Aryl azoles based scaffolds for disrupting tumor microenvironment

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• The tumor microenvironment (TME) plays a critical role in cancer progression and immune evasion.
• Targeting TME components offers a promising strategy for novel cancer therapies.
• Azole derivatives are a class of compounds with diverse biological activities.

Purpose of the Study:

• To synthesize and evaluate novel aryl azoles, triazoles, and tetrazoles as potential TME disruptors.
• To assess the antiproliferative effects of these compounds on various cancer cell lines.
• To investigate the impact of lead compounds on specific TME-related molecular targets and cellular processes.

Main Methods:

• Synthesis of 39 aryl azoles, 13 triazoles, and 27 tetrazoles.
• Antiproliferative assays on HT-29, A-549, MCF-7 (tumor), and HEK-293 (non-tumor) cell lines.
• Evaluation of PD-L1, CD-47, c-Myc, and VEGFR-2 expression in HT-29 cells.
• Co-culture studies with HT-29 and THP-1 monocytes to assess antiproliferative activity and IL-6 secretion.
• Angiogenesis and vasculogenic mimicry assays on HMEC-1 and HEK-293 cells, respectively.

Main Results:

• Compounds with an amino group on the phenyl ring and a halogen on the benzyl ring demonstrated significant TME-disrupting activity.
• The most potent compound markedly reduced HT-29 cell populations in co-culture with THP-1 monocytes.
• This lead compound also significantly decreased IL-6 secretion and showed moderate effects on PD-L1, CD-47, and c-Myc expression.
• Selected compounds exhibited anti-angiogenic and anti-vasculogenic mimicry effects.

Conclusions:

• Novel azole derivatives show promise as agents for disrupting the tumor microenvironment.
• The identified lead compound exhibits potent anti-cancer effects by modulating TME components and cellular crosstalk.
• Further investigation of these compounds could lead to the development of new cancer therapeutics targeting the TME.