European Journal of Medicinal Chemistry 2009-12-01

Anti-nitric oxide production activity of isothiocyanates correlates with their polar surface area rather than their lipophilicity.

Toshiro Noshita, Yumi Kidachi, Hirokazu Funayama, Hiromasa Kiyota, Hideaki Yamaguchi, Kazuo Ryoyama

Index: Eur. J. Med. Chem. 44 , 4931-6, (2009)

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Abstract

There is increasing demand for novel anti-inflammatory drugs with different mechanisms of action. We synthesized a series of isothiocyanates 2b-h based on 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC) found in the pungent spice Wasabia japonica. Inhibitory activities against in-vitro growth of tumor cells and production of nitric oxide (NO) using the mouse macrophage-like cell line J774.1 were noted. All isothiocyanates were optimized by Hartree-Fock/3-21G model, and the logP values and the polar surface area (PSA) values were calculated. Substitution of the methylsulfinyl group (CH(3)S(O)-R) in 6-MITC with a formyl (CHO-R), a methylsulfanyl (CH(2)S-R) or a methyl (CH(3)-R) group reduced the activities of the parent isothiocyanate. Substitution with a formyl group resulted in lower lipophilicity (logP value) whereas substitution with a methylsulfanyl or methyl group resulted in a lower PSA value. The inhibitory activity of isothiocyanates showed better correlation with their PSA values rather than their partition coefficient (logP) values. Isothiocyanates with higher PSA values and some degree of logP value may have potent biological activity.