6 research outputs found
Improvements in viral cultures and applications to the isolation of antiviral compounds
Thesis (B.S.)--Univeristy of Illinois at Urbana-Champaign, 1997.Includes bibliographical reference (leaf 18)U of I OnlyTheses restricted to UIUC community onl
Total Synthesis of (−)-Lasonolide A
The lasonolides are novel polyketides
that have displayed remarkable biological activity in vitro against
a variety of cancer cell lines. Herein we describe our first-generation
approach to the formal synthesis of lasonolide A. The key findings
from these studies ultimately allowed us to go on and complete a total
synthesis of lasonolide A. The convergent approach unites two highly
complex fragments utilizing a Ru-catalyzed alkene–alkyne coupling.
This type of coupling typically generates branched products; however,
through a detailed investigation, we are now able to demonstrate that
subtle structural changes to the substrates can alter the selectivity
to favor the formation of the linear product. The synthesis of the
fragments features a number of atom-economical transformations which
are highlighted by the discovery of an engineered enzyme to perform
a dynamic kinetic reduction of a β-ketoester to establish the
absolute stereochemistry of the southern tetrahydropyran ring with
high levels of enantioÂselectivity
Broad-Spectrum Antiherpes Activities of 4-Hydroxyquinoline Carboxamides, a Novel Class of Herpesvirus Polymerase Inhibitors
Through broad screening of the compound library at Pharmacia, a naphthalene carboxamide was identified as a nonnucleoside inhibitor of human cytomegalovirus (HCMV) polymerase. Structure-activity relationship studies demonstrated that a quinoline ring could be substituted for naphthalene, resulting in the discovery of a 4-hydroxyquinoline-3-carboxamide (4-HQC) class of antiviral agents with unique biological properties. In vitro assays with the 4-HQCs have demonstrated potent inhibition of HCMV, herpes simplex virus type 1 (HSV-1), and varicella-zoster virus (VZV) polymerases but no inhibition of human α, δ, and γ polymerases. Antiviral cell culture assays have further confirmed that these compounds are active against HCMV, HSV-1, HSV-2, VZV, and many animal herpesviruses. However, these compounds were not active against several nonherpesviruses representing different DNA and RNA virus families. A strong correlation between the viral DNA polymerase and antiviral activity for this class of compounds supports inhibition of the viral polymerase as the mechanism of antiviral activity. Northern blot analysis of immediate-early and late viral transcripts also pointed to a block in the viral life cycle consistent with inhibition of viral DNA replication. In vitro HCMV polymerase assays indicate that the 4-HQCs are competitive inhibitors of nucleoside binding. However, no cross-resistance could be detected with ganciclovir-resistant HCMV or acyclovir-resistant HSV-1 mutants. The unique, broad-spectrum activities of the 4-HQCs may offer new opportunities for treating many of the diseases caused by herpesviruses
Discovery of the Selective CYP17A1 Lyase Inhibitor BMS-351 for the Treatment of Prostate Cancer
Efforts to identify a potent, reversible,
nonsteroidal CYP17A1
lyase inhibitor with good selectivity over CYP17A1 hydroxylase and
CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate
cancer (CRPC) culminated in the discovery of BMS-351 (compound <b>18</b>), a pyridyl biaryl benzimidazole with an excellent <i>in vivo</i> profile. Biological evaluation of BMS-351 at a dose
of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction
in testosterone levels with minimal glucocorticoid and mineralcorticoid
perturbation. Based on a favorable profile, BMS-351 was selected as
a candidate for further preclinical evaluation