Steroid sulfatase inhibitors based on sulfamated derivatives of 4-(1-phenyl-1H-[1,2,3]triazol-4-yl)-phenol as potential anticancer agents

Cancer disease is one of the most common cause of death worldwide. Interestingly, most of the types of cancer demonstrated hormone-dependent nature (e.g., approximately 90% of breast cancer depends on hormones). Therefore, The World Health Organization lists active hormones as major factors responsible for tumor growth induction. The biosynthesis process of active steroids (e.g., estradiol) depends on a few enzymatic pathway, e.g., steroid sulfatase (STS). In the light of the recent studies, STS became a new and interesting molecular target in the treatment of hormone-dependent cancers. This project will realize the next research on novel STS inhibitors based on sulfamated derivatives of 4-(1-phenyl-1H-[1,2,3]triazol-4-yl)-phenol, which were obtained during implementation of PRELUDIUM grant (2015/19/N/NZ7/00938). The basic research indicated that abovementioned compounds are able to inhibit the activity of STS much more effectively than Irosustat – STS inhibitors evaluated in clinical trials. Furthermore, abovementioned compounds occurred to be effective in in vivo studies indicating high anticancer activity and no-toxicity what make them very promising drug candidates in treatment of hormone-dependent cancers. In the course of realization this project we plan to perform conceptual and development work: - providing patent protection for the abovementioned compounds - promotion of obtained results in the world, - performing activities aimed at acquiring a business partner, - performing research on physicochemical properties of sulfamated derivatives of 4-(1-phenyl-1H-[1,2,3]triazol-4-yl)-phenol – determination of logP, pKa parameters, as well as solubility and stability in aqueous solution, - performing research on polymorphic forms and complexing properties to metal ions (mainly calcium).

Details

Financial Program Name:

TANGO

Organization:

Narodowe Centrum Badań i Rozwoju (NCBR) (The National Centre for Research and Development)

Agreement:

TANGO-IV-A/0004/2019-00 z dnia 2020-08-28

Realisation period:

2020-10-01 - 2022-12-31

Project manager:

dr inż. Mateusz Daśko

Team members:

Contractor dr hab. inż. Sebastian Demkowicz
Head dr inż. Mateusz Daśko

Realised in:

Department of Inorganic Chemistry

Project's value:

250 000.00 PLN

Request type:

National Research Programmes

Domestic:

Domestic project

Verified by:

Gdańsk University of Technology

Papers associated with that project

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total: 3

Year 2022

Development of Sulfamoylated 4‑(1-Phenyl‑1H‑1,2,3-triazol-4-yl)phenol Derivatives as Potent Steroid Sulfatase Inhibitors for Efficient Treatment of Breast Cancer
Publication
- K. Biernacki
- O. Ciupak
- M. Daśko
- J. Rachoń (formerly: J. Rachon)
- W. Kozak
- J. Rak
- K. Kubiński
- M. Masłyk
- A. Martyna
- M. Śliwka-Kaszyńska... and 5 others
- JOURNAL OF MEDICINAL CHEMISTRY - Year 2022
We present here the advances achieved in the development of new sulfamoylated 4-(1-phenyl-1H-1,2,3-triazol-4-yl)phenol derivatives as potent steroid sulfatase (STS) inhibitors for the treatment of breast cancer. Prompted by promising biological results and in silico analysis, the initial series of similar compounds were extended, appending a variety of m-substituents at the outer phenyl ring. The inhibition profiles of the newly...

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Year 2021

New potent steroid sulphatase inhibitors based on 6-(1-phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives
Publication
- O. Ciupak
- M. Daśko
- K. Biernacki
- J. Rachoń
- M. Masłyk
- K. Kubiński
- A. Martyna
- S. Demkowicz
- JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY - Year 2021
In the present work, we report a new class of potent steroid sulphatase (STS) inhibitors based on 6-(1-phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives. Within the set of new STS inhibitors, 6-(1-(1,2,3-trifluorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate 3L demonstrated the highest activity in the enzymatic assay inhibiting the STS activity to 7.98% at 0.5 µM concentration. Furthermore, to verify...

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Novel 1,2,3-Triazole Derivatives as Mimics of Steroidal System—Synthesis, Crystal Structures Determination, Hirshfeld Surfaces Analysis and Molecular Docking
Publication
- MOLECULES - Year 2021
Herein, we present the synthesis and crystal structures determination of five 4-(1-phenyl-1H-1,2,3-triazol-4-yl)phenol derivatives containing halogen atoms, 6a–e, which may be used as an excellent mimic of steroids in the drug development process. Good quality crystals obtained for all of the synthesized compounds allowed the analysis of their molecular structures. Subsequently, the determined crystal structures were used to calculate...

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