Leinamycin antitumor activity

A recent study on the reactivity of the parent benzo-l,2-dithiolan-3-one 1-oxide 79a (R = R = H) and o- and /i-substituted derivatives 79b-g with -propyl thiol in acetone/water mixture (7/3) was prompted (Table 5) by the observation that the DNA-cleaving activity and antitumor activity of leinamycin 5 depends, in part <2005JOC6968>, on initial thiol attack on its l,3-dioxo-l,2-dithiolane functionality. Experimental results have proved that the presence of chlorine as an electron acceptor in the /i ra-position relative to the sulfmyl sulfur S-1 of precursor 79e and ortho-substituents with lone electron pairs in the case of precursors 79b and 79d are responsible for increased product formation of polysulfanes 80 and 81. A rationale in terms of substituent effects, operating through-space and through-bond of the intermediates a and b, respectively, was suggested. In other words, the reaction is favored by ortho-substituents with lone pair electrons next to the dithiolanone-oxide (S-1) reaction center or a decrease of the electron density at the /i ra-position. 

Kanda, Y, Ashizawa, T., Kakita, S., Takahashi, Y, Kono, M., Yoshida, M., Saitoh, Y, Okabe, M. Synthesis and antitumor activity of novel thioester derivatives of leinamycin. J. Med. Chem. 1999, 42, 1330-1332. 

The half-life of the antitumor antibiotic leinamycin in aqueous solution at pH 7 at 37°C is about 6 h and the hydrolysis of the reactive dithiolanone moiety could be one of the reasons of instability. However, this dithiolanone moiety of leinamycin has been shown to be essential for its DNA-cleaving activity and antiproliferative activity. Accordingly, Kanda et al devised more stable thioester derivatives, resulting from various alkylations in presence of potassium carbonate (Figure 41.7). 

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