James A. Sikorski

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.

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.

Replacements for lysine in l-seryl-l-lysyl dipeptide amide inhibitors of candida albicans myristoyl-CoA:protein N-myristoyltransferase

Abstract A survey of potential cyclic and acyclic lysine replacements in known l -seryl- l -lysyl dipeptide inhibitors of C. albicans NMT identified the thioether 16 and glycinamide 18 as submicromolar inhibitors of C. albicans NMT, which retained good selectivity over the human enzyme. All of the heterocyclic lysine mimetics that were examined exhibited dramatically weaker affinity with the fungal enzyme.

Chapter 22. Cholesteryl ester transfer protein as a potential therapeutic target to improve the HDL to LDL cholesterol ratio

Publisher Summary This chapter analyzes cholesteryl ester transfer protein (CETP) as a potential therapeutic target to improve the high density lipoprotein (HDL) to low density lipoprotein (LDL) cholesterol ratio. CETP mediates the transfer of cholesteryl esters (CE) from HDL to VLDL with a balanced reciprocal exchange of TG. CETP moves CE from HDL that is known to protect against coronary heart disease (CHD) into proatherogenic VLDL and LDL. Studies support the theory that CETP is atherogenic. More recently, data from transgenic mouse studies and detailed evaluation of human genetic epidemiology suggest CETP may also be able to serve a protective role against CHD. CETP may be cardio-protective by its participation in a process termed “reverse cholesterol transport” (RCT), that is, the transfer of cholesterol from peripheral tissues to the liver via HDL. Species variation in CETP expression correlates with their HDL-C levels and susceptibility to dietary cholesterol-induced atherosclerosis. The chapter discusses inhibition of CETP as a therapeutic target. Chemistry of small molecule CETP inhibitors is explained and an overview of tetrahydroquinoline and tetrahydronaphthalene inhibitors is also presented.