Furanfurin and thiophenfurin: Two novel tiazofurin analogues. Synthesis, structure, antitumor activity, and interactions with inosine monophosphate dehydrogenase

Palmarisa Franchetti, Loredana Cappellacci, Mario Grifantini, Anna Barzi, Giuseppe Nocentini, Hongyoan Yang, Ayrn O'Connor, Hiremagalur N. Jayaram, Christopher Carrell, Barry M. Goldstein

Research output: Contribution to journalArticle

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Abstract

The syntheses of furan and thiophene analogues of tiazofurin (furanfurin and thiophenfurin, respectively) are described. Direct stannic chloride-catalyzed C-glycosylation of ethyl 3-furancarboxylate (6) or ethyl 3-thiophencarboxylate (18) with 1,2,3,5-tetra-O-acetyl-D-ribofuranose gave 2- and 5-glycosylated regioisomers, as a mixture of α- and β-anomers, and the β-2,5-diglycosylated derivatives. Deprotection of ethyl 5-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)furan-3-carboxylate (9β) and ethyl 5-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)thiophene-3-carboxylate (20β) with sodium ethoxide afforded ethyl 5-β-D-ribofuranosylfuran-3-carboxylate (12β) and ethyl 5-β-D-ribofuranosylthiophene-3-carboxylate (23β) which were converted into 5-β-D-ribofurano-sylfuran-3-carboxamide (furanfurin, 4) and 5-β-D-ribofuranosylthiophene-3-carboxamide (thiophenfurin, 5) by reaction with ammonium hydroxide. The anomeric configuration and the site of glycosylation were established by 1H-NMR and proton-proton nuclear Overhauser effect difference spectroscopy. The structure of compound 23β was confirmed by X-ray crystallography. Thiophenfurin was found to be cytotoxic in vitro toward murine lymphocytic leukemia P388 and L1210, human myelogenous leukemia K562, human promyelocytic leukemia HL-60, human colon adenocarcinoma LoVo, and B16 melanoma at concentrations similar to that of tiazofurin. In the same test furanfurin proved to be inactive. Thiophenfurin was found active in vivo in BD2F1 mice inoculated with L1210 cells with a % T/C of 168 at 25 mg/kg. K562 cells incubation with thiophenfurin resulted in inhibition of inosine monophosphate (IMP) dehydrogenase (63%) and an increase in IMP pools (6-fold) with a concurrent decrease in GTP levels (42%). Incubation of adenosine-labeled K562 cells with tiazofurin, thiophenfurin, and furanfurin resulted in a 2-fold higher NAD analogue formulation by thiophenfurin than by tiazofurin. Furanfurin was converted to the NAD analogue with only 10% efficiency. The results obtained support the hypothesis that the presence of S in the heterocycle in position 2 with respect to the glycosidic bond is essential for the cytotoxicity and IMP dehydrogenase activity of tiazofurin, while the N atom is not.

Original languageEnglish
Pages (from-to)3829-3837
Number of pages9
JournalJournal of Medicinal Chemistry
Volume38
Issue number19
StatePublished - 1995

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tiazofurin
Inosine Monophosphate
Oxidoreductases
Thermodynamic properties
Glycosylation
Thiophenes
K562 Cells
NAD
Protons
Ammonium Hydroxide
Leukemia P388
Lymphoid Leukemia
Leukemia L1210
Experimental Melanomas
Myeloid Leukemia
X ray crystallography
X Ray Crystallography
Cytotoxicity
Guanosine Triphosphate
furanfurin

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Franchetti, P., Cappellacci, L., Grifantini, M., Barzi, A., Nocentini, G., Yang, H., ... Goldstein, B. M. (1995). Furanfurin and thiophenfurin: Two novel tiazofurin analogues. Synthesis, structure, antitumor activity, and interactions with inosine monophosphate dehydrogenase. Journal of Medicinal Chemistry, 38(19), 3829-3837.

Furanfurin and thiophenfurin : Two novel tiazofurin analogues. Synthesis, structure, antitumor activity, and interactions with inosine monophosphate dehydrogenase. / Franchetti, Palmarisa; Cappellacci, Loredana; Grifantini, Mario; Barzi, Anna; Nocentini, Giuseppe; Yang, Hongyoan; O'Connor, Ayrn; Jayaram, Hiremagalur N.; Carrell, Christopher; Goldstein, Barry M.

In: Journal of Medicinal Chemistry, Vol. 38, No. 19, 1995, p. 3829-3837.

