• 약학회지
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• 제44권1호
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• pp.9-15
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• 2000

Four 3-alkoxy-6-allylthiopyridazines and 3-chloro-6-allylthiopyridazine were synthesized and their protective effects against oxidative stress and UV-C irradiation were tested. 3-Methoxy-6-allylthiopyridazine and 3-ethoxy-6-allylthiopyridazine did not show protective effect on the oxidative stress but showed the strongest protective effect on UV-C irradiation among the tested compounds. Especially 500 $\mu\textrm{g}$/$m\ell$ of the two compounds was the most effective concentration.

• 약학회지
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• 제46권3호
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• pp.155-160
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• 2002

Through a modification of allicin structure a disagreeable odor and chemical instability of allicin can be improved. 3-Alkoxy-6-allylthiopyridazine derivatives exhibit a superior effect for prevention and treatment of hepatic diseases induced by carbon tetrachloride and aflatoxin B1 and for prevention of human tissues from radiation. These compounds inhibit also efficiently SK-Hep-1 cell proliferation through induction of apoptosis. So another 4,5-mono- or di-substituted 3-alkyloxy-6-allylthiopyridazine derivatives were synthesized on purpose to find out SAR of allylthiopyridazine in hepatoprotective and hepatotherapeutic acitivitis and to develop more effective drug candidate.

• Archives of Pharmacal Research
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• 제26권5호
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• pp.351-357
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• 2003

Five kinds of allylthiopyridazine derivatives were synthesized and their chemoprotective activities examined in rats exposed to aflatoxin $B_1$-toxicant. Rats were pretreated with five allylthiopyridazine derivatives at daily oral doses of 50 mg/kg for 10 consecutive days, and during this period with one or three repeated doses of the potent hepatotoxin, aflatoxin $B_1$. The hepatoprotective effects of the allylthiopyridazine derivatives against aflatoxin $B_1$ (1 mg/kg, three times at intervals of 3 days, i.p., or at 3 mg/kg, once at final days, i.p.) administration were showed the significantly normal as compared with control in body and liver weights. Aspartate aminotransferase and alanine aminotransferase levels were markedly elevated after aflatoxin $B_1$ administration, and pretreatment with allylthiopyridazine derivatives, before aflatoxin $B_1$ administration, resulted in decreased levels of these enzymes. In addition, the allylthiopyridazine derivatives, K6 (3-methoxy-), K8 (3-chloro-), K16 (3-ethoxy-) and K17 (3-n-propoxy), induced elevated hepatic GSH levels. Four kinds of allylthiopyridazine derivatives investigated were effective against aflatoxin $B_1$ -induced hepatotoxicity.

• 약학회지
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• 제60권3호
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• pp.101-106
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• 2016

Allylthiopyridazine derivatives were synthesized and evaluated for anti-proliferative activities in the previous study. In this study, selected two allylthiopyridazine derivatives (compound I, 3-heptylamino-6-allylthiopyridazine and compound II, 3-dipentylamino-6-allylthiopyridazine) were assessed for cytotoxicity and chronic proliferation in human colon carcinoma RKO cells. Two derivatives dose-dependently inhibited cell viability and proliferation. To elucidate the anticancer mechanism of two derivatives, we investigated the expression level of apoptosis-related proteins in RKO cells. Compound I induced the activation of JNK and expression of p53 and p21. On the other hand, compound II showed no change of p53 level. Interestingly, compound II inhibited the nuclear translocation of NF-${\kappa}B$. This result suggested that compound II suppressed cell proliferation. These different mechanisms of these compounds might have occurred through different steric conformation.

• 약학회지
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• 제49권4호
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• pp.335-339
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• 2005

In this study we investigated the effect of 3-methoxy-6-allylthiopyridazine on cell growth in BxPC3 and PANC1 human pancreatic cancer cells. The treatment with 3-methoxy-6-allylthiopyridazine for 48h decreased cell viability and induced apoptotic cell death in a dose-dependent manner, assessed by using the MTT assay and the flow cytometry, respectively. These results suggest that 3-methoxy-6-allylthiopyridazine may be a good candidate for the therapeutic management of human pancreatic cancers.

• Archives of Pharmacal Research
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• 제28권4호
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• pp.391-394
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• 2005

The allylthio group of allicin and other organosulfur compounds, isolated from garlic, is considered a pharmacophore, and a key structure component of the molecule, which affords biological activities. In the foregoing studies, various 3-alkoxy-6-allylthiopyridazine derivatives (K­compounds) were synthesized, and their biological activities tested in animals. As expected, the various derivatives showed good hepatoprotective activities on carbon tetrachloride-treated mice and aflatoxin B1-treated rats, and chemopreventive activities on hepatocarcinoma cells in rats. Other new pyridazine derivatives, with the oxygen atom at the 3-position of the 3-alkoxy­6-allylthiopyridazine displaced by sulfur (S), were synthesized, and their activities tested in vitro. Thio-K6, one of the sulfur-substituted compounds, showed better chemopreventive activity toward hepatocarcinoma cells.

• Biomolecules & Therapeutics
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• 제13권2호
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• pp.113-117
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• 2005

Organosulfur compounds have been shown to exert an anti-cancer activity. In an attempt to develop novel chemopreventive and anti-cancer agents for liver cancer, we synthesized allylthiopyridazine derivatives. We have previously shown that allylthiopyridazine derivatives exert inhibitory effects on proliferation, invasion and migration of SK-Hep-1 hepatocarcinoma cells in vitro. The in vivo anti-tumor effect of 3-methvl-6-allylthiopy-ridazine, named as K6, was also reported. In this study, we further investigated the preclinical anti-cancer efficacy of K6 for hepatocarcinoma using nude mice xenografted with Hep-G2 hepatocellular carcinoma cells. K6(20-100 mg/kg, orally administered everyday for 30 days) markedly decreased the tumor volume of Hep-G2 cell-transplanted nude mice as evidenced by ultrasonographic and plethysmogranhic analyses. The inhibitory effect on tumor volume was lower than that exerted by doxorubicin (2 mg/kg), intravenously injected) which was used as a positive control. This study shows that K6 efficiently suppresses xenograft tumor growth, revealing K6 as apotential anti-cancer agent for suppressing in vivo progression of liver cancer. Given that hepatocarcinoma is among the most prevalent and lethal malignancies and there is no effective treatment to date, our study may contribute to the potential drug development for liver cancer.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.172.2-173
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• 2003

3-Alkoxy-6-allylthiopyridazine derivatives showed the strongest protective effect against oxidative stress and their anticancer effect determined on the growth of SK-Hep-l hepatocellular carcinomar cells. The allythio group as a pharmacologically active group was introduced into pyridazine nucleus and a substituent such as halogen or alkoxy was also introduced into paraposition of allylthio group. Five kinds of 3-alkoxy-6-allylthiopyridazine derivatives were synthesized and their chemoprotective activities examined in rats exposed to aflatoxin $B_1$-toxicant. (omitted)

• Biomolecules & Therapeutics
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• 제13권2호
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• pp.123-126
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• 2005

The single dose toxicity of 3-methoxy-6-allylthiopyridazine (K-6) was studied with Sprague-Dawley rats. K-6 was administered orally with dosages of 4.0, 3.0, 1.5, 1.0, 0.5, 0.25 and 0.1 g/kg to the rats. We observed daily the number of death, clinical signs, body weights and gross findings. All rats (6) were dead within a day after administration when doses of 4.0and 3.0 g/kg were administered. When dose of 2.0 g/kg was administered, 2 rats among 3 rats were dead. Any significant toxicity below 1.5g/kg of K6 was not observed when the different doses of 1.5, 1.0, 0.5, 0.25 and 0.1 g/kg were administered to 6 rats respectively.

• 대한약학회:학술대회논문집
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• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.1
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• pp.188.2-189
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• 2002