Hydroxynaphthalenecarboxamides and substituted
piperazinylpropandiols, two new series of BRAF inhibitors. A
theoretical and experimental study

J 2020

Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study

CAMPOS, L.E., F. GARIBOTTO, E. ANGELINA, J. KOS, Tomáš GONĚC et. al.

Basic information

Original name

Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study

Authors

CAMPOS, L.E., F. GARIBOTTO, E. ANGELINA, J. KOS, Tomáš GONĚC (203 Czech Republic, belonging to the institution), Pavlína MARVANOVÁ (203 Czech Republic, belonging to the institution), M. VETTORAZZI, M. ORAVEC, I. JENDRZEJEWSKA, J. JAMPILEK, S.E. ALVAREZ (guarantor) and R.D. ENRIZ

Edition

Bioorganic Chemistry, SAN DIEGO, ACADEMIC PRESS INC ELSEVIER SCIENCE, 2020, 0045-2068

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30104 Pharmacology and pharmacy

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 5.275

RIV identification code

RIV/00216224:14160/20:00116795

Organization unit

Faculty of Pharmacy

DOI

http://dx.doi.org/10.1016/j.bioorg.2020.104145

UT WoS

000575790500004

Keywords in English

BRAF inhibitors; Melanoma; Molecular modeling; Cell viability; ERK phosphorylation

Abstract

V originále

The oncogenic mutated kinase BRAF(V600E) is an attractive molecular target because it is expressed in several human cancers, including melanoma. To present, only three BRAF small inhibitors are approved by the FDA for the treatment of patients with metastatic melanoma: Vemurafenib, Dabrafenib and Encorafenib. Although many protocol treatments have been probed in clinical trials, BRAF inhibition has a limited effectiveness because patients invariably develop resistance and secondary toxic effects associated with the therapy. These limitations highlight the importance of designing new and better inhibitors with different structures that could establish different interactions in the active site of the enzyme and therefore decrease resistance progress. Considering the data from our previous report, here we studied two series of derivatives of structural scaffolds as potential BRAF inhibitors: hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols. Our results indicate that structural analogues of substituted piperazinylpropandiols do not show significantly better activities to that previously reported. In contrast, the hydroxynaphthalenecarboxamides derivatives significantly inhibited cell viability and ERK phosphorylation, a measure of BRAF activity, in Lul 205 BRAF(V600E) melanoma cells. In order to better understand these experimental results, we carried out a molecular modeling study using different combined techniques: docking, MD simulations and quantum theory of atoms in molecules (QTAIM) calculations. Thus, by using this approach we determined that the molecular interactions that stabilize the different molecular complexes are closely related to Vemurafenib, a well-documented BRAF inhibitor. Furthermore, we found that bi-substituted compounds may interact more strongly respect to the mono-substituted analogues, by establishing additional interactions with the DFG-loop at the BRAF-active site. On the bases of these results we synthesized and tested a new series of hydroxynaphthalenecarboxamides bi-substituted. Remarkably, all these compounds displayed significant inhibitory effects on the bioassays performed. Thus, the structural information reported here is important for the design of new BRAF(V600E) inhibitors possessing this type of structural scaffold.

Citovat

CAMPOS, L.E., F. GARIBOTTO, E. ANGELINA, J. KOS, Tomáš GONĚC, Pavlína MARVANOVÁ, M. VETTORAZZI, M. ORAVEC, I. JENDRZEJEWSKA, J. JAMPILEK, S.E. ALVAREZ and R.D. ENRIZ. Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study. Bioorganic Chemistry. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE, 2020, vol. 103, No 104145, p. 1-13. ISSN 0045-2068. Available from: https://dx.doi.org/10.1016/j.bioorg.2020.104145.

@article{1688616,
   author = {Campos, L.E. and Garibotto, F. and Angelina, E. and Kos, J. and Goněc, Tomáš and Marvanová, Pavlína and Vettorazzi, M. and Oravec, M. and Jendrzejewska, I. and Jampilek, J. and Alvarez, S.E. and Enriz, R.D.},
   article_location = {SAN DIEGO},
   article_number = {104145},
   doi = {http://dx.doi.org/10.1016/j.bioorg.2020.104145},
   keywords = {BRAF inhibitors; Melanoma; Molecular modeling; Cell viability; ERK phosphorylation},
   language = {eng},
   issn = {0045-2068},
   journal = {Bioorganic Chemistry},
   title = {Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study},
   url = {https://www.sciencedirect.com/science/article/pii/S0045206820314425},
   volume = {103},
   year = {2020}
}

TY  - JOUR
ID  - 1688616
AU  - Campos, L.E. - Garibotto, F. - Angelina, E. - Kos, J. - Goněc, Tomáš - Marvanová, Pavlína - Vettorazzi, M. - Oravec, M. - Jendrzejewska, I. - Jampilek, J. - Alvarez, S.E. - Enriz, R.D.
PY  - 2020
TI  - Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study
JF  - Bioorganic Chemistry
VL  - 103
IS  - 104145
SP  - 1-13
EP  - 1-13
PB  - ACADEMIC PRESS INC ELSEVIER SCIENCE
SN  - 00452068
KW  - BRAF inhibitors
KW  - Melanoma
KW  - Molecular modeling
KW  - Cell viability
KW  - ERK phosphorylation
UR  - https://www.sciencedirect.com/science/article/pii/S0045206820314425
L2  - https://www.sciencedirect.com/science/article/pii/S0045206820314425
N2  - The oncogenic mutated kinase BRAF(V600E) is an attractive molecular target because it is expressed in several human cancers, including melanoma. To present, only three BRAF small inhibitors are approved by the FDA for the treatment of patients with metastatic melanoma: Vemurafenib, Dabrafenib and Encorafenib. Although many protocol treatments have been probed in clinical trials, BRAF inhibition has a limited effectiveness because patients invariably develop resistance and secondary toxic effects associated with the therapy. These limitations highlight the importance of designing new and better inhibitors with different structures that could establish different interactions in the active site of the enzyme and therefore decrease resistance progress. Considering the data from our previous report, here we studied two series of derivatives of structural scaffolds as potential BRAF inhibitors: hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols. Our results indicate that structural analogues of substituted piperazinylpropandiols do not show significantly better activities to that previously reported. In contrast, the hydroxynaphthalenecarboxamides derivatives significantly inhibited cell viability and ERK phosphorylation, a measure of BRAF activity, in Lul 205 BRAF(V600E) melanoma cells. In order to better understand these experimental results, we carried out a molecular modeling study using different combined techniques: docking, MD simulations and quantum theory of atoms in molecules (QTAIM) calculations. Thus, by using this approach we determined that the molecular interactions that stabilize the different molecular complexes are closely related to Vemurafenib, a well-documented BRAF inhibitor. Furthermore, we found that bi-substituted compounds may interact more strongly respect to the mono-substituted analogues, by establishing additional interactions with the DFG-loop at the BRAF-active site. On the bases of these results we synthesized and tested a new series of hydroxynaphthalenecarboxamides bi-substituted. Remarkably, all these compounds displayed significant inhibitory effects on the bioassays performed. Thus, the structural information reported here is important for the design of new BRAF(V600E) inhibitors possessing this type of structural scaffold.
ER  -

CAMPOS, L.E., F. GARIBOTTO, E. ANGELINA, J. KOS, Tomáš GONĚC, Pavlína MARVANOVÁ, M. VETTORAZZI, M. ORAVEC, I. JENDRZEJEWSKA, J. JAMPILEK, S.E. ALVAREZ and R.D. ENRIZ. Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study. \textit{Bioorganic Chemistry}. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE, 2020, vol.~103, No~104145, p.~1-13. ISSN~0045-2068. Available from: https://dx.doi.org/10.1016/j.bioorg.2020.104145.

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