Synthesis and Structure‐Activity Relationships of A Novel Class of Dithiocarbamic Acid Esters as Anticancer Agent

Abstract

Based on a novel lead compound 4-methylpiperazine-1-carbodithioic acid 3-cyano-3,3-diphenylpropyl ester 1, the systematic structural modification was carried out. All the synthesized compounds were evaluated for their in-vitro anticancer activities on four to six different cell lines at three different concentrations. Most of the tested compounds could selectively inhibit the growth of HL-60 and Bel-7402 cell lines at a medium concentration. Four compounds (3f, 3g, 3n, and 5) were selected for the IC(50) test, and the results revealed that three compounds (3g, 3n, and 5) showed almost the same or a slightly weaker activity than compound 1 against HL-60, and three compounds (3f, 3g, and 3n) showed >2-fold higher potency than compound 1 against Bel-7402. The in-vivo efficacy of 3n · HCl was evaluated with transplanted hepatocyte carcinoma 22 as an in-vivo test model. It was found that 3n · HCl could inhibit significantly the growth of tumor, and that this effect was dose-dependent. Meanwhile, the compound 3n · HCl showed low toxicity compared with compound 1 · HCl as evidenced by the little body-weight loss. These results confirmed that compound 3n · HCl is more potent than the lead compound 1 · HCl. Preliminary structure-activity relationships indicated that: a) Both nitrile group and the cyclic amine containing at least two nitrogens were indispensable moieties to keep the activity; b) substitution of the piperazine ring is unfavorable for the improvement of activity; c) the suitable linker joining the piperazinyl dithiocarboxyl and diphenylacetonitril group should be ethylene; d) a non-coplanar arrangement of the two benzene rings appears to be essential for activity.

Photochemical Generation of 9H‐Fluorenyl Radicals

“…150–151°C (lit. 151–152°C); 1 H‐NMR δ ppm: 7.80 (d, J = 7.5 Hz, 2H); 7.52 (d, J = 7.6 Hz, 2H); 7.48 (2t, 4H); 4.96 (s, 1H).…”

Rigid Scaffolds: Synthesis of 2,6‐Bridged Piperazines with Functional Groups in all three Bridges

“…Altogether, bridged piperazines with a mixed ketal (20,21), an OH moiety (37) and a vinyl group (39) at the carbon bridge were obtained in low yields, whereas piperazines with a threecarbon bridge bearing a sulfinamido group (35,36) and a methylene moiety (41) were obtained in high yields. The 3,9diazabicyclo[3.3.1]nonanes 35, 36 and 41 will be exploited for synthesis of pharmacologically active compounds.…”

“…In order to establish the bridge providing the desired bicyclic compounds of type 8 key intermediate piperazine-2,6-diones (e. g. 12, 17) should react with various dielectrophiles stepwise or in a one-pot procedure. Piperazine-2,6-diones can be prepared either by alkylation of α-amino acid esters with bromoacetamide and subsequent cyclization [19,20] or by condensation of iminodiacetic acid derivatives with primary amines or NH 3 . [21][22][23][24] As reported in literature, iminodiacetic acids 13 and 14 (structures see Scheme 2) were reacted with primary amines under microwave irradiation.…”

Large-Scale Synthesis of Piperazine-2,6-dione and Its Use in the Synthesis of Dexrazoxane Analogues

“…We first attempted to prepare piperazine-2,6-dione by using known methods. [13][14][15][16][17] Piperazine-2,6-dione can be prepared by hydrolysis of 2,6-bishydroxyiminopiperazine. However, the reported preparation of 2,6-bishydroxyiminopiperazine starting from iminodiacetonitrile and hydroxylamine suffers from very low yield (14%).…”