Correlation of structural features of novel 1,2,3-triazoles with their neurotoxic and tumoricidal properties

Abstract

Triazoles are interesting templates for novel chemotherapeutic drugs. We synthesized here 17 1,3,4-substituted-1,2,3-triazoles that differed in their 1'-substituent (variable alkyl chain lengths C3-C12), the 3'-substituent (no substituent, -methyl or -propyl) or the salt form obtained. Several of the compounds were cytotoxic (μM range) for tumor cells (HL-60, Jurkat, MCF-7, HCT-116), and when the effect was compared to non-transformed cells (Vero), selectivity ratios of up to 23-fold were obtained. To estimate the liability of these potential drug candidates for triggering neurotoxicity, we used the LUHMES cell-based NeuriTox assay. This test quantifies damage to the neurites of human neurons. The four most potent tumoricidal compounds were found to be neurotoxic in a concentration range similar to the one showing tumor cell toxicity. As the neurites of the LUHMES neurons were affected at >4-fold lower concentrations than the overall cell viability, the novel triazoles were classified as specific neurotoxicants. The structure-activity relationship (SAR) for neurotoxicity was sharply defined and correlated with the one for anti-neoplastic activity. Based on this SAR, two non-neurotoxic compounds were predicted, and testing in the NeuriTox assay confirmed this prediction. In summary, the panel of novel triazoles generated and characterized here, allowed to define structural features associated with cytotoxicity and neurotoxicity. Moreover, the study shows that potential neurotoxic side effects may be predicted early in drug development if highly sensitive test methods for neurite integrity are applied.

CuAAC-ensembled 1,2,3-triazole-linked isosteres as pharmacophores in drug discovery: review

“…The IC 50 value is below 10 mM for the cancer cell lines and for the non-tumor cell, IC 50 values were less than 100 mM. 51 Pyrazolo[3,4-d]pyrimidin-4(5H)-ones tied to 1,2,3-triazoles were synthesized with different substituents. Among the series of synthesized compounds, few were highly effective towards C6 glioma cell line and U87 cancer cell lines.…”

Synthesis and In Vitro Cytotoxicity and Antibacterial Activity of Novel 1,2,3-Triazol-5-yl-Phosphonates

“…After that, the domino reaction was performed with substituted benzyl azides (4-methylbenzyl azide 2-, 3-or 4-fluorobenzyl azide or 4-(trifluoromethyl)benzyl azide). Carrying out the reaction of phenylacetylene and 4-methylbenzyl azide with dimethyl-, diethyl-or dibutyl phosphite, the desired triazol-5-yl-phosphonates (16)(17)(18) could be isolated in yields of 40%, 52% and 42%, respectively. Finally the domino reaction of phenylacetylene, and dibutyl phosphite was also carried out with 2-, 3-or 4-fluorobenzyl azide or 4-(trifluoromethyl)benzyl azide, and the corresponding dibutyl (1-benzyl-4-phenyl-1H-1,2,3-triazol-5-yl)phosphonate derivatives (19)(20)(21)(22) were synthesized in yields of 30-39%.…”

“…Compounds containing the 1,2,3-triazole scaffold may have versatile biological activities, such as antibacterial, antiviral, antifungal, anticancer or anti-inflammatory effects [11][12][13]. Some novel triazole-based heterocycles showed activity against bacterial strains (Bacillus subtilis and Escherichia coli) [14][15][16], and in vitro cytotoxicity against tumor cell lines HL-60 (myeloid leukemia), MCF-7 (breast cancer), A549 (lung cancer) and HCT-116 (colon cancer) [17][18][19]. Furthermore, the unique structural properties of 1,2,3-triazoles enable the introduction of various functional groups obtaining new biologically active molecules.…”

“…(4-methylbenzyl)-4-phenyl-1,2,3-triazol-5-yl]phosphonate(17): yield: 52% (0.20 g), colorless oil;31 P NMR (CDCl 3 ) δ 4.3; 1 H NMR (CDCl 3 ) δ 0.99 (t, 6H, 3 J HH = 7.0, OCH 2 CH 3 ), 2.32 (s, 3H, PhCH 3 ), 3.58-3.72 (m, 2H, OCH 2 CH 3 ), 3.85-3.95 (m, 2H, OCH 2 CH 3 ), 6.00 (s, 2H, CH 2 Ph), 7.14 (d, 2H, 3 J HH = 7.8, C 3' H), 7.30 (d, 2H, 3 J HH = 8.0, C 2' H), 7.38-7.44 (m, 3H, C 3 H, C 4 H), 7.74 (dd, 2H, 3 J HH = 7.7, J HH = 2.0, C 2 H); 13 C NMR (CDCl 3 ) δ 15.9 (d, 3 J CP =7.0, OCH 2 CH 3 ), 21.2 (CH 3 Ph), 54.0 (CH 2 Ph), 63.1 (d, 2 J CP =5.1, OCH 2 CH 3 ), 121.5 (d, 1 J CP = 217.7, P(O)C=), 128.2 (C 2 ), 128.3 (C 2' ), 129.0 (C 1 ), 129.3 (C 3' ), 129.4 (C 3 ), 130.4 (C 4 ), 132.9 (C 1' ), 138.2 (C 4' ), 153.5 (d, 2 J CP = 19.1, PhC=); [M + H] + found = 386.1633, C 20 H 25 N 3 O 3 P requires 386.1628. Dibutyl [1-(4-methylbenzyl)-4-phenyl-1,2,3-triazol-5-yl]phosphonate (18): yield: 42% (0.19 g), colorless oil; 31 P NMR (CDCl 3 ) δ 3.…”

Shortened derivatives from native antimicrobial peptide LyeTx I: In vitro and in vivo biological activity assessment

“…Cytotoxicity was investigated by assessing the neurotoxicity parameter of original LyeTx I and shortened derivative LyeTx I mnΔK, as recently described. 18 In brief, Lund Human Mesencephalic (LUHMES) cells were kept in proliferation medium (Adv DMEM/F12 containing 2 mM L-glutamine, 1× N2 supplement) enriched with 40 ng·mL −1 recombinant human basic fibroblast growth factor and cultured in 5% CO 2 at 37°C. Cell culture dishes and flasks were coated with 50 µg·mL −1 poly-L-ornithine and 1 µg·mL −1 fibronectin.…”