The Experts below are selected from a list of 51 Experts worldwide ranked by ideXlab platform
Hiremagalur N. Jayaram - One of the best experts on this subject based on the ideXlab platform.
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cytotoxicity and cellular differentiation activity of methylenebis phosphonate analogs of tiazofurin and mycophenolic acid adenine dinucleotide in human cancer cell lines
2002Co-Authors: Joel A Yalowitz, Krzysztof W Pankiewicz, Steven E Patterson, Hiremagalur N. JayaramAbstract:Mycophenolic acid (MPA) is a fungally-derived inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH). MPA binds IMPDH at the nicotinamide sub-site of the NAD cofactor binding domain leaving the adenosine sub-site empty. In order to improve the binding affinity we synthesized MPA analogs by linking adenosine 5'-methylenebis(phosphonate) with mycophenolic alcohols containing 2-, 4-, and 6-carbon atoms in their aliphatic side chain. Adenine dinucleotide analogs of tiazofurin, Selenazofurin and benzamide riboside were synthesized as P1, P2-disubstituted pyrophosphates. Cytotoxicity of each analog was examined in human colon adenocarcinoma HT-29 and erythroleukemia K562 cells, and induction of differentiation in K562 cells by these agents was determined. Mycophenolic acid is currently used as an immunosuppressant but its anticancer action is limited by inactivation due to rapid glucuronidation. The new analogs show resistance to metabolism to inactive species and exhibit enhanced cytotoxicity in tumor cell lines, and therefore could be useful as anticancer agents.
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studies on the mechanism of action of benzamide riboside a novel inhibitor of imp dehydrogenase
2002Co-Authors: Kamran Gharehbaghi, Werner Grunberger, Hiremagalur N. JayaramAbstract:Benzamide is a well known inhibitor of poly(ADP-ribose)polymerase, an enzyme involved in DNA repair. However, benzamide exhibited neuotoxicity in animals and hence, in the hope of overcoming this problem, benzamide riboside (BR) was synthesized. Our mechanism of action studies on BR suggested that the agent was being metabolized to its 5'-monophosphate and then to its NAD analogue (BAD, benzamide adenine dinucleotide) that inhibits Inosine 5'-monophosphate dehydrogenase (IMPDH). IMPDH is the rate-limiting enzyme of the branched purine nucleotide synthetic pathway that provides guanylates including GTP and dGTP. There are two isoforms of IMPDH, type I that is constitutively present in all cells, and type II that is inducible and is present in highly proliferating cells such as cancer. Ongoing studies with BR analogues suggest that they are more selective in inhibiting IMPDH type II. Our studies have characterized the metabolites of BR, especially its NAD analogue, BAD, by synthesizing this active metabolite by enzymatic means, and identifying its structure by NMR and mass spectrometry. We have partially purified IMPDH from tumor cells and have examined the kinetics of inhibition of IMPDH by BAD. We have also compared biochemical and cytotoxic activities of BR with tiazofurin and Selenazofurin, that share similar mechanisms of action with BR. Our studies demonstrated that 2-3-fold more BAD is formed compared to TAD and SAD, the active metabolites of tiazofurin and Selenazofurin, respectively. BR has demonstrated potent cytotoxic activity in a diverse group of human tumor cells, specifically more active in sarcomas and CNS neoplasms compared to tiazofurin or Selenazofurin. Future in vivo animal studies should set a stage for determining its effectiveness in clinical Phase I studies.
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consequences of imp dehydrogenase inhibition and its relationship to cancer and apoptosis
1999Co-Authors: Hiremagalur N. Jayaram, D A Cooney, Michael Grusch, Georg KrupitzaAbstract:Inosine 5 -monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme for the synthesis of GTP and dGTP. Two isoforms of IMPDH have been identified. IMPDH Type I is ubiquitous and predominantly present in normal cells, whereas IMPDH Type II is predominant in malignant cells. IMPDH plays an important role in the expression of cellular genes, such as p53, c-myc and Ki-ras. IMPDH activity is transformation and progression linked in cancer cells. IMPDH inhibitors, tiazofurin, Selenazofurin, and benzamide riboside share similar mechanism of action and are metabolized to their respective NAD analogues to exert antitumor activity. Tiazofurin exhibits clinical responses in patients with acute myeloid leukemia and chronic myeloid leukemia in blast crisis. These responses relate to the level of the NAD analogue formed in the leukemic cells. Resistance to tiazofurin and related IMPDH inhibitors relate mainly to a decrease in NMN adenylyltransferase activity. IMPDH inhbitors induce apoptosis. IMPDH inhitors are valuable probes for examining biochemical functions of GTP as they selectively reduce guanylate concentration. Incomplete depletion of cellular GTP level seems to down-regulate G-protein function, thereby inhibit cell growth or induce apoptosis. Inosine 5'-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) catalyzes the dehydrogenation of IMP to XMP utilizing NAD as the proton acceptor. Studies have demonstrated that IMPDH is a rate-limiting step in the de novo synthesis of guanylates, including GTP and dGTP. The importance of IMPDH is central because dGTP is required for the DNA synthesis and GTP plays a major role not only for the cellular activity but also for cellular regulation. Two isoforms of IMPDH have been demonstrated. IMPDH Type I is ubiquitous and predominately present in normal cells, whereas the IMPDH Type II enzyme is predominant in malignant cells. Although guanylates could be salvaged from guanine by the enzyme hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8), the level of circulating guanine is low in dividing cells and this route is probably insufficient to satisfy the needs of guanylates in the cells.
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synthesis structure and antiproliferative activity of selenophenfurin an inosine 5 monophosphate dehydrogenase inhibitor analogue of Selenazofurin
1997Co-Authors: Palmarisa Franchetti, Loredana Cappellacci, Barry M. Goldstein, Hiremagalur N. Jayaram, Ghassan Abu Sheikha, V V Gurudutt, T Sint, Bryan P Schneider, William D Jones, G PerraAbstract:The synthesis and biological activity of selenophenfurin (5-β-d-ribofuranosylselenophene-3-carboxamide, 1), the selenophene analogue of Selenazofurin, are described. Glycosylation of ethyl selenophene-3-carboxylate (6) under stannic chloride-catalyzed conditions gave 2- and 5-glycosylated regioisomers, as a mixture of α- and β-anomers, and the β-2,5-diglycosylated derivative. Deprotected ethyl 5-β-d-ribofuranosylselenophene-3-carboxylate (12β) was converted into selenophenfurin by ammonolysis. The structure of 12β was determined by 1H- and 13C-NMR, crystallographic, and computational studies. Selenophenfurin proved to be antiproliferative against a number of leukemia, lymphoma, and solid tumor cell lines at concentrations similar to those of Selenazofurin but was more potent than the thiophene and thiazole analogues thiophenfurin and tiazofurin. Incubation of K562 cells with selenophenfurin resulted in inhibition of IMP dehydrogenase (IMPDH) (76%) and an increase in IMP pools (14.5-fold) with a concurrent...
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furanfurin and thiophenfurin two novel tiazofurin analogues synthesis structure antitumor activity and interactions with inosine monophosphate dehydrogenase
1995Co-Authors: Palmarisa Franchetti, Loredana Cappellacci, Mario Grifantini, Afsaneh Barzi, Giuseppe Nocentini, Hongyoan Yang, Ayrn Oconnor, Christopher J Carrell, Hiremagalur N. Jayaram, Barry M. GoldsteinAbstract:carboxylate (6) or ethyl 34hiophencarboxylate (18) with 1,2,3,5-tetra-O-acetyl-~-ribofuranose gave 2- and 5-glycosylated regioisomers, as a mixture of a- and 8-anomers, and the 8-2,5diglycosylated derivatives. Deprotection of ethyl 5-(2,3,5-tri-0-acetyl-B-~-ribofuranosyl)furan3-carboxylate (98) and ethyl 5-(2,3,5-tri-0-acetyl-~-~-ribofuranosyl)t~ophene-3-carboxyla~ (20,8) with sodium ethoxide afforded ethyl 5-~-~-ribofuranosylfuran-3-carboxylate (128) and ethyl 5-~-~-ribofuranosylthiophene-3-carboxylate (238) which were converted into 5-,8-D-ribofuranosylfuran-3-carboxamide (furanfurin, 4) and 5-~-~-ribofuranosylthiophene-3-carboxamide (thiophenfurin, 5) by reaction with ammonium hydroxide. The anomeric configuration and the site of glycosylation were established by lH-NMR and proton-proton nuclear Overhauser effect difference spectroscopy. The structure of compound 238 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 BDzFl mice inoculated with L1210 cells with a % T/C of 168 at 25 mgkg. K562 cells incubation with thiophenfurin resulted in inhibition of inosine monophosphate (IMP) dehydrogenase (63%) and an increase in IMP pools (&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. Tiazofurin (2-~-~-ribofuranosylthiazole-4-carboxamide, NSC-286193, 1) and Selenazofurin (2-p-D-ribofuranosylselenazole-4-carboxamide, NSC-340847,2) are two widely studied C-nucleosides endowed with several biological effects. These include effective antitumor activity both in vitro and in ~ivol~-~ and the ability to induce differentiation in neoplastic cells,2 to inhibit the G protein-mediated cellular signaling me~hanism,~ and to downregulate oncogene a~tivity.~ The biological effects of these nucleosides, which are structurally related to riba~irin,~ appear to be due to inhibition of inosine monophosphate dehydrogenase (IMPDH), which induces the shutdown of guanine nucleotide ~ynthesis.~~,~~~ ,~ In sensitive cells, tiazo- and Selenazofurin are converted into analogues of the cofactor nicotinamide adenine dinucleotide (NAD). These NAD analogues, called TAD (thiazole-4-carboxamide
Barry M. Goldstein - One of the best experts on this subject based on the ideXlab platform.
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synthesis structure and antiproliferative activity of selenophenfurin an inosine 5 monophosphate dehydrogenase inhibitor analogue of Selenazofurin
1997Co-Authors: Palmarisa Franchetti, Loredana Cappellacci, Barry M. Goldstein, Hiremagalur N. Jayaram, Ghassan Abu Sheikha, V V Gurudutt, T Sint, Bryan P Schneider, William D Jones, G PerraAbstract:The synthesis and biological activity of selenophenfurin (5-β-d-ribofuranosylselenophene-3-carboxamide, 1), the selenophene analogue of Selenazofurin, are described. Glycosylation of ethyl selenophene-3-carboxylate (6) under stannic chloride-catalyzed conditions gave 2- and 5-glycosylated regioisomers, as a mixture of α- and β-anomers, and the β-2,5-diglycosylated derivative. Deprotected ethyl 5-β-d-ribofuranosylselenophene-3-carboxylate (12β) was converted into selenophenfurin by ammonolysis. The structure of 12β was determined by 1H- and 13C-NMR, crystallographic, and computational studies. Selenophenfurin proved to be antiproliferative against a number of leukemia, lymphoma, and solid tumor cell lines at concentrations similar to those of Selenazofurin but was more potent than the thiophene and thiazole analogues thiophenfurin and tiazofurin. Incubation of K562 cells with selenophenfurin resulted in inhibition of IMP dehydrogenase (IMPDH) (76%) and an increase in IMP pools (14.5-fold) with a concurrent...
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furanfurin and thiophenfurin two novel tiazofurin analogues synthesis structure antitumor activity and interactions with inosine monophosphate dehydrogenase
1995Co-Authors: Palmarisa Franchetti, Loredana Cappellacci, Mario Grifantini, Afsaneh Barzi, Giuseppe Nocentini, Hongyoan Yang, Ayrn Oconnor, Christopher J Carrell, Hiremagalur N. Jayaram, Barry M. GoldsteinAbstract:carboxylate (6) or ethyl 34hiophencarboxylate (18) with 1,2,3,5-tetra-O-acetyl-~-ribofuranose gave 2- and 5-glycosylated regioisomers, as a mixture of a- and 8-anomers, and the 8-2,5diglycosylated derivatives. Deprotection of ethyl 5-(2,3,5-tri-0-acetyl-B-~-ribofuranosyl)furan3-carboxylate (98) and ethyl 5-(2,3,5-tri-0-acetyl-~-~-ribofuranosyl)t~ophene-3-carboxyla~ (20,8) with sodium ethoxide afforded ethyl 5-~-~-ribofuranosylfuran-3-carboxylate (128) and ethyl 5-~-~-ribofuranosylthiophene-3-carboxylate (238) which were converted into 5-,8-D-ribofuranosylfuran-3-carboxamide (furanfurin, 4) and 5-~-~-ribofuranosylthiophene-3-carboxamide (thiophenfurin, 5) by reaction with ammonium hydroxide. The anomeric configuration and the site of glycosylation were established by lH-NMR and proton-proton nuclear Overhauser effect difference spectroscopy. The structure of compound 238 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 BDzFl mice inoculated with L1210 cells with a % T/C of 168 at 25 mgkg. K562 cells incubation with thiophenfurin resulted in