Selenium‐containing Bis(alkylselanyl)pyridazines: Synthesis, and Evaluation of Antiproliferative Activities

Abstract

The first organoselenium compound, diethyl selenide was prepared by Löwig in 1836. Recently, the organoselenium chemistry has developed rapidly in the area of selenoaminoacids.1 Selenium element can be introduced in an organic substrate via nucleophilic and electrophilic agents. Today selenium compounds are applied in many areas including organic synthesis, and biochemistry. Selenium is an essential trace element that has the ability to prevent cancer in several animal models. 2The pyridazine nucleus has been amalgamated with an allylseleno group. Allylselenoalkoxypyridazines and allylselenoalkythiopyridazines 3 show especially good antitumor activities against breast cancer cells. The same group atomic substitution of the oxygen (or sulfur) by a selenium atom generates bis(alkylselanyl)pyridazine compounds (Figure 1).Even though synthetic pathways for 3-alkylselanylpyridazines were developed by Kim et al., 3 and Lee et al., 4 the synthesis of alkylselanylaralkylselanylpyridazines has not been previously reported. We applied a general method of preparing alkoxypyridazines from aryl halides and alkoxy anion. The key intermediates in these preparations are 3-alkylselanyl-6-chloropyridazines 3a-3e, which was obtained from the corresponding dichloropyridazinyl diselenide 2a by reaction with alkyl halide. Condensation of the intermediate 3a-3e with dibenzyl diselenide 2b (or diphenethyl diselenide 2c) produces the final target alkylselanylaralkylselanylpyridazines 4a-4e and 5a-5c.Target compounds were synthesized through the processes of diselenylation, hydrolysis, Se-alkylation, and alkylselenylation from 3,6-dichloropyridazine. We tested the ability of these synthetic compounds to inhibit the growth of human breast cancer MCF-7 cell lines. Because we expect that synthesized compounds and reported allylselenoalkoxypyridazines have similar mechanism of action, 3 the MCF-7 cells were selected for antitumor assay.As pharmacologically active groups, the alkylselanyl and the aralkylselanyl moieties were introduced into the pyridazine ring in order to prepare new organoselenium compounds. Two seleniums were incorporated between a pyridazine nucleus and an alkyl and an aralkyl moiety. We designed the target products to include an alkylselanyl group at the 3-position and an aralkylselanyl group at the 6-position of the nucleus.Many reports have been published on the nucleophilic substitution reaction of aryl halides. Pyridazinyl halides react with nucleophilic selenium anion to give the corresponding bis(alkylselanyl)pyridazines. We applied a synthetic method of preparing allylselenopyridazines from pyridazinyl halides and thiols (or alcohols).2 Also, a method of splitting the selenium-selenium bond, Se-alkylation of dichloropyridazinyl diselenide 2a was applied.5 Dichloropyridazinyl diselenide 2a was obtained through diselenylation according to reported procedures of Bhasin et al. 6,7 A series of 3-alkylselanyl-6-aralkylselanylpyridazines 4a-4e and 5a-5c was prepared by synthetic procedure shown in Scheme 1. An alkylselany...

Synthesis and Evaluation of Novel 3‐Allylseleno‐6‐Alkylsulfonylpyridazine Derivatives with Potential Anticancer Properties

“…Several modifications of the alkylselenopyridazine pharmacophore have been reported. Allylselenoalkoxypyridazines, allylselenoalkylthiopyridazines, alkylselenoalkylamino‐pyridazines, and bis(alkylselanyl)pyridazines have been shown to have good antiproliferative effects on breast cancer MCF‐7 cells.…”