Design, Synthesis, and Biological Evaluation of Selenium‐incorporated Aminopyridazines as Anticancer Agents

2017

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A new series of 3‐allylseleno‐6‐alkylsulfonylpyridazines and 3‐allylseleno‐6‐alkylsulfinylpyridazines were synthesized from 3,6‐dichloropyridazine for anticancer agent development. The inhibitory effects of 3‐allylseleno‐6‐alkylsulfonylpyridazines on human cancer cell lines were investigated. The synthesis involved thiolation, oxidation, selenylation, and Se‐allylation of alkylthiols. That is, sodium methanethiolate, ethanethiol, propanethiol, butanethiol, pentanethiol, and hexanethiol were inserted into the 6‐position of the pyridazine nucleus. These new synthetic compounds exhibited antiproliferative activity against human breast cancer (MCF‐7), hepatocarcinoma (Hep3B), and human colon carcinoma (RKO) cells in CCK‐8 assays, and are potential candidates for cancer chemotherapy.

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

2017

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“…All 3‐alkoxy‐6‐chloropyridazines 3b–3d and 3‐alkylthio‐6‐chloropyridazines 4b–4e were prepared following the synthetic methods of existing literature . The intermediate dichloropyridazinyl diselenide 2 was obtainable from the corresponding 3,6‐dichloropyridazine 1 by reaction with sodium diselenide . A synthetic pathway for dipyridyl diselenide has been developed and the synthesis of substituted dipyridazinyl diselenide has been reported .…”

Section: Methodsmentioning

confidence: 99%

“…The intermediate dichloropyridazinyl diselenide 2 was obtainable from the corresponding 3,6‐dichloropyridazine 1 by reaction with sodium diselenide . A synthetic pathway for dipyridyl diselenide has been developed and the synthesis of substituted dipyridazinyl diselenide has been reported . We applied a general method of preparing diaryl (or dialkyl) diselenide from diaryl (or dialkyl) halides and sodium diselenide .…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Antiproliferative Activities of Chloropyridazine Derivatives Retain Alkylsulfonyl Moiety

2016

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Some chloropyridazine derivatives have shown interesting pharmacodynamics properties in terms of antioxidant 1 and anti-human rotavirus (HRV) activities ( Figure 1). 2,3 To date, however, no study has evaluated the antiproliferative effects of chloropyridazines in other types of human cancer cells.Therefore, the replacement of the heterocycle of chloropyridazines by heteroatoms (or moieties) such as oxygen (O), sulfur (S), selenium (Se), sulfinyl (SO), and sulfonyl (SO 2 ) yields the target compounds ( Figure 1). We designed substituted 3-chloropyridazine derivatives as possible antitumor candidates. These derivatives have three basic structures, namely chloropyridazine region, heteroatoms, and alkyl chain. We made an examination of antiproliferative activities for target chloropyridazines of five groups against breast cancer (MCF-7) and hepatocellular carcinoma (Hep3B) cells in Cell Counting Kit-8 (CCK-8) assays. As a result, we describe herein the preparation of some chloropyridazine derivatives and the refinement of potential proliferative inhibitors on human cancer cell lines.The chloropyridazines were obtained mostly through the substitution reaction. Scheme 1 depicts the preparation of desired substituted chloropyridazine derivatives. We previously reported the synthesis of 3-allylthio-6chloropyridazine in 95% yield through allylthiolation. 4 All 3-alkoxy-6-chloropyridazines 3b-3d and 3-alkylthio-6-chloropyridazines 4b-4e were prepared following the synthetic methods of existing literature. 5,6 The intermediate dichloropyridazinyl diselenide 2 was obtainable from the corresponding 3,6-dichloropyridazine 1 by reaction with sodium diselenide. 7 A synthetic pathway for dipyridyl diselenide has been developed 7,8 and the synthesis of substituted dipyridazinyl diselenide has been reported. 9 We applied a general method of preparing diaryl (or dialkyl) diselenide from diaryl (or dialkyl) halides and sodium diselenide. 10-12 A series of alkylselenylpyridazines 5b-5f was prepared by Se-Se bond cleavage and Se-alkylation.Treatment of alkylthiopyridazines 4a-4e with 35% hydrogen peroxide afforded corresponding alkylsulfinylchloropyridazine 6a-6e and alkylsulfonylchloropyridazine 7a-7e. Target 6a-6e and 7a-7e were synthesized as illustrated in Scheme 1. Figure 1. Bioactive chloropyridazines and target chloropyridazines. Scheme 1. Synthetic routes for target chloropyridazine analogues.

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

Lee

2016

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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...