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Title:Biosynthetic Studies on Pactamycin
Author(s):Adams, Erik Stuart
Doctoral Committee Chair(s):Rinehart, Kenneth L., Jr.
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Biology, Microbiology
Chemistry, Organic
Abstract:Pactamycin (1), a cytotoxic antibiotic produced by Streptomyces pactum, var. pactum, contains several interesting structural features, including a cyclopentanoid ring, which is rare among natural products, a 6-methylsalicylic acid (6-MSA) unit derived from acetate via a polyketide route, and a m-aminoacetophenone unit, which represents the m-C$\sb7$N unit found in many antibiotics. It was expected that 6-MSA would be an advanced precursor to the corresponding unit on pactamycin, but feeding experiments with 6-methyl (carboxy-$\sp $C) salicylic acid and methyl 6-methyl (carboxy-$\sp $C) salicylate failed to show significant incorporation into either pactamycin or its analogue pactamycate. In addition, these precursors were apparently toxic to S. pactum, causing pronounced acidification of the production medium and substantial reduction of pactamycin production.(DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE DAI)
From the feeding experiments with methyl 6-methyl (carboxy-$\sp $C) salicylate, an unexpected glucuronylated metabolite of this precursor, 2-carbomethoxy-3-methylphenyl-$\beta$- scD-glucopyranosiduronic acid (2), was isolated as the triethylammonium salt, and its structure was proven by synthesis via a Konigs-Knorr route. Although conjugation of toxic substrates with glucuronic acid for purposes of detoxification is common in animals, this apparently represents the first reported instance of this phenomenon in bacteria.
A new pactamycin analogue, 5$\sp{\prime\prime}$-fluoropactamycin, has also been obtained by directed biosynthesis by supplementing the production medium with 3-amino-5-fluorobenzoic acid hydrochloride. The five-step synthesis of this precursor from 4-fluoro-2-nitroaniline is described. Administration of 3-amino-5-methylbenzoic acid hydrochloride, synthesized in an analogous fashion, did not result in production of the corresponding methylpactamycin, but instead inhibited pactamycin production. The bioactivities of 5$\sp{\prime\prime}$-fluoropactamycin and pactamycin by L1210 murine leukemia cell cytoxicity assay and antimicrobial assay versus B. subtilis were compared and showed no appreciable differences.
Issue Date:1993
Description:152 p.
Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1993.
Other Identifier(s):(UMI)AAI9328955
Date Available in IDEALS:2014-12-17
Date Deposited:1993

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