Research output: Contribution to journalArticle

Franchetti, P, Cappellacci, L, Grifantini, M, Barzi, A, Nocentini, G, Yang, H, O'Connor, A, Jayaram, HN, Carrell, C & Goldstein, BM 1995, 'Furanfurin and thiophenfurin: Two novel tiazofurin analogues. Synthesis, structure, antitumor activity, and interactions with inosine monophosphate dehydrogenase', Journal of Medicinal Chemistry, vol. 38, no. 19, pp. 3829-3837.
Franchetti, Palmarisa ; Cappellacci, Loredana ; Grifantini, Mario ; Barzi, Anna ; Nocentini, Giuseppe ; Yang, Hongyoan ; O'Connor, Ayrn ; Jayaram, Hiremagalur N. ; Carrell, Christopher ; Goldstein, Barry M. / Furanfurin and thiophenfurin : Two novel tiazofurin analogues. Synthesis, structure, antitumor activity, and interactions with inosine monophosphate dehydrogenase. In: Journal of Medicinal Chemistry. 1995 ; Vol. 38, No. 19. pp. 3829-3837.
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abstract = "The syntheses of furan and thiophene analogues of tiazofurin (furanfurin and thiophenfurin, respectively) are described. Direct stannic chloride-catalyzed C-glycosylation of ethyl 3-furancarboxylate (6) or ethyl 3-thiophencarboxylate (18) with 1,2,3,5-tetra-O-acetyl-D-ribofuranose gave 2- and 5-glycosylated regioisomers, as a mixture of α- and β-anomers, and the β-2,5-diglycosylated derivatives. Deprotection of ethyl 5-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)furan-3-carboxylate (9β) and ethyl 5-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)thiophene-3-carboxylate (20β) with sodium ethoxide afforded ethyl 5-β-D-ribofuranosylfuran-3-carboxylate (12β) and ethyl 5-β-D-ribofuranosylthiophene-3-carboxylate (23β) which were converted into 5-β-D-ribofurano-sylfuran-3-carboxamide (furanfurin, 4) and 5-β-D-ribofuranosylthiophene-3-carboxamide (thiophenfurin, 5) by reaction with ammonium hydroxide. The anomeric configuration and the site of glycosylation were established by 1H-NMR and proton-proton nuclear Overhauser effect difference spectroscopy. The structure of compound 23β was confirmed by X-ray crystallography. Thiophenfurin was found to be cytotoxic in vitro toward murine lymphocytic leukemia P388 and L1210, human myelogenous leukemia K562, human promyelocytic leukemia HL-60, human colon adenocarcinoma LoVo, and B16 melanoma at concentrations similar to that of tiazofurin. In the same test furanfurin proved to be inactive. Thiophenfurin was found active in vivo in BD2F1 mice inoculated with L1210 cells with a {\%} T/C of 168 at 25 mg/kg. K562 cells incubation with thiophenfurin resulted in inhibition of inosine monophosphate (IMP) dehydrogenase (63{\%}) and an increase in IMP pools (6-fold) with a concurrent decrease in GTP levels (42{\%}). Incubation of adenosine-labeled K562 cells with tiazofurin, thiophenfurin, and furanfurin resulted in a 2-fold higher NAD analogue formulation by thiophenfurin than by tiazofurin. Furanfurin was converted to the NAD analogue with only 10{\%} efficiency. The results obtained support the hypothesis that the presence of S in the heterocycle in position 2 with respect to the glycosidic bond is essential for the cytotoxicity and IMP dehydrogenase activity of tiazofurin, while the N atom is not.",
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T1 - Furanfurin and thiophenfurin

T2 - Two novel tiazofurin analogues. Synthesis, structure, antitumor activity, and interactions with inosine monophosphate dehydrogenase

AU - Franchetti, Palmarisa

AU - Cappellacci, Loredana

AU - Grifantini, Mario

AU - Barzi, Anna

AU - Nocentini, Giuseppe

AU - Yang, Hongyoan

AU - O'Connor, Ayrn

AU - Jayaram, Hiremagalur N.

AU - Carrell, Christopher

AU - Goldstein, Barry M.

PY - 1995

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N2 - The syntheses of furan and thiophene analogues of tiazofurin (furanfurin and thiophenfurin, respectively) are described. Direct stannic chloride-catalyzed C-glycosylation of ethyl 3-furancarboxylate (6) or ethyl 3-thiophencarboxylate (18) with 1,2,3,5-tetra-O-acetyl-D-ribofuranose gave 2- and 5-glycosylated regioisomers, as a mixture of α- and β-anomers, and the β-2,5-diglycosylated derivatives. Deprotection of ethyl 5-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)furan-3-carboxylate (9β) and ethyl 5-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)thiophene-3-carboxylate (20β) with sodium ethoxide afforded ethyl 5-β-D-ribofuranosylfuran-3-carboxylate (12β) and ethyl 5-β-D-ribofuranosylthiophene-3-carboxylate (23β) which were converted into 5-β-D-ribofurano-sylfuran-3-carboxamide (furanfurin, 4) and 5-β-D-ribofuranosylthiophene-3-carboxamide (thiophenfurin, 5) by reaction with ammonium hydroxide. The anomeric configuration and the site of glycosylation were established by 1H-NMR and proton-proton nuclear Overhauser effect difference spectroscopy. The structure of compound 23β was confirmed by X-ray crystallography. Thiophenfurin was found to be cytotoxic in vitro toward murine lymphocytic leukemia P388 and L1210, human myelogenous leukemia K562, human promyelocytic leukemia HL-60, human colon adenocarcinoma LoVo, and B16 melanoma at concentrations similar to that of tiazofurin. In the same test furanfurin proved to be inactive. Thiophenfurin was found active in vivo in BD2F1 mice inoculated with L1210 cells with a % T/C of 168 at 25 mg/kg. K562 cells incubation with thiophenfurin resulted in inhibition of inosine monophosphate (IMP) dehydrogenase (63%) and an increase in IMP pools (6-fold) with a concurrent decrease in GTP levels (42%). Incubation of adenosine-labeled K562 cells with tiazofurin, thiophenfurin, and furanfurin resulted in a 2-fold higher NAD analogue formulation by thiophenfurin than by tiazofurin. Furanfurin was converted to the NAD analogue with only 10% efficiency. The results obtained support the hypothesis that the presence of S in the heterocycle in position 2 with respect to the glycosidic bond is essential for the cytotoxicity and IMP dehydrogenase activity of tiazofurin, while the N atom is not.

AB - The syntheses of furan and thiophene analogues of tiazofurin (furanfurin and thiophenfurin, respectively) are described. Direct stannic chloride-catalyzed C-glycosylation of ethyl 3-furancarboxylate (6) or ethyl 3-thiophencarboxylate (18) with 1,2,3,5-tetra-O-acetyl-D-ribofuranose gave 2- and 5-glycosylated regioisomers, as a mixture of α- and β-anomers, and the β-2,5-diglycosylated derivatives. Deprotection of ethyl 5-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)furan-3-carboxylate (9β) and ethyl 5-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)thiophene-3-carboxylate (20β) with sodium ethoxide afforded ethyl 5-β-D-ribofuranosylfuran-3-carboxylate (12β) and ethyl 5-β-D-ribofuranosylthiophene-3-carboxylate (23β) which were converted into 5-β-D-ribofurano-sylfuran-3-carboxamide (furanfurin, 4) and 5-β-D-ribofuranosylthiophene-3-carboxamide (thiophenfurin, 5) by reaction with ammonium hydroxide. The anomeric configuration and the site of glycosylation were established by 1H-NMR and proton-proton nuclear Overhauser effect difference spectroscopy. The structure of compound 23β was confirmed by X-ray crystallography. Thiophenfurin was found to be cytotoxic in vitro toward murine lymphocytic leukemia P388 and L1210, human myelogenous leukemia K562, human promyelocytic leukemia HL-60, human colon adenocarcinoma LoVo, and B16 melanoma at concentrations similar to that of tiazofurin. In the same test furanfurin proved to be inactive. Thiophenfurin was found active in vivo in BD2F1 mice inoculated with L1210 cells with a % T/C of 168 at 25 mg/kg. K562 cells incubation with thiophenfurin resulted in inhibition of inosine monophosphate (IMP) dehydrogenase (63%) and an increase in IMP pools (6-fold) with a concurrent decrease in GTP levels (42%). Incubation of adenosine-labeled K562 cells with tiazofurin, thiophenfurin, and furanfurin resulted in a 2-fold higher NAD analogue formulation by thiophenfurin than by tiazofurin. Furanfurin was converted to the NAD analogue with only 10% efficiency. The results obtained support the hypothesis that the presence of S in the heterocycle in position 2 with respect to the glycosidic bond is essential for the cytotoxicity and IMP dehydrogenase activity of tiazofurin, while the N atom is not.

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