Molecular Symmetry and Biological Activities of New Symmetrical Tris(2-aminoethyl)amine Derivatives

Abstract

In terms of molecular symmetry and bioactivity, new C 3 -and C S -symmetrical derivatives based on the tris(2-aminoethyl)amine scaffold were designed and synthesized. The synthesized compounds were evaluated for antiviral activity with herpes simplex virus type 1 (HSV-1) by a plaque reduction assay and for cytotoxic activity with Vero cells. Most of the compounds showed no significant anti-HSV-1 activity, but some of the symmetrical derivatives showed high levels of cytotoxic activitiy.Key words tris(2-aminoethyl)amine; tripodal; anti-herpes simplex virus type 1; C 3 symmetry; C S symmetry; plaque reduction assay There have been many reports on the molecular recognition properties of symmetrical molecules, 1) and it is known that the symmetrical feature is frequently observed in many biological stages. Two-fold and three-fold symmetrical macromolecular structures are common features in specialized biological functions.2-4) Regarding the molecular symmetry, small symmetrical molecules with a C 2 -symmetrical or C 3 -symmetrical structure have often been found in various synthetic biologically active compounds. 5-7)In the course of our work on new antiviral compounds, we have presented a new class of antiviral candidates. For example, we have already reported that most of the triarylmethane derivatives showed a wide range of antiviral activities against herpes simplex virus type 1 (HSV-1). 8,9) In continuation with our work for finding potent antiviral derivatives, synthetic molecular modifications directed our attention to the molecular symmetry for the biological activity. Our recent studies on heteroaryl-substituted triarylmethane derivatives indicated that compounds bearing a prochiral symmetric feature (possessing C S symmetry) showed a higher level of antiviral activity than that of the corresponding C 3 -symmetrical molecules 9,10)

Synthesis and Biological Evaluation of Symmetrical 2,4,6-Trisubstituted 1,3,5-Triazine Derivatives

“…Thus, the TAZ template seems to be a preferable template for antiviral compounds rather than the TAEA template, 3) because antiviral activities of most of the C S -symmetrical compounds in this study were observed at lower concentrations than those of the corresponding cytotoxicities. In addition, many trisubstituted target C S -symmetrical TAZ derivatives described in this paper showed wide ranges of antiviral (anti-HSV-1) activities.…”

“…Therefore, for the purpose of preparation of designed alkoxy-amino-TAZ derivatives as our target molecules, the synthetic procedure via alkoxy-substituted chloro-TAZ is expected to be superior to the procedure via amine-substituted chloro-TAZs. Chart 2 shows the strategic point of synthetic pathways via alkoxy-chloro-TAZ derivatives (7,8) to alkoxy-amino-TAZ derivatives (3,4). Our method via alkoxy-substituted chloro-TAZ intermediates for target alkoxy-amino-TAZs consisting of stepwise nucleophilic substitutions gave moderate to excellent results as shown in Table 2.…”

“…Considering the nature of an introduced substituent characterizing the lipophilicity of a molecule, further modifications for finding more promising antiviral leads with better selectivity indexes are now under investigation. Based on the results of our previous studies on a few types of symmetrical compounds, [3][4][5] we speculate that a symmetrical molecule constructed on a symmetric template or with a linker may be an efficient structural feature. For the elucidation of sugar recognition properties of some of the highly bioactive symmetrical compounds such as 3ds, 3dt, 3is, and 4dss described in this article, we are also planning to carry out calorimetric experiments.…”

“…3) We have also reported an interesting lectin-like property for sugar recognition of some of these tripodal receptor type TAEA molecules. 4) In order to achieve a suprafacial three-dimensional interaction of a bioactive symmetrical molecule for its binding site, the nature of substituents in the molecule is thought to be very important for preferential interactions.…”

“…[3][4][5] With reference to the molecular symmetry, small molecules having C 3 -, C S -, or C 2 -symmetrical geometry frequently appear in various biologically active compounds. [6][7][8] Such small symmetrical molecules are usually constructed on a corresponding symmetrical template.…”