Synthesis, structure and enantiomeric resolution of ferrocenylalkyl mercaptoazoles. Antitumor activity in vivo

• Ferrocenylalkylation of 2-mercaptoazoles proceeds exclusively on the N-position.
• There is no electronic interaction between the ferrocene and 2-mercaptoazoles.
• In vivo study antitumor activity of N-(ferrocenylethyl)-2-thiobenzimidazole.

Ferrocenylalkyl 2-mercaptobenzimidazoles 3 (a–e) and 2-mercaptobenzo[d]thiazole-2(3H)-thiones 5 (a–e) were prepared via the reaction of the α-(hydroxy)alkyl ferrocenes, FcCHR(OH) (1a–e; Fc = ferrocenyl; R = H, Me, Et, i-Pr, Ph), either with thiobenzimidazole in acetone at room temperature in the presence of TFA (catalytic amounts), in yields of 55–74%, or with thiobenzothiazole in methylendicloride in presence of aqueous HBF4 (equimolar amounts) at r.t., in yields of 41–58%. The structures, electrochemical properties and enantiomeric resolution 3a–e and 5a–e (using HPLC on modified amylose as chiral selector) were investigated. In cyclic voltammetry all studied compounds exhibited a reversible one-electron oxidation–reduction wave owing to the ferrocene–ferricenium redox couple with a positive shift (0.56–0.80 V) compared with that of ferrocene (0.50 V). X-ray determinations of molecular structures of 3-ferrocenylmethylbenzo[d]thiazole-2(3H)-thione (5a) 3-ferrocenylethylbenzo[d]thiazole-2(3H)-thione (5b) and 3-ferrocenylphenylmethylbenzo[d]thiazole-2(3H)-thione (5d) were carried out. The toxicity and antitumor activity of N-(ferrocenylethyl)-2-thiobenzimidazole (3b) were evaluated in vivo. Maximum tolerated dose (MTD) value for the compound 3b was found to be equal to 800 mg kg−1. The effectiveness of compound under investigation against murine solid tumor system, carcinoma Ca755 (Ca755), was studied in a wide range of doses and significant antitumor effects were found. The index of tumor growth inhibition (TGI) on Ca755 equaled 87% in comparison with control.

Ferrocenylalkyl 2-mercaptobenzimidazoles and 2-mercaptobenzo[d]thiazole-2(3H)-thiones were prepared and studied. The single crystal X-ray structure analysis was performed for three of the synthesized compounds. The toxicity and antitumor activity of N-(ferrocenylethyl)-2-thiobenzimidazole (3b) were evaluated in vivo.Figure optionsDownload as PowerPoint slide