Figure 1
From: Phenylethynylbenzyl-modified biguanides inhibit pancreatic cancer tumor growth
(A) Structure and crystal packing of previously studied PEB-disubstituted (A.1) and monosubstituted (A.2 and A.3) benzimidazolium salts13. Compound A.1 is an efficient chloride transporter forming channels and generating holes in bacterial membranes and red blood cellular membranes. Compound A.2 penetrates phospholipid membranes but is less efficient as ion transporter as it forms more compact aggregates; its toxicity on RBC is lower than compound A.1. The replacement of the phenyl group with a methyl group in compound A.3 results in the formation of even more compact aggregates with even lower toxicity on RBC. (B) Structure of PEB-substituted biguanidium salts. For each biguanide we prepared three series of biguanidium salts with different counterions. (C) Synthesis of 4-(phenylethynyl)benzylbiguanide 1 and 4-(phenylethyl)benzylbiguanide 2; (a) Phenylacetylene, PdCl2PPh3, CuI, PPh3, Et3N, THF, 70 °C, o.n. (b) NaCN(BH3)3, EtOHNH4OAc sat./NH3, 80 °C, o.n (c) Dicyandiamide, TMSCl, THFanh., 145 °C, 1 h (d) Pd/C 10%, H2, EtOH/AcOEt, 60 °C, 2 h. (D) Synthesis of 4-(phenylethynylphenyl)biguanidium 3 and 4-(phenylethylphenyl)biguanidium 4 (a) (1) Boc2O, THF, 2 h, (2) Phenylacetylene, PdCl2PPh3, CuI, PPH3, Et3N, THF, 70°, o.n. (b) TFA, DCM, 60 °C, 2 h (c) Dicyandiamide, TMSCl, THFanh, 145 °C, 1 h (d) Pd/C 10%, H2, EtOH/AcOEt, 60 °C, 2 h. The NMR spectra of the synthesized compounds are given in Supplementary Figs. S1–S24. (E) Relative growth of NB508 mouse pancreatic ductal adenocarcinoma cells and IMR90 fibroblasts exposed to 5 µM of PEB-biguanidium salts. Cells were incubated for 72 h at 37 °C. Errors bars represent the standard error of the mean (SEM), *p < 0.05, **p < 0.01, Student’s t test. (F) Crystal structure of 1b showing its self-assembly in the solid state. Crystal data is available in Supplementary Tables S1–S8 and crystal packing in Supplementary Fig. S25.
