Synthesis of Substituted 6-Amino-4-(2,4-dimethoxyphenyl)-[1,2]dithiolo[4,3-<i>b</i>]pyrrol-5-ones and Their Raising Leukocyte Count Activities

Abstract

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...

Dithiolopyrrolones: biosynthesis, synthesis, and activity of a unique class of disulfide-containing antibiotics

“…Wang and co-workers expanded on the Welichem results with N-aryl substituted analogues by incorporating N-carbonyl groups on the exo-cyclic nitrogen, presumably to improve solubility of the otherwise lipophilic moiety. 87 The original compound, ZL-004, was initially disclosed in the patent literature, with subsequent analogues reported in the primary literature in 2013. While the investigators did not report a naturally occurring DTP, such as holomycin or thiolutin in their assays, they did demonstrate potent elevation of leukocyte counts in normal mice peripheral blood relative to recombinant human granulocyte colony stimulating factor (rhG-CSF) as a positive control.…”

Discovery of novel N‐aryl pyrrothine derivatives as bacterial RNA polymerase inhibitors

“…The synthesis procedures for N ‐aryl pyrrothine derivatives are shown in Scheme 1, following the synthesis routes on previous reports with minor modifications (Li, Wever, et al, 2014; Li, Sun, et al, 2014; Tan et al., 2013). The starting material of compound 1 was obtained according to previous procedure (Tan et al., 2013). Compounds 2a – j were synthesized from compound 1 and chlorocarbonate derivatives (R 1 OCOCl) by amidation reaction at room temperature for 3–10 hr.…”

“…Natural dithiolopyrrolones exhibit relatively broad‐spectrum antibiotic activity against many Gram‐positive and Gram‐negative bacteria (Qin et al., 2013). In recent years, N ‐aryl pyrrothine derivatives have been reported to have anticancer (Li et al., 2007) and anti‐leukopenia activity (Li, Wever, et al, 2014; Li, Sun, et al, 2014; Tan et al., 2013).…”

Bacterial pathogens: threat or treat (a review on bioactive natural products from bacterial pathogens)

“…[194][195][196][197][198][199] N-Aryl DTP analogues have been shown antitumor activity 198 and antileukopenia activity. 194,197 N-Aryl DTP with 2,4-dimethoxyphenyl moiety displayed potent antibacterial activity against clinical isolates of MRSA, RRSA, vancomycin-resistant S. aureus (VRSA), and moderately penicillin-resistant S. pneumoniae (MPRSP) with MIC values in the range of 0.125-2 mg mL À1 comparable to the antibiotic rifampin. 195 Previous works also showed that the biosynthetic pathway of DTPs is susceptible to be manipulated by feeding different organic acids or fatty acids to the cultures to modify the lateral acyl chain.…”