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Synthesis of a new series of heteroaryl 4-chloro- 2-mercaptophenylsulfonylisothiourea derivatives with potential antitumor activity

Beata Żołnowska 1,  Jarosław J. Sławiński 1,  Kamila Hablutzel 

1. Medical University of Gdańsk, Department of Organic Chemistry, Gen. J. Hallera Street 107, Gdańsk 80-416, Poland

Abstract
In continuation of our effort to get new chemotherapeutic agents [1-5], we herein report the synthesis of the heteroaryl 2-mercaptophenylsulfonylisothiourea derivatives and their antiproliferative activity. Till now there are no patterns of biological active 2-mercaptobenzenesulfonamides bearing sulfonamide nitrogen atom substituted with heteroaryl carbimidothioate moieties. The aim of the present investigations was to extend our studies in this class of compounds. Therefore, we elaborated the synthesis and anticancer evaluations in vitro of novel N-substituted analogues of the lead structure (MBSAs), being thus the heteroaryl 4-chloro-2-(R2-methylthio)phenylsulfonylcarbamimidothioate derivatives as depicted in scheme below.

The synthesis of the desired heteroaryl 4-chloro-2- (R2-methylthio)-R1-phenylsulfonylisothiourea derivatives were achieved by reacting of the corresponding N-(2-alkylthio-benzenesulfo- nyl)cyanamide potassium salts with suitable mercapto-azoles/benzazoles in dry toluene in the presence of p-toluenesulfonic acid (PTSA) at reflux.

Anticancer in vitro screening performed at the NCI (Bethesda MD, USA) using 60 cell lines derived from 9 types of human tumors revealed moderate or reasonable anticancer activity of tested compounds. The distinctive compound e.i. 1-methyl-1H-imidazol-2-yl 4-chloro-2-[(6-chlorobenzo-1,3-dioxol-5-yl)methylthio]-5-methylphenylsulfonylcarbamimidothioate showed remarkable activity against 14 human tumor cell lines representing leukemia, lung, colon,CNS, melanoma, ovarian, renal, prostate and breast at the low micromolar GI50 level in the range of 0.38-4.93 μM.

References:

1. Sławiński J., Eur. J. Med. Chem., 39, 179 (2004).
2. Sławiński J., Gdaniec M., Eur. J. Med. Chem., 40, 377 (2005).
3. Sławiński J., Brzozowski Z., Eur. J. Med. Chem., 41, 1180 (2006).
4. Sławiński J., Żołnowska B., et al., J. Enzyme Inhib. Med. Chem. doi: 10.3109/14756366.2011.625024.
5. Sławiński J., Brożewicz K., Fruziński A., Główka M.L., Heterocycles, 83, 1093 (2011).                                      
 

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Presentation: Poster at VIII Multidyscyplinarna Konferencja Nauki o Leku, by Beata Żołnowska
See On-line Journal of VIII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2012-03-08 08:50
Revised:   2012-05-11 02:19