Design, synthesis, and in vitro evaluation of BP-1-102 analogs with modified hydrophobic fragments for STAT3 inhibition.

Abstract

Twelve novel analogs of STAT3 inhibitor BP-1-102 were designed and synthesised with the aim to modify hydrophobic fragments of the molecules that are important for interaction with the STAT3 SH2 domain. The cytotoxic activity of the reference and novel compounds was evaluated using several human and two mouse cancer cell lines. BP-1-102 and its two analogs emerged as effective cytotoxic agents and were further tested in additional six human and two murine cancer cell lines, in all of which they manifested the cytotoxic effect in a micromolar range. Reference compound S3I-201.1066 was found ineffective in all tested cell lines, in contrast to formerly published data. The ability of selected BP-1-102 analogs to induce apoptosis and inhibition of STAT3 receptor-mediated phosphorylation was confirmed. The structure-activity relationship confirmed a demand for two hydrophobic substituents, i.e. the pentafluorophenyl moiety and another spatially bulky moiety, for effective cytotoxic activity and STAT3 inhibition.

• Authors: Patrik Oleksak, Miroslav Psotka, Marketa Vancurova, Olena Sapega, Jana Bieblova, Milan Reinis, David Rysanek, Romana Mikyskova, Katarina Chalupova, David Malinak, Jana Svobodova, Rudolf Andrys, Helena Rehulkova, Vojtech Skopek, Pham Ngoc Lam, Jiri Bartek, Zdenek Hodny, Kamil Musilek
• Journal: Journal of enzyme inhibition and medicinal chemistry (J Enzyme Inhib Med Chem) Vol. 36 Issue 1 Pg. 410-424 (Dec 2021) ISSN: 1475-6374 [Electronic] England
• PMID: 33440995 (Publication Type: Journal Article)

Chemical References

• Aminosalicylic Acids
• Antineoplastic Agents
• BP-1-102
• STAT3 Transcription Factor
• STAT3 protein, human
• Sulfonamides

Topics

• Aminosalicylic Acids (chemical synthesis, chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Drug Design
• Humans
• Hydrophobic and Hydrophilic Interactions
• Mice
• Mice, Inbred C57BL
• Molecular Structure
• Phosphorylation (drug effects)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Sulfonamides (chemical synthesis, chemistry, pharmacology)