Keith Krumpe

The application of disubstituted vinylogous iminium salts and related synthons to the regiocontrolled preparation of unsymmetrical 2,3,4-trisubstituted pyrroles

Abstract Reactions of 2,3-disubstituted chloropropeniminium salts and related synthons with ethyl glycinate, ethyl N-methylglycinate, and ethyl N-benzylglycinate have been studied under acidic, basic and neutral conditions. Such reactions have resulted in efficient and selective methodology for the synthesis of unsymmetrical 2,3,4-trisubstituted pyrrole systems.

The application of vinylogous iminium salt derivatives to a regiocontrolled and efficient relay synthesis of lukianol a and related marine natural products

Abstract Numerous novel pyrrole containing marine natural products have been shown to possess interesting biological properties. These compounds have been the synthetic targets of several research groups and we have previously reported synthetic methods which utilize vinylogous iminium salt derivatives as building blocks for analogous pyrrrole systems. We now report a novel and regiocontrolled synthesis of a known pyrrole synthetic precursor to the compounds Lukianol A and Lammelarin O dimethyl ether based on this synthetic methodology.

Lipid-Lowering Effects of Ethyl 2-Phenacyl-3-aryl-1H-pyrrole- 4-carboxylates in Rodents

A series of substituted 2-phenacyl-3-phenyl-1H-pyrrole-4-carboxylates were prepared from substituted acetophenones in 6 steps. The final condensations between a chloroenal and an aminoketone were carried out under neutral conditions in parallel to yield the series listed below. Selected pyrrole derivatives proved to be potent hypolipidemic agents lowering serum triglyceride concentrations in CF-1 male mice after 14 days of I.P. administration. One agent orally lowered serum cholesterol in Sprague-Dawley male rats at 2mg/kg/day after 14 days. The agents demonstrated a lowering of mouse serum LDL- cholesterol levels and selected compounds showed an elevation of serum HDL-cholesterol levels. The cholesterol concentrations in the liver were raised while the cholesterol and triglyceride contents of the aorta were significantly lowered by the selected trisubstituted pyrrole.

Cytotoxicity of substituted alkyl-3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylates in L1210 lymphoid leukemia cells.

Two alkyl‐3,4‐bis(4‐methoxyphenyl)pyrrole‐2‐carboxylates proved to be potent cytotoxic agents in the murine L1210 lymphoid leukemia screen. DNA synthesis was preferentially inhibited with the major target of the agents being de novo purine biosynthesis at the regulatory enzyme sites of PRPP‐amido transferase and IMP dehydrogenase. Other enzymatic activities which were suppressed by the drugs were DNA polymerase α, RNA polymerases, ribonucleoside reductase and dihydrofolate reductase. The d[NTP] pools, nucleoside kinase and the pyrimidine pathway were not affected by the presence of drugs. The DNA molecule itself was not the target of the agents, i.e. no alkylation of nucleotide bases, intercalation between bases or cross‐linking of DNA strands occurred. The agents did cause L1210 DNA fragmentation after 24 h incubation at 100 μM.

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 successfully prepared and demonstrated potent cytotoxicity against the growth of suspended murine and human tumors, i.e. leukemia and lymphomas, acute monocytic leukemia, and HeLa‐S3 uterine carcinoma. The brominated compounds were more selective in inhibiting the growth of tumors derived from human solid 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 Tmolt4 T cell leukemia cells DNA synthesis was reduced over 60 min from 25 to 100 μM followed by RNA synthesis reduction. De novo purine synthesis was retarded with the regulatory enzyme PRPP‐amido transferase being markedly inhibited with less effects on the activities of IMP dehydrogenase, dihydrofolate reductase,, and the nucleoside kinases. After 60 min incubations d[TTP] and d[GTP] pools were marginally reduced. In vitro ct‐DNA studies suggest that the agents may affect the DNA molecule itself with increased DNA viscosity and the Tmolt4 studies suggest that DNA cross‐linking of DNA strands may be present.