Synthesis and antitumoral activity of novel biaryl hydroxy-triazole and fluorene-triazole hybrids

Abstract

Aim: The development of selective and potent antitumor agents remains a significant challenge. This study aimed to synthesize and evaluate biaryl hydroxy-1,2,3-triazoles and 9H-fluorene-1,2,3-triazole hybrids, inspired by previously identified bioactive 1,2,3-triazoles, for their cytotoxic potential against human cancer cell lines.

Methods: A library of 13 biaryl hydroxy-1,2,3-triazoles and 11 fluorene-1,2,3-triazoles was synthesized using optimized Suzuki and telescopic one-pot reactions, with yields ranging from 16% to 97%. The cytotoxicity of these compounds was tested against HCT-116 (colorectal cancer), SNB-19 (astrocytoma), MDA-MB-231 (triple-negative breast cancer), and MOLM-13 (acute myeloid leukemia, FLT3-ITD mutant) cell lines.

Results: Two fluorene-triazoles, 1-(2-bromophenyl)-4-(9H-fluoren-9-yl)-1H-1,2,3-triazole (LSO258) and 1-(4-bromophenyl)-4-(2-fluoro-9H-fluoren-9-yl)-1H-1,2,3-triazole (LSO272), both containing bromine substituents, exhibited selective cytotoxicity against MOLM-13, with half-maximal inhibitory concentration (IC₅₀) values of 25.5 μM and 12.5 μM, respectively. Furthermore, LSO258 and LS0272 showed a selectivity index ≥ 2 towards the MOLM-13 cell line. Biaryl hydroxy-1,2,3-triazoles displayed broader activity, with [1,1’-biphenyl]-2-yl(1-(2,5-dibromophenyl)-1H-1,2,3-triazol-4-yl)methanol (LSO278), featuring two bromine groups, demonstrating potency across HCT-116, MDA-MB-231, and MOLM-13 (IC₅₀: 23.4 μM, 34.3 μM, and 18.7 μM, respectively). However, structural rigidity did not consistently predict activity, as 1-(2,5-dibromophenyl)-4-(9H-fluoren-9-yl)-1H-1,2,3-triazole (LSO275), a rigid fluorene-triazole, was inactive. MOLM-13 was the most sensitive cell line, with compounds such as 4-(9H-fluoren-9-yl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazole (LSO259) and (1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)(4’-fluoro-[1,1’-biphenyl]-2-yl)methanol (LSO280), achieving maximum growth inhibition (MGI > 55%) despite not reaching IC₅₀ values.

Conclusions: The results highlight the critical role of bromine substitution on the aryl azide-derived ring in modulating cytotoxic activity. The study reinforces the potential of rigid fluorene-based scaffolds as promising leads for the development of targeted therapies against FLT3-mutant leukemia, aligning with previous reports on 1,2,3-triazole hybrids antiproliferative activity in leukemia models.

Keywords

1,2,3-Triazole / 9H-fluorene / cycloaddition / enaminone / leukemia / cancer

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