Triguanide Derivatives: Synthesis, Crystal Structure and Evaluation of the Proliferation Effect on Some Tumor Cell Lines

Abstract

One‐pot synthesis of new pentasubstituted triguanides 1a–e starting from the corresponding monosubstituted guanidine derivatives and diisopropylcarbodiimide is described and a mechanism for formation of the products observed is proposed. The structures of 1a–d were elucidated by spectroscopic analyses of their acetate salts. The structure of compound 1e was also confirmed by X‐ray crystallography using its sulfate salt. The X‐ray structure provided strong evidence of extensive electron delocalization within the triguanide core despite its non‐planar structure. In addition, the effect of tautomerism on the course of the reaction, with emphasis on possible reaction paths leading to the side products, is discussed in some detail. Finally, antiproliferative effects of the acetate salts of the newly prepared compounds on five cancer lines in vitro were evaluated. It was found that acetates of 1a–c exhibit strong cytostatic and cytotoxic activity, with the strongest effect observed for the acetate of benzyl derivative 1c.

Synthesis of Highly Basic Hexasubstituted Biguanides by Environmentally Friendly Methods

“…Gas-phase basicities and proton affinities of biguanides 3a-g were calculated at B3LYP/6-311+G-(2df,p)//B3LYP/6-31G(d) level of theory. Calculation of their pK a in acetonitrile solution was conducted using either IPCM/B3LYP/6-311+G(2df,p)//B3LYP/6-31G(d) (M1 18 ) or IEF-PCM/B3LYP/6-311+G(2df,p)//B3LYP/6-31G(d) (M2 19 ) models which were proved to give very good agreement with the experimental data on structurally similar compounds in our previous papers. 18 The pK a values of biguanides 3a-g with exception for the most basic ones (3b and 3d) were also measured by UV spectroscopy (in MeCN, Table 2).…”

The Synthesis and Structural Characterization of Peralkylated Triguanide Superbases

“…It should be noted that HPLC and NMR analyses of the reaction mixtures did not show the formation of triazine-like byproducts, as it was the case with pentasubstituted triguanides. [9] Also, the isolated triguanide salts are stable under standard conditions and do not seem to decompose further. This observation supports the hypothesis that the elimination of hydrogen atoms (which allows the existence of a single tautomer) from the triguanide structure increases its chemical stability.…”

“…cyclization to 1,2-dihydrotriazines. [9,12] Additionally, the larger number of alkyl groups in the structure has a positive effect on the basicity since the corresponding cation is stabilized by the polarizability effect exerted by the alkyl substituents. [13] In our first trial, a stoichiometric reaction involving one equivalent of guanidine and two equivalents of Vilsmeier salt 2 was conducted (Fig.…”

“…This observation is in line with the reported crystal structure of pentasubstituted triguanide sulfate salt. [9] The three guanidine subunits containing C1, C2, and C3 atoms are essentially planar, where the carbon atoms are displaced by 0.010-0.053 Å from the mean plane defined by the corresponding nitrogen atoms. The pyramidalization for atoms N1, N2, N4, N6, and N7 amounts to 5.1, 0.5, 1.1, 4.1, and 1.0 %, respectively, and is consistent with the protonated state of 4a.…”

“…[8b-f] Our group has recently made a contribution towards the synthesis, structure, and reactivity of pentasubstituted triguanide derivatives. [9] These compounds have been prepared in a one-pot reaction between monosubstituted guanidines and a carbodiimide, followed by a tedious workup involving preparative HPLC. The protocol additionally suffered from the formation of several by-products as a result of diverse and hard to control reactivity of monosubstituted guanidines and pentasubstituted triguanides.…”