The design and synthesis of a series of substituted 6-amino-4-(2,4-dimethoxyphenyl)-[1,2]dithiolo[4,3-b]-pyrrol-5-ones are described. All the synthesized compounds were evaluated for raising leukocyte count activities in normal mice. Four compounds (8a, b, d, h) exhibited raising leukocyte count activities close or higher than positive control recombinant human granulocyte colony stimulating factor (rhG-CSF), and some (8e-g, k, p, r) had a moderate effect. Among them, the most potent compound 8a was evaluated for its antileukopenia activity in cyclophosphamide (CTX) treated mice. Interestingly, 8a exhibited significant antileukopenia activity as compared to rhG-CSF. The results suggest that this kind of compounds might be utilized for the development of new candidate for treatment of leukocytopenia. and from other organisms since that time.2-4) This group of compounds includes thiolutin, aureothricin, isobutyropyrrothin, holomycin, xenorhabdins and thiomarinols A-G 5-9) ( Fig. 1). Dithiolopyrrolones are reported with diverse biological activities including against various Gram-positive and Gram-negative bacteria, yeasts, fungi and amoeboid parasites.10-12) Dithiolopyrrolones have also been reported to have anticancer activity.
13,14)The modifications of the dithiolopyrrolones have been extensively reported in literature. [15][16][17][18][19][20][21] However, all the modifications were intended to improve the antibacterial or anticancer activity. In our previous work, we first observed that ZL-004 (Fig. 2) exhibited antileukopenia activity, 22) which can significantly raise the white blood cells (WBC) count in normal mice and chemotherapy-induced mice. The mechanism of ZL-004 23) is to act on the mouse bone marrow causing proliferation and differentiation, the elevation of WBC is due to an increase in the absolute neutrophil count, which could promote the recovery of hemopoiesis. Also, it can raise WBC count in a dose-dependent manner without significant changes in erythrocyte, platelet counts or hemoglobin concentrations.In order to better understand the structure-activity relationship (SAR) and discover novel antileukopenia agents with higher potency and good safety profiles, we embarked on design and synthesis of analogues of ZL-004. In this study, we reported the practical synthesis, the SAR, the raising leukocyte count activity in normal mice and the antileukopenia activity in CTX-treated mice of the newly synthesized dithiolopyrrolones.
24,25)
Results and DiscussionChemistry The synthesis of the target compounds was accomplished by the procedures shown in Chart 1. 1,3-Bis(tert-butylthio)propan-2-one was prepared from 1,3-dichloroacetone in the presence of potassium carbonate in acetone, which was coupled with 2,4-dimethoxyanile in toluene utilizing p-toluenesulfonic acid as catalyst. The reaction mixture was refluxed for 5h, and then the mixture was allowed to cool to −5°C, oxayl chlorite was added to the reaction mixture to generate the compound 3 in 75% yield. Ammonization of 3 by in situ synthesis of amm...
