We describe the synthesis and results of biological evaluation of newly designed 2,4,6-trisubstituted symmetrical 1,3,5-triazine (TAZ) derivatives. Among the tested trisubstituted TAZ derivatives, some C Ssymmetrical alkoxy-amino-substituted TAZ derivatives, including 7ggp and 6dpp, showed significant antiviral activity against herpes simplex virus type 1 (HSV-1). The compound with the highest level of antiviral activity was C 3 -symmetrical trialkoxy-TAZ derivative 4bbb, which showed a considerably high selectivity index (IC 50 /EC 50 256.6). The structure-activity relationships for anti-HSV-1 activity of the tested 2,4,6-trisubstituted TAZ derivatives are also described.Key words 1,3,5-triazine; anti-herpes simplex virus type 1; cytotoxic activity; C S symmetry; C 3 symmetry; plaque reduction assay Supramolecular interaction of two-fold (C 2 ) or three-fold (C 3 ) symmetrical geometry macromolecules with many bioactive compounds is one of the common features of many important biological processes, [1][2][3] and small molecules having C 3 -, C S -, or C 2 -symmetrical geometry often appear in various biologically active compounds contrasted on a symmetrical template. [4][5][6] We have therefore expected that such small symmetrical molecules would be promising new candidates or leads in the search for biologically active compounds that interfere with the sugar recognition process in a controlled biological response. From this aspect of molecular symmetry, we have already reported a few examples of such types of new symmetrical molecules for the purpose of finding new biological active compounds. 7-9)We have recently reported some molecular modifications of 2,4,6-trichloro-1,3,5-triazine (TCTAZ) to C 3 -, or C Ssymmetrical trisubstituted TAZ molecules and the results of biological evaluation of synthesized symmetrical 2,4,6-trisubstituted TAZ derivatives. 7) Among previously targeted TAZ derivatives, some alkoxy-amino-substituted derivatives showed significant anti-herpes simplex virus type 1 (HSV-1) activities. The previous analysis of anti-HSV-1 active molecular features indicated that a C S -symmetrical TAZ derivative with two alkoxy groups and one amine moiety seemed to be a required structure for preferred anti-HSV-1 activity with a good selectivity index.For an extension of our study, we examined further modifications of this symmetrical class of compounds in order to investigate the structure-activity relationship (SAR) of alkoxyamino-substituted TAZ molecules as well as their biological evaluation. In this paper, we report the results of preparation of newly targeted C S -symmetrical TAZ derivatives together with the results of biological evaluation of obtained symmetrical 2,4,6-trisubstituted TAZ derivatives.Chemistry In our previous article, 7) we reported that synthesis of target alkoxy-amino-trisubstituted TAZ derivatives is easily achieved by a procedure via alkoxy-substituted chloro-TAZ intermediates starting from TCTAZ (1). This procedure consists of two-stage nucleophilic substitutions of compound...

We report the preparation of new C- and C-symmetrical molecules constructed on a triazine (TAZ) template. Anti-herpes simplex virus type 1 (anti-HSV-1) and cytotoxic activities against Vero cells of synthesized TAZ derivatives were evaluated. The results suggested that the presence of an electron-donating group(s) on the benzene ring in benzylamine groups on the TAZ template is an important structural factor for expressing a high level of anti-HSV-1 activity and low cytotoxicity for these C types of TAZ derivatives. Among the tested TAZ derivatives, compounds 4f and 7h showed the highest anti HSV-1 activities (EC=0.98 and 1.23 µM, respectively) and low cytotoxic activities to Vero cells (50% cytotoxic concentration (CC)=292.2 and >200 µM, respectively).

It has been shown that commercial tomato juice packaged in 900 g plastic bottles contains rare, naturally occurring steroidal solanocapsine-type tomato glycosides in which the saponins consist of esculeosides B-1 (2) and B-2 (3) in 0.041% as major components lacking esculeoside A. We suggest that these saponins are derived from esculeoside A (1) when the juice in plastic bottles is prepared by treatment with boiling water, similar to the process used in preparing canned tomatoes. Herein, the obtained tomato saponins (2) and (3) provided sapogenols esculeogenin B 1 (4) and B 2 (5), respectively, by acid hydrolysis. The former was identical to esculeogenin B previously reported, and the latter was a new sapogenol characterized to be (5α,22S,23S,25S)-22,26-epimino-16β,23-epoxy-3β,23,27-trihydroxycholestane.

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As one of our projects, we here report some new molecular modifications of 2,4,6-trichloro-1,3,5-triazine (TCTAZ: 1) to symmetrical 2,4,6-trialkoxy-or 2,4,6-triaryloxy-substituted 1,3,5-triazine (TAZ) molecules, as well as the results of anti-herpes simplex virus type 1 (anti-HSV-1) activity evaluation of synthesized 2,4,6-trisubstituted TAZ derivatives. Among the tested 2,4,6-trisubstituted TAZ derivatives, we reconfirmed that a C 3 -symmetrical TAZ derivative, 4e, shows the highest level of anti-HSV-1 activity with a good selectivity index. In this paper, we also report the results of the preparation of newly targeted TAZ derivatives and the structure-activity relationships (SARs) of these trialkoxy-substituted TAZ derivatives and related compounds. The sugar recognition properties of C 3 -symmetrical TAZ derivative 4e are also described.Key words 1,3,5-triazine; C 3 symmetry; anti-herpes simplex virus type 1; structure-activity relationship; plaque reduction assay; isothermal titration calorimetryThe glycocalyx at the cell surface, containing glycoproteins, proteoglycans and glicolipids, plays an important role in various cell-to-cell communications. Specific interactions of these carbohydrates with lectins (protein receptors) are important biological processes, including the processes of bacterial or viral infection and tumor metastasis. 1-3)From the viewpoint of molecular symmetry, many host receptors that consist of homo-oligometric units (homomultiligands) often construct symmetric macromolecule architectures such as C 2 -or C 3 -symmetrical geometry receptor systems. These phenomena of macromolecules connected with many biological stages have encouraged scientists to develop new multivalent symmetrical synthetic molecules to find new bioactive compounds or leads. Results of many works related to the above conception have been published over the past few decades. [4][5][6][7] The terms identical twin-drugs and tripletdrugs (symmetrical bivalent and trivalent molecules) are now commonly used in medicinal chemistry and related scientific fields. In connection with our synthetic works on such symmetrical molecules, we have already designed and synthesized a few new symmetrical molecules and evaluated their bioactivities in order to find new types of bioactive compounds. 8-17)In connection with the above projects, we have recently reported some molecular modifications of 2,4,6-trichloro-1,3,5-triazine (TCT AZ) (1) to symmetrical 2,4,6-trisubstituted 1,3,5-triazine (TAZ) molecules and the results of biological evaluation of synthesized symmetrical 2,4,6-trisubstituted TAZ derivatives. 8,9) Among previously targeted trisubstituted TAZ derivatives, we found that a C 3 -symmetrical TAZ derivative with three isopropoxy groups on a TAZ template such as compound 4e showed a high level of anti-herpes simplex virus (HSV)-1 activity and low cytotoxity, and it therefore seemed to be a potential lead in the search for preferred anti-HSV-1 activity with a good selectivity index (SI).In this paper, we report the results of...