Edward B. Skibo

Design of quinolinedione-based geldanamycin analogues

Quinoline-5,8-dione-based compounds were designed from the structure of the geldanamycin-bound Hsp-90 active site. The active site model predicted that aromatic substituents should be present at the 2-position, to take advantage of a hydrophobic pocket, and amino substituents should be present at the 6- or 7-position. COMPARE analysis revealed that the LC(50) profile of 2-phenyl-6-(2-chloroethylamino)quinoline-5,8-dione has the highest geldanamycin-like activity (0.74 correlation coefficient).

Rational design of purine nucleoside phosphorylase inhibitors: Design of 2-(2′-Haloethyl) and 2-ethenyl substituted quinazolinone alkylating agents.

Abstract The synthesis, elimination/addition mechanism, and purine nucleoside phosphorylase inhibitory properties of 2-(2′-bromoethyl) and 2-ethenyl substituted quinazolinone-based quinones are described herein. Both 2-substituted quinazolinone derivatives were designed to act as reductive alkylating agents of glutamate residues in the purine nucleoside phosphorylase active site. Mechanistic studies provided evidence of a novel alkylation process involving a quinazolinone prototropic tautomer. The tautomer is the result of a prototropic shift of the C(1′) proton of the 2-alkyl group to the N(1) position of the quinazolinone ring. Both 2-substituted quinazolinones rapidly and irreversibly inactivate purine nucleoside phosphorylase.

Pyrrolobenzimidazoles in cancer treatment

This review presents a discussion of the design, chemistry, cytotoxicity and antitumour activity of agents based on the pyrrolobenzimidazole or azomitosene ring system. The focus is the 6-aziridinylquinone derivatives (PBIs) and 6-acetamidoquinone derivatives (APBIs) of this ring system (see Figure 1). Comparisons will be made with related benzimidazole and indole-based antitumour agent systems reported in the patent literature. The pyrrolobenzimidazoles will be shown to represent a new and useful class of antitumour agent with advantages over other such agents. The 6-aziridinyl derivatives (PBIs) alkylate and cleave DNA upon two-electron reduction as a result of phosphate alkylation by the protonated aziridine ring. In contrast, the 6-acetamido quinone derivatives (APBIs) do not require reductive activation to exert cytotoxicity. The 6-acetamido quinone derivatives act as DNA intercalating agents and inhibit the first step of topoisomerase II-mediated DNA relaxation. Some PBIs were found to exhibit high ...

Inosine monophosphate dehydrogenase from porcine (Sus scrofa domestica) thymus: Purification and properties

1. IMP dehydrogenase (EC 1.1.1.205) from porcine thymus glands has been purified to homogeneity. 2. The enzyme has a subunit MW of 57 kDa and an amino acid composition similar to those obtained from other normal and cancerous mammalian cells. 3. The apparent Km values at pH 8.0 for IMP and NAD+ are 7 and 16 microM, respectively. 4. GMP, XMP and AMP are competitive inhibitors towards IMP and Ki values of 50, 85 and 282 microM, respectively. 5. The effectiveness of nucleotides to protect inactivation by CI-IMP is IMP > GMP > XMP > AMP.