N-Glycosyl-thiophene-2-carboxamides: synthesis, structure and effects on the growth of diverse cell types.
A range of N-glycosyl-thiophene-2-carboxamides, including a 6H-thieno[2,3-c]pyridin-7-one and a bivalent compound, have been synthesised and assayed for their effects on DNA synthesis in bovine aortic endothelial cells or on the growth of synoviocytes. Per-O-acetylated analogues of the glycoconjugates were significantly more effective inhibitors when compared to their corresponding non-acetylated analogues, indicating that the lower potency observed for hydroxylated derivatives is due to less efficient transport of these compounds across the cell membrane. Thiophene-2-carboxamide was inactive as an inhibitor of bFGF induced proliferation, confirming the requirement of the carbohydrate residue for the observed biological properties. Glucose, mannose, galactose and 2-amino-2-deoxy-glucose analogues were active as were a variety of substituted thiophene derivatives; the 6H-thieno[2,3-c]pyridin-7-one conjugate was inactive. Conformational analysis of the title compounds was investigated. X-ray crystal structural analysis of four N-glucosyl-thiophene-2-carboxamides showed that the pyranose rings adopted the expected 4C1 conformations and that Z-anti structures were predominant (H1-C1-N-H anomeric torsion angle varied from -168.2 degrees to -175.0 degrees ) and that the carbonyl oxygen and sulfur of the thiophene adopted an s-cis conformation in three of the isomers. In a crystal structure of a 3-alkynyl derivative, the hydrogen atom of the NH group was directed toward the acetylene group. The distance between the hydrogen atom and acetylene carbons and angles between nitrogen, hydrogen and carbon atoms were consistent with hydrogen bonding and this was supported by IR and NMR spectroscopic studies. The geometries of thiophene-2-carboxamides were explored by density functional theory (DFT) and Møller-Plesset (MP2) calculations and the s-cis conformer of thiophene-2-carboxamide was found to be more stable than its s-trans isomer by 0.83 kcal mol(-1). The s-cis conformer of 3-ethynyl-thiophene-2-carboxamide was 5.32 kcal mol(-1) more stable than the s-trans isomer. The larger stabilisation for the s-cis conformer in the 3-alkynyl derivatives is explained to be due to a moderate hydrogen bonding interaction between the alkyne and NH group.
Rawe
Sarah L
SL
Centre for Synthesis and Chemical Biology and UCD School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland.
Doyle
Dearbhla
D
Zaric
Violeta
V
Rozas
Isabel
I
McMahon
Kevin
K
Tosin
Manuela
M
Bunz
Helge Müller
HM
Murphy
Evelyn P
EP
O' Boyle
Kathy M
KM
Murphy
Paul V
PV
D000818:Animals; D002417:Cattle; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004247:DNA / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006027:Glycosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D013055:Spectrophotometry, Infrared; D013583:Synovial Membrane / Q000166:cytology / Q000254:growth & development; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D006027:Glycosides; D013876:Thiophenes; D004247:DNA