Non-reducing polyketide synthases (NR-PKSs) are unique among PKSs in their domain structure, notably including a starter unit:acyl-carrier protein (ACP) transacylase (SAT) domain that selects an acyl group as the primer for biosynthesis, most commonly acetyl-CoA from central metabolism. This clan of mega-enzymes resembles fatty acid synthases (FASs) by both sharing their central chain elongation steps and their capacity for iterative catalysis. In this mode of synthesis, catalytic domains involved in chain extension exhibit substrate plasticity to accommodate growing chains as small as two carbons to 20 or more. PksA is the NR-PKS central to the biosynthesis of the mycotoxin aflatoxin B1 and whose SAT domain accepts an unusual hexanoyl starter from a dedicated yeast-like FAS. Explored in this paper is the ability of PksA to utilize a selection of potential starter units as substrates to initiate and sustain extension and cyclization to on-target, programmed polyketide synthesis. Most of these starter units were successfully accepted and properly processed by PksA to achieve biosynthesis of the predicted naphthopyrone product. Analysis of the on-target and derailment products revealed trends of tolerance by individual PksA domains to alternative starter units. In addition, natural and unnatural variants of the active site cysteine were examined and found to be capable of biosynthesis, suggesting possible direct loading of starter units onto the β-ketoacyl synthase (KS) domain. In light of the data assembled here, the predictable synthesis of un-natural products by NR-PKSs is more fully defined.
Six fluoroquinolone ribonucleosides were synthesized by using microwave irradiation starting from fluoroanilines. In most cases the microwave application proved superior in time and yield, especially the one step decarboxylation of the carboxyquinolone esters3a-3cand the Vorbrüggen glycosylation. The former led to the new type of fluoroquinolone ribosides8a-8c. Compound8cin the crystal structure showed C3'-endo and anti conformation. The nucleosides were examined, but found inactive against the replication of HIV-1(IIIB) in cell culture, while they were toxic for the cells at a 50% cytotoxic concentration ranging from 31 to >125 μg/ml. But measurements of the inhibitory effects against HIV-1 integrase enzymatic activity showed an interesting activity for compound8c.
Nucleic acids U 0700Microwave-Assisted Synthesis of Fluoroquinolones and Their Nucleosides as Inhibitors of HIV Integrase. -Slightly modified known methods and the use of microwave irradiation lead to improved results in the synthesis of 6 fluoroquinolone ribonucleosides (I) and (II). Pharmacological studies reveal positive effects in the case of (IIc). -(ADAMS, M. M.; BATS, J. W.; NIKOLAUS, N. V.; WITVROUW, M.; DEBYSER, Z.; ENGELS*, J. W.; Collect. Czech. Chem. Commun. 71 (2006) 7, 978-990; Inst. Org. Chem. Chem. Biol., Johann Wolfgang Goethe-Univ., D-60439 Frankfurt/M., Germany; Eng.) -S. Adam 01-205
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.