Identification of Lead Compounds as Inhibitors of STAT3: Design, Synthesis and Bioactivity

Antonio Botta; Esther Sirignano; Ada Popolo; Carmela Saturnino; Stefania Terracciano; Antonio Foglia; Maria Stefania Sinicropi; Pasquale Longo; Simone Di Micco

doi:10.1002/minf.201500043

Identification of Lead Compounds as Inhibitors of STAT3: Design, Synthesis and Bioactivity

Mol Inform. 2015 Oct;34(10):689-97. doi: 10.1002/minf.201500043. Epub 2015 Jul 1.

Authors

Antonio Botta¹, Esther Sirignano¹, Ada Popolo¹, Carmela Saturnino², Stefania Terracciano¹, Antonio Foglia¹, Maria Stefania Sinicropi³, Pasquale Longo⁴, Simone Di Micco⁵

Affiliations

¹ Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Salerno, Italy phone/fax: +39 089969176 (S. D. M.); +39 089969769 (C. S.); +39 089969602 (fax).
² Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Salerno, Italy phone/fax: +39 089969176 (S. D. M.); +39 089969769 (C. S.); +39 089969602 (fax). saturnino@unisa.it.
³ Dipartimento di Chimica e Biologia, Università degli Studi di Salerno Via Giovanni Paolo II 132, 84084 Fisciano, Salerno, Italy.
⁴ Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Università della Calabria, 87036 Arcavacata di Rende, Cosenza, Italy.
⁵ Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Salerno, Italy phone/fax: +39 089969176 (S. D. M.); +39 089969769 (C. S.); +39 089969602 (fax). sdimicco@unisa.it.

PMID: 27490969
DOI: 10.1002/minf.201500043

Abstract

STAT3 belongs to the signal transducers and activators of transcription (STAT) family. It has been demonstrated that STAT3 is constitutively activated in many tumors, playing a role in carcinogenesis and tumor progression. For this reason, it has being considered a potential target for cancer therapy. In this context, we have designed, synthesized and evaluated 1,4-dimethyl-carbazole derivatives, targeting the STAT3 protein. Moreover, MTT assay performed on A375 and HeLa, showed significant antiproliferative activity of some of synthesized compounds (3-5). The same compounds (3-5) considerably reduced STAT3 expression, as demonstrated by Western blot analysis. Our multidisciplinary approach shows that 1,4-dimethyl-carbazoles are potential building blocks to develop more affinity ligands of STAT3.

Keywords: 1,4-dimethyl-carbazoles; Antitumor compound; Molecular docking; STAT3; STAT3 inhibitor.

MeSH terms

Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Carbazoles* / chemical synthesis
Carbazoles* / chemistry
Carbazoles* / pharmacology
Cell Proliferation / drug effects*
HeLa Cells
Humans
Lead* / chemistry
Lead* / pharmacology
Neoplasm Proteins* / antagonists & inhibitors
Neoplasm Proteins* / chemistry
Neoplasm Proteins* / metabolism
Neoplasms* / chemistry
Neoplasms* / drug therapy
Neoplasms* / metabolism
STAT3 Transcription Factor* / antagonists & inhibitors
STAT3 Transcription Factor* / chemistry
STAT3 Transcription Factor* / metabolism

Substances

Antineoplastic Agents
Carbazoles
Neoplasm Proteins
STAT3 Transcription Factor
STAT3 protein, human
Lead