Synthesis and cytotoxicity of 2,4-disubstituted and 2,3,4-trisubstituted brominated pyrroles in murine and human cultured tumor cells

The 2,4-disubstituted and 2,3,4-trisubstituted brominated pyrroles were suc cessfully prepared and demonstrated potent cytotoxicity against the growth of suspended murine and human tumors, i.e. leukemia and lymphomas, acute mo nocytic leukemia, and HeLa-S-3 uterine carcinoma. The brominated compounds were more selective in inhibiting the growth of tumors derived from human s olid tumors. Nevertheless activity with some of the derivatives occurred in the human KB nasopharynx, SW-480 colon, and HCT ileum adenocarcinoma, and lung A549 carcinoma screens. In Tmolt(4) T cell leukemia cells DNA synthesi s was reduced over 60 min from 25 to 100 mu M followed by RNA synthesis red uction. De novo purine synthesis was retarded with the regulatory enzyme PR PP-amino transferase being markedly inhibited with less effects dehydrogena se, dihydrofolate reductase,, nucleoside kinases. After 60 min incubations d[TTP] and d[GTP] pools were marginally reduced. In vitro ct-DNA studies th at the agents may affect the DNA molecule itself with DNA viscosity and the Tmolt(4) studies suggest that DNA cross-linking of DNA strands may be pres ent.