 12.
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title = "Synthesis of novel purpurealidin analogs and evaluation of their effect on the cancer-relevant potassium channel KV10.1",
abstract = "In the search for novel anticancer drugs, the potassium channel K(V)10.1 has emerged as an interesting cancer target. Here, we report a new group of K(V)10.1 inhibitors, namely the purpurealidin analogs. These alkaloids are produced by the Verongida sponges and are known for their wide variety of bioactivities. In this study, we describe the synthesis and characterization of 27 purpurealidin analogs. Structurally, bromine substituents at the central phenyl ring and a methoxy group at the distal phenyl ring seem to enhance the activity on K(V)10.1. The mechanism of action of the most potent analog 5 was investigated. A shift of the activation curve to more negative potentials and an apparent inactivation was observed. Since K(V)10.1 inhibitors can be interesting anticancer drug lead compounds, the effect of 5 was evaluated on cancerous and non-cancerous cell lines. Compound 5 showed to be cytotoxic and appeared to induce apoptosis in all the evaluated cell lines.",
keywords = "317 Pharmacy, SPONGE PSAMMAPLYSILLA-PURPU REA, MARINE SPONGE , BROMOTYROSINE ALKALOIDS , CANCER , METABOLITES , APOPTOSIS , CELLS",
author = "Lien Moreels and Chinmaya Bhat and Manuela Vor{\'a}čov{\'a} and Steve Peigneur and Hannah Goovaerts and Eero M{\"a}ki-Lohiluoma and Farrah Zahed and Pardo, {Luis A.} and Yli-Kauhaluoma, {Jari Tapani} and Kiuru, {Paula Sinikka} and Jan Tytgat",
year = "2017",
month = "12",
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volume = "12",
journal = "PLoS One",
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Moreels, L, Bhat, C, Voráčová, M, Peigneur, S, Goovaerts, H, Mäki-Lohiluoma, E, Zahed, F, Pardo, LA, Yli-Kauhaluoma, JT, Kiuru, PS & Tytgat, J 2017, 'Synthesis of novel purpurealidin analogs and evaluation of their effect on the cancer-relevant potassium channel KV10.1' PLoS One, vol. 12, no. 12, 0188811. https://doi.org/10.1371/journal.pone.0188811

Synthesis of novel purpurealidin analogs and evaluation of their effect on the cancer-relevant potassium channel KV10.1. / Moreels, Lien; Bhat, Chinmaya; Voráčová, Manuela; Peigneur, Steve; Goovaerts, Hannah; Mäki-Lohiluoma, Eero; Zahed, Farrah; Pardo, Luis A.; Yli-Kauhaluoma, Jari Tapani; Kiuru, Paula Sinikka; Tytgat, Jan.

In: PLoS One, Vol. 12, No. 12, 0188811, 08.12.2017.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Synthesis of novel purpurealidin analogs and evaluation of their effect on the cancer-relevant potassium channel KV10.1

AU - Moreels, Lien

AU - Bhat, Chinmaya

AU - Voráčová, Manuela

AU - Peigneur, Steve

AU - Goovaerts, Hannah

AU - Mäki-Lohiluoma, Eero

AU - Zahed, Farrah

AU - Pardo, Luis A.

AU - Yli-Kauhaluoma, Jari Tapani

AU - Kiuru, Paula Sinikka

AU - Tytgat, Jan

PY - 2017/12/8

Y1 - 2017/12/8

N2 - In the search for novel anticancer drugs, the potassium channel K(V)10.1 has emerged as an interesting cancer target. Here, we report a new group of K(V)10.1 inhibitors, namely the purpurealidin analogs. These alkaloids are produced by the Verongida sponges and are known for their wide variety of bioactivities. In this study, we describe the synthesis and characterization of 27 purpurealidin analogs. Structurally, bromine substituents at the central phenyl ring and a methoxy group at the distal phenyl ring seem to enhance the activity on K(V)10.1. The mechanism of action of the most potent analog 5 was investigated. A shift of the activation curve to more negative potentials and an apparent inactivation was observed. Since K(V)10.1 inhibitors can be interesting anticancer drug lead compounds, the effect of 5 was evaluated on cancerous and non-cancerous cell lines. Compound 5 showed to be cytotoxic and appeared to induce apoptosis in all the evaluated cell lines.

AB - In the search for novel anticancer drugs, the potassium channel K(V)10.1 has emerged as an interesting cancer target. Here, we report a new group of K(V)10.1 inhibitors, namely the purpurealidin analogs. These alkaloids are produced by the Verongida sponges and are known for their wide variety of bioactivities. In this study, we describe the synthesis and characterization of 27 purpurealidin analogs. Structurally, bromine substituents at the central phenyl ring and a methoxy group at the distal phenyl ring seem to enhance the activity on K(V)10.1. The mechanism of action of the most potent analog 5 was investigated. A shift of the activation curve to more negative potentials and an apparent inactivation was observed. Since K(V)10.1 inhibitors can be interesting anticancer drug lead compounds, the effect of 5 was evaluated on cancerous and non-cancerous cell lines. Compound 5 showed to be cytotoxic and appeared to induce apoptosis in all the evaluated cell lines.

KW - 317 Pharmacy

KW - SPONGE PSAMMAPLYSILLA-PURPU REA

KW - MARINE SPONGE

KW - BROMOTYROSINE ALKALOIDS

KW - CANCER

KW - METABOLITES

KW - APOPTOSIS

KW - CELLS

U2 - 10.1371/journal.pone.0188811

DO - 10.1371/journal.pone.0188811

M3 - Article

VL - 12

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 12

M1 - 0188811

ER -

Moreels L, Bhat C, Voráčová M, Peigneur S, Goovaerts H, Mäki-Lohiluoma E et al. Synthesis of novel purpurealidin analogs and evaluation of their effect on the cancer-relevant potassium channel KV10.1. PLoS One. 2017 Dec 8;12(12). 0188811. https://doi.org/10.1371/journal.pone.0188811