Danny Gauvreau

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The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to(More)
Nuclear magnetic resonance has been employed to characterize fourteen new antibiotics belonging to the quinoxaline group, produced by feeding aromatic acids to Streptomyces echinatus. Twelve of the antibiotics are the expected substituted quinomycins and adopt conformations very similar to that of echinomycin. This is discussed in relation to their(More)
Streptomyces echinatus A8331 cultured on a maltose minimal salts medium normally produces a single antibiotic, echinomycin (quinomycin A), containing two quinoxaline-2-carbonyl chromophores. Echinomycin is powerfully active against experimental tumours and can be assayed by its activity against Gram-positive bacteria. Grown in the presence of aromatic(More)
New antibiotics produced by Streptomyces echinatus A8331 cultured in the presence of heterocyclic aromatic acids can be separated and purified by high-performance liquid chromatography using reversed phase columns. Natural quinoxaline antibiotics and certain quinoline derivatives can also be efficiently separated in normal phase systems. Details of(More)
Practical, chromatography-free syntheses of 5-lipoxygenase inhibitor MK-0633 p-toluenesulfonate (1) are described. The first route used an asymmetric zincate addition to ethyl 2,2,2-trifluoropyruvate followed by 1,3,4-oxadiazole formation and reductive amination as key steps. An improved second route features an inexpensive diastereomeric salt resolution of(More)
Two novel antibiotics were isolated, designated compounds 1QN and 2QN respectively, having quinoline rings in place of one or both of the quinoxaline chromophores of echinomycin. Each removes and reverses the supercoiling of closed circular duplex DNA from bacteriophage PM2 in the fashion characteristic of intercalating drugs. For compound 1QN, the(More)
A practical and efficient synthesis of bradykinin B(1) antagonist 1 is described. A convergent strategy was utilized which involved synthesis of three fragments: 3, 6, and 7. Cross coupling of fragments 6 and 7 followed by amidation with 3 enabled efficient synthesis of 1 in 19 steps total, a 35% overall yield from commercially available pyridine 10. The(More)
In this paper, we report the development of different synthetic routes to MK-7246 (1) designed by the Process Chemistry group. The syntheses were initially designed as an enabling tool for Medicinal Chemistry colleagues in order to rapidly explore structure-activity relationships (SAR) and to procure the first milligrams of diverse target molecules for in(More)
Washed suspensions of Streptomyces echinatus, and protoplasts derived from them, have been shown to synthesise echinomycin in the absence of growth. Protoplast suspensions free from significant contamination with unlysed mycelia are obtained by incubation with lysozyme followed by filtration through layers of tightly packed glass wool. Although(More)
A practical large-scale chromatography-free synthesis of EP4 antagonist MF-310, a potential new treatment for chronic inflammation, is presented. The synthetic route provided MF-310 as its sodium salt in 10 steps and 17% overall yield from commercially available pyridine dicarboxylate 7. The key features of this sequence include a unique regioselective(More)