Daniel J. Parks

Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo.

The activity and stability of the p53 tumor suppressor are regulated by the human homologue of the mouse double minute 2 (Hdm2) oncoprotein. It has been hypothesized that small molecules disrupting the Hdm2:p53 complex would allow for the activation of p53 and result in growth suppression. We have identified small-molecule inhibitors of the Hdm2:p53 interaction using our proprietary ThermoFluor microcalorimetry technology. Medicinal chemistry and structure-based drug design led to the development of an optimized series of benzodiazepinediones, including TDP521252 and TDP665759. Activities were dependent on the expression of wild-type (wt) p53 and Hdm2 as determined by lack of potency in mutant or null p53-expressing cell lines or cells engineered to no longer express Hdm2 and wt p53. TDP521252 and TDP665759 inhibited the proliferation of wt p53-expressing cell lines with average IC50s of 14 and 0.7 μmol/L, respectively. These results correlated with the direct cellular dissociation of Hdm2 from wt p53 observed within 15 minutes in JAR choriocarcinoma cells. Additional activities of these inhibitors in vitro include stabilization of p53 protein levels, up-regulation of p53 target genes in a DNA damage–independent manner, and induction of apoptosis in HepG2 cells. Administration of TDP665759 to mice led to an increase in p21waf1/cip1 levels in liver samples. Finally, TDP665759 synergizes with doxorubicin both in culture and in an A375 xenograft model to decrease tumor growth. Taken together, these data support the potential utility of small-molecule inhibitors of the Hdm2:p53 interaction for the treatment of wt p53-expressing tumors. [Mol Cancer Ther 2006;5(1):160–9]

Synthesis of a novel series of tetra-substituted furan[3,2-b]pyrroles

Furan[3,2-b]pyrroles are important isosteres for the indole scaffold in which the benzene ring is replaced by the furan ring. A series of novel tetra-substituted furan[3,2-b]pyrroles was synthesized from a simple furaldehyde. The divergent synthesis allows for substitution on multiple positions on the scaffold, creating the potential for the formation of large libraries.

Synthesis of a novel series of 10-oxa-3-aza-tricyclo[5.2.1.01,5]dec-8-en-4-ones through an intramolecular Diels–Alder reaction

Abstract The synthesis of a novel series of 10-oxa-3-aza-tricyclo[5.2.1.0 1,5 ]dec-8-en-4-ones through the use of the intramolecular Diels–Alder reaction is presented. The use of this reaction allows for the synthesis of functionalized polycyclic systems in a stereocontrolled manner.

The synthesis of ethanolamine libraries from olefin scaffolds

Abstract A solution-phase, multi-reaction sequence has been developed for the parallel synthesis of ethanolamine libraries. This approach uses 2,3-dibromopropene as a template for the synthesis of a small olefin sub-library, which is then further functionalized to form the final ethanolamine library. The methodology is demonstrated by the synthesis of a 5×4 array of ethanolamines.