Design, Synthesis, and Pharmacological Evaluation of First-in-Class Multitarget N-Acylhydrazone Derivatives as Selective HDAC6/8 and PI3Kα Inhibitors

Daniel A Rodrigues; Fabiana S Guerra; Fernanda S Sagrillo; Pedro de Sena M Pinheiro; Marina A Alves; Sreekanth Thota; Lorrane S Chaves; Carlos M R Sant'Anna; Patrícia D Fernandes; Carlos A M Fraga

doi:10.1002/cmdc.201900716

Design, Synthesis, and Pharmacological Evaluation of First-in-Class Multitarget N-Acylhydrazone Derivatives as Selective HDAC6/8 and PI3Kα Inhibitors

ChemMedChem. 2020 Mar 18;15(6):539-551. doi: 10.1002/cmdc.201900716. Epub 2020 Feb 17.

Authors

Daniel A Rodrigues^{1

2}, Fabiana S Guerra³, Fernanda S Sagrillo¹, Pedro de Sena M Pinheiro^{1

4}, Marina A Alves⁵, Sreekanth Thota¹, Lorrane S Chaves^{1

4}, Carlos M R Sant'Anna^{1

6}, Patrícia D Fernandes³, Carlos A M Fraga^{1

2

4}

Affiliations

¹ Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, PO Box 68023, 21941-902, Rio de Janeiro, RJ, Brazil.
² Programa de Pós-Graduação em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, 21941-909, Rio de Janeiro, RJ, Brazil.
³ Laboratório de Farmacologia da Dor e da Inflamação, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
⁴ Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
⁵ Laboratório de Apoio ao Desenvolvimento Tecnológico (LADETEC), Instituto de Química, Avenida Horácio Macedo, 1281, Polo de Química, Bloco C, Cidade Universitária, 21941-598, Rio de Janeiro, RJ, Brazil.
⁶ Departamento de Química, Instituto de Ciências Exatas, Universidade Federal Rural do Rio de Janeiro, 23970-000, Seropédica, RJ, Brazil.

PMID: 32022441
DOI: 10.1002/cmdc.201900716

Abstract

Targeting histone deacetylases (HDACs) and phosphatidylinositol 3-kinases (PI3Ks) is a very promising approach for cancer treatment. This manuscript describes the design, synthesis, in vitro pharmacological profile, and molecular modeling of a novel class of N-acylhydrazone (NAH) derivatives that act as HDAC6/8 and PI3Kα dual inhibitors. The surprising selectivity for PI3Kα may be related to differences in the conformation in the active site. Cellular studies showed that these compounds act in HDAC6 inhibition and the PI3/K/AKT/mTOR pathway. The compounds that are selective for inhibition of HDAC6/8 and inhibit PI3Kα show potential for the treatment of cancer.

Keywords: HDAC6; N-acylhydrazone; PI3Kα; cancer; multitarget inhibitors..

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Drug Design
Histone Deacetylase 6 / antagonists & inhibitors*
Histone Deacetylase 6 / metabolism
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / metabolism
Humans
Hydrazones / chemical synthesis
Hydrazones / chemistry
Hydrazones / pharmacology*
Models, Molecular
Molecular Structure
Phosphatidylinositol 3-Kinases / metabolism*
Phosphoinositide-3 Kinase Inhibitors / chemical synthesis
Phosphoinositide-3 Kinase Inhibitors / chemistry
Phosphoinositide-3 Kinase Inhibitors / pharmacology*
Repressor Proteins / antagonists & inhibitors*
Repressor Proteins / metabolism
Tumor Cells, Cultured

Substances

Histone Deacetylase Inhibitors
Hydrazones
Phosphoinositide-3 Kinase Inhibitors
Repressor Proteins
HDAC6 protein, human
HDAC8 protein, human
Histone Deacetylase 6
Histone Deacetylases