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Design and synthesis of fluorescent pilicides and curlicides: bioactive tools to study bacterial virulence mechanisms.

Chorell E, Pinkner JS, Bengtsson C, Edvinsson S, Cusumano CK, Rosenbaum E, Johansson LB, Hultgren SJ, Almqvist F - Chemistry (2012)

Bottom Line: To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized.This was achieved by using a strategy based on structure-activity knowledge, in which key pilicide and curlicide substituents on the ring-fused dihydrothiazolo 2-pyridone central fragment were replaced by fluorophores.We created fluorescent pilicides and curlicides by introducing coumarin and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide central fragment.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Umeå University, 90187 Umeå, Sweden.

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a) i) (COCl)2, CH2Cl2, RT, 17 h; ii) TEA, cysteine methyl ester, CH2Cl2, 0 °C to RT, 4.5 h, 64 %; b) i) TiCl4, CH2Cl2, 0 °C to RT, 4.5 h; ii) BF3⋅OEt2, CH2Cl2, RT, 40 min, 75 %; c) 21, TFA, dichloroethane, MWI: 120 °C, 140 s, 64 %; d) i) LiI, pyridine, MWI: 140 °C, 15 min; ii) TEA, BF3⋅OEt2, dichloroethane, 80 °C, 15 min, 29 %.
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sch4: a) i) (COCl)2, CH2Cl2, RT, 17 h; ii) TEA, cysteine methyl ester, CH2Cl2, 0 °C to RT, 4.5 h, 64 %; b) i) TiCl4, CH2Cl2, 0 °C to RT, 4.5 h; ii) BF3⋅OEt2, CH2Cl2, RT, 40 min, 75 %; c) 21, TFA, dichloroethane, MWI: 120 °C, 140 s, 64 %; d) i) LiI, pyridine, MWI: 140 °C, 15 min; ii) TEA, BF3⋅OEt2, dichloroethane, 80 °C, 15 min, 29 %.

Mentions: To increase the probability of identifying a bioactive compound with useful fluorescence properties, the possibility of introducing a different fluorophore on the central fragment was investigated. 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) is a known fluorophore that normally gives high quantum yields, carries no net charges, is relatively insensitive to the choice of solvent, and should give a different emission color as compared to the coumarins.20 The synthesis of the BODIPY core structure is often accompanied by low yields. The desired 8-propanoic acid-functionalized 1,3,5,7-tetramethyl-substituted BODIPY (24) has previously been synthesized in 21 % yield.25 From 24, the introduction of a BODIPY substituent in the C8 position of the pilicide/curicide central fragment could be pursued. Coupling 24 using a standard coupling procedure with methylester-protected cysteine gave the intermediate 25 in 64 % yield (Scheme 4). Ring closure of 25 to give 26 followed by acyl-ketene imine cyclocondensation with Meldrum’s acid derivative 21 gave the BODIPY-substituted dihydrothiazolo ring-fused 2-pyridone 27 in 64 % yield. The following hydrolysis proved to be problematic and the harsh conditions needed for this transformation ultimately gave 28 in 29 % yield as a racemate (Scheme 4). However, on the basis of previous reports showing that both enantiomers of the pilicide central fragment are biologically active, it was still entirely possible that racemic 28 could display interesting bioactivity.9, 26


Design and synthesis of fluorescent pilicides and curlicides: bioactive tools to study bacterial virulence mechanisms.

Chorell E, Pinkner JS, Bengtsson C, Edvinsson S, Cusumano CK, Rosenbaum E, Johansson LB, Hultgren SJ, Almqvist F - Chemistry (2012)

a) i) (COCl)2, CH2Cl2, RT, 17 h; ii) TEA, cysteine methyl ester, CH2Cl2, 0 °C to RT, 4.5 h, 64 %; b) i) TiCl4, CH2Cl2, 0 °C to RT, 4.5 h; ii) BF3⋅OEt2, CH2Cl2, RT, 40 min, 75 %; c) 21, TFA, dichloroethane, MWI: 120 °C, 140 s, 64 %; d) i) LiI, pyridine, MWI: 140 °C, 15 min; ii) TEA, BF3⋅OEt2, dichloroethane, 80 °C, 15 min, 29 %.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569613&req=5

sch4: a) i) (COCl)2, CH2Cl2, RT, 17 h; ii) TEA, cysteine methyl ester, CH2Cl2, 0 °C to RT, 4.5 h, 64 %; b) i) TiCl4, CH2Cl2, 0 °C to RT, 4.5 h; ii) BF3⋅OEt2, CH2Cl2, RT, 40 min, 75 %; c) 21, TFA, dichloroethane, MWI: 120 °C, 140 s, 64 %; d) i) LiI, pyridine, MWI: 140 °C, 15 min; ii) TEA, BF3⋅OEt2, dichloroethane, 80 °C, 15 min, 29 %.
Mentions: To increase the probability of identifying a bioactive compound with useful fluorescence properties, the possibility of introducing a different fluorophore on the central fragment was investigated. 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) is a known fluorophore that normally gives high quantum yields, carries no net charges, is relatively insensitive to the choice of solvent, and should give a different emission color as compared to the coumarins.20 The synthesis of the BODIPY core structure is often accompanied by low yields. The desired 8-propanoic acid-functionalized 1,3,5,7-tetramethyl-substituted BODIPY (24) has previously been synthesized in 21 % yield.25 From 24, the introduction of a BODIPY substituent in the C8 position of the pilicide/curicide central fragment could be pursued. Coupling 24 using a standard coupling procedure with methylester-protected cysteine gave the intermediate 25 in 64 % yield (Scheme 4). Ring closure of 25 to give 26 followed by acyl-ketene imine cyclocondensation with Meldrum’s acid derivative 21 gave the BODIPY-substituted dihydrothiazolo ring-fused 2-pyridone 27 in 64 % yield. The following hydrolysis proved to be problematic and the harsh conditions needed for this transformation ultimately gave 28 in 29 % yield as a racemate (Scheme 4). However, on the basis of previous reports showing that both enantiomers of the pilicide central fragment are biologically active, it was still entirely possible that racemic 28 could display interesting bioactivity.9, 26

Bottom Line: To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized.This was achieved by using a strategy based on structure-activity knowledge, in which key pilicide and curlicide substituents on the ring-fused dihydrothiazolo 2-pyridone central fragment were replaced by fluorophores.We created fluorescent pilicides and curlicides by introducing coumarin and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide central fragment.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Umeå University, 90187 Umeå, Sweden.

Show MeSH
Related in: MedlinePlus