Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1

The treatment of Human African Trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important and pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp. has been identified as a candidate target and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from T. brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. 8 compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development

A commensal strain of Staphylococcus epidermidis protects against skin neoplasia.

We report the discovery that strains of Staphylococcus epidermidis produce 6-N-hydroxyaminopurine (6-HAP), a molecule that inhibits DNA polymerase activity. In culture, 6-HAP selectively inhibited proliferation of tumor lines but did not inhibit primary keratinocytes. Resistance to 6-HAP was associated with the expression of mitochondrial amidoxime reducing components, enzymes that were not observed in cells sensitive to this compound. Intravenous injection of 6-HAP in mice suppressed the growth of B16F10 melanoma without evidence of systemic toxicity. Colonization of mice with an S. epidermidis strain producing 6-HAP reduced the incidence of ultraviolet-induced tumors compared to mice colonized by a control strain that did not produce 6-HAP. S. epidermidis strains producing 6-HAP were found in the metagenome from multiple healthy human subjects, suggesting that the microbiome of some individuals may confer protection against skin cancer. These findings show a new role for skin commensal bacteria in host defense. Sci Adv 2018 Feb 28; 4(2):eaao450

The chemistry and biology of zoanthamine alkaloids and Illicium sesquiterpenes

Natural products, or secondary metabolites, have proven significant to the existence of life. They have been used for countless reasons throughout history, including nonessential purposes such as dyes for textiles and paints. Less trivial uses, such as those related to health better demonstrate the importance of natural products. Toxic natural products had been used to bolster hunting efficiency and insect pheromones. Therapeutic natural products have long been used as dietary supplements and medicines. The ubiquitous nature of natural products and their derivatives in current medicinal validates continued investigations in all areas of natural product research. Our laboratory has a longstanding tradition in the synthesis and evaluation of biologically interesting natural products. We have viewed natural product synthesis as a tool to expand our understanding of organic chemistry. Of particular are natural products with novel architectures. The synthetic study of these natural products often inspires creativity to solve complicated synthetic challenges, and leads to the development of new methodologies. Novel structural characteristics and attractive bioactivities of two natural product families, zoanthamine alkaloids and Illicium sesquiterpenes, caught our interest for the stated reasons. Research herein describes work directed towards synthesis of the ABC ring system of norzoanthamine, total syntheses of Illicium sesquiterpenes jiadifenolide and jiadifenin. Chapters 1 and 2 narrate the background and research related to the norzoanthamine ABC ring motif. Chapters 3 and 4 report the total syntheses of jiadifenolide and jiadifenin, and their biological studies related to their neurotrophic activit

A commensal strain of Staphylococcus epidermidis protects against skin neoplasia.

We report the discovery that strains of Staphylococcus epidermidis produce 6-N-hydroxyaminopurine (6-HAP), a molecule that inhibits DNA polymerase activity. In culture, 6-HAP selectively inhibited proliferation of tumor lines but did not inhibit primary keratinocytes. Resistance to 6-HAP was associated with the expression of mitochondrial amidoxime reducing components, enzymes that were not observed in cells sensitive to this compound. Intravenous injection of 6-HAP in mice suppressed the growth of B16F10 melanoma without evidence of systemic toxicity. Colonization of mice with an S. epidermidis strain producing 6-HAP reduced the incidence of ultraviolet-induced tumors compared to mice colonized by a control strain that did not produce 6-HAP. S. epidermidis strains producing 6-HAP were found in the metagenome from multiple healthy human subjects, suggesting that the microbiome of some individuals may confer protection against skin cancer. These findings show a new role for skin commensal bacteria in host defense

<i>In Vitro</i> and <i>In Vivo</i> Evaluation of APX001A/APX001 and Other Gwt1 Inhibitors against Cryptococcus

Cryptococcal meningitis (CM), caused primarily by Cryptococcus neoformans , is uniformly fatal if not treated. Treatment options are limited, especially in resource-poor geographical regions, and mortality rates remain high despite current therapies. </jats:p

Structure-Based Design of New Dihydrofolate Reductase Antibacterial Agents: 7‑(Benzimidazol-1-yl)-2,4-diaminoquinazolines

A new series of dihydrofolate reductase (DHFR) inhibitors, the 7-(benzimidazol-1-yl)-2,4-diaminoquinazolines, were designed and optimized for antibacterial potency and enzyme selectivity. The most potent inhibitors in this series contained a five-membered heterocycle at the 2-position of the benzimidazole, leading to highly potent and selective compounds that exploit the differences in the size of a binding pocket adjacent to the NADPH cofactor between the bacterial and human DHFR enzymes. Typical of these compounds is 7-((2-thiazol-2-yl)­benzimidazol-1-yl)-2,4 diaminoquinazoline, which is a potent inhibitor of S. aureus DHFR (Ki = 0.002 nM) with 46700-fold selectivity over human DHFR. This compound also has high antibacterial potency on Gram-positive bacteria with an MIC versus wild type S. aureus of 0.0125 μg/mL and a MIC versus trimethoprim-resistant S. aureus of 0.25 μg/mL. In vivo efficacy versus a S. aureus septicemia was demonstrated, highlighting the potential of this new series