Synthesis and Cytotoxic Action of 3,5‐Isoxazolidinediones and 2‐Isoxazolin‐5‐ones in Murine and Human Tumors

Abstract

The 3,5-isoxazolidinediones and 2-isoxazolin-5-ones demonstrated potent cytotoxicity against the growth of human Tmolt3 T cell leukemia, murine P388 and L1210 leukemias, as well as human HeLa-S3 uterine carcinoma and glioma tumor cell growth. The specificity of the 3,5-isoxazolidinedione and 2-isoxazoline-5-one derivatives as cytotoxic agents varied with the histological type of tumor cell. Selected compounds were active against solid HeLa uterine. KB nasopharynx, skin A431, SW-480 adenocarcinoma, osteosarcoma and glioma growth. Selected compounds demonstrated in vivo antineoplastic activity against Ehrlich ascites carcinoma growth. In L-1210 leukemia cells, the agents blocked DNA and protein synthesis at 25, 50 and 100 microM over 60 min. The agents were effective in reducing rate limiting enzymes in the de novo purine and pyrimidine pathways. In addition they suppressed dihydrofolate reductase and ribonucleoside reductase activities with moderate inhibition of DNA and RNA polymerase activities. DNA itself was not a target of the agents.

Cytotoxicity of Substituted Alkyl-3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylates in L1210 Lymphoid Leukemia Cells

“…Compounds 1 and 2 afforded excellent cytotoxicity in the murine L1210 lymphoid leukemic, P388 lymphocytic leukemia, and human Tmolt 3 and Tmolt 4 T cell leukemia, HL-60 leukemia, HuT-8 lymphoma, THP-1 monocytic leukemia, EH118 MG glioma and HeLa-S 3 uterine carcinoma screens with ED 50 values less than 20 µM which compared well with the clinical anti-neoplastic standards [ Table 1]. …”

“…For the concentration response studies, inhibition of enzyme activity was determined at 25, 50 and 100 µM of compounds 1 and 2, after 60 min incubations. These concentrations of the agents were selected for 1 hour incubation to establish the mode of action of the derivatives quickly and are consistent with literature models [1][2][3][4][5][6][7][8][9][10][11][12][13] . DNA polymerase α activity was determined in cytoplasmic isolated extracts [22] .…”

“…These include 1-acyl-and 1,2-diacyl-4,4-diethyl-3,5-pyrazolidinediones [1] , 1-acyl-and 1,2-diacyl-1,2,4-triazolidinedione-3,5-diones [2] , 3,5-isoxazolidinediones and 2-isoxazoline-5-ones [3] , 2-alkoxycarbonyl-5-aryl-1,3,5-triazine-4,6(1H,5H)diones [4] , 3 -imino-1-oxaisoindolines [5] , 5,6-substituted 1(2)H-indazole-4,7-diones [6] , N-pyridinyl and N-quinolinyl substituted phthalimides and succinimides [7] , diazomethyl ketone and chloromethyl ketone analogues of N-tosyl amino acids [8] , furan derivatives [9] , and vinyl, cyanomethyl and pyranyl activated esters of 2-furoic acid and 2-furylacrylic acids [10] , [(N-alkyl-1,3-dioxo-1H,3H-isoindolin-5-yl)oxy]-alkanoic acids [11] , [ (N-alkyl-1H,3H-1-oxoisoindolin-5-yl-oxyalkanoates [12] , and 5,6-disubstituted 1(2)H-indazole-4,7-diones [13] . Recently, the marine natural product rigidin, which is a pyrrolopyrimidine, has demonstrated several types of biological activity [14] .…”

Tmolt4 Leukemic Type II Isoform of IMP Dehydrogenase as a Target for 1,2,4-Triazolidine-3,5-diones, 1-(1-(3-Methylphenyl)ethylidineamino)-4,4-diethyl-3,5-azetidinediones, 3,5-Isoxazolidinediones, and 4,4-Disubstituted-3,5-pyrazolidinediones

“…Previously a series of 1,2,4-triazolidine-3,5-diones [1] (1-8), 1-(1-(3-methylphenyl)ethylidineamino)-4,4-diethyl-3,5-azetidinediones [2] (14-20), 3,5-isoxazolidinediones [3] (11, 12), and 4,4-disubstituted-3,5-pyrazolidinediones [4] (9,10) were shown to be effective antineoplastic agents that inhibited DNA and purine syntheses. Some of these agents inhibited the activities of both regulatory enzymes in the purine pathway (i.e., PPRP-amido transferase and IMPDH); others only inhibited IMPDH activity [1][2][3][4] .…”

“…Some of these agents inhibited the activities of both regulatory enzymes in the purine pathway (i.e., PPRP-amido transferase and IMPDH); others only inhibited IMPDH activity [1][2][3][4] . It has recently been established that the IMPDH enzyme exists as two isoforms: Type I is constitutively expressed in resting or normal cells and Type II predominates in neoplastic or replicating cells [5][6][7] .…”