Structural expansion of benzimidazole-based FLAP inhibitors: identification of dual-action agents targeting leukotriene biosynthesis and Cancer cell proliferation
Bioorganic and Medicinal Chemistry, cilt.144, 2027 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 144
- Basım Tarihi: 2027
- Doi Numarası: 10.1016/j.bmc.2026.118831
- Dergi Adı: Bioorganic and Medicinal Chemistry
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, Chimica, EMBASE, MEDLINE, Academic Search Ultimate (EBSCO)
- Anahtar Kelimeler: Benzimidazole, Cancer, Cytotoxicity, Inflammation, Leukotriene
- Gazi Üniversitesi Adresli: Evet
Özet
The 5-lipoxygenase-activating protein (FLAP) is an essential regulator of leukotriene (LT) biosynthesis, a pathway implicated in both chronic inflammation and tumor progression. Building on our benzimidazole lead, whose FLAP potency was compromised by prior structural modifications, we systematically remodeled the scaffold at the C(5) and C(2) positions to define the precise steric, electronic and polarity requirements for cellular FLAP inhibition. A structurally diverse library of derivatives was synthesized and evaluated in intact human polymorphonuclear leukocytes. Structure-activity relationship analysis revealed that conventional aromatic motifs within the address region are fully replaceable by polar, sterically hindered aliphatic substituents, yielding highly potent FLAP inhibitors. Conversely, the core bioisostere region proved considerably more restrictive, strongly favoring the parent aliphatic motif and tolerating only neutral, non-basic replacements. Comprehensive lipid mediator profiling in primary human leukocytes and distinct macrophage phenotypes confirmed that the optimized analogues selectively suppress FLAP-dependent leukotrienes while leaving alternative arachidonic acid metabolic pathways largely unaffected. Parallel screening against glioblastoma, breast, and colon carcinoma lines uncovered an additional, independent antiproliferative activity intrinsic to the benzimidazole scaffold. Several analogues successfully combined robust cellular FLAP inhibition with significant growth inhibition, particularly against colon cancer cells. Because antiproliferative efficacy did not correlate with FLAP inhibition across the series, the data establish that these complementary pharmacological activities are mechanistically distinct and independently tunable. Ultimately, these dual-action agents offer a promising novel chemotype for modulating the pro-inflammatory tumor microenvironment, providing a clear foundation for future mechanistic investigations to identify their specific distinct anticancer targets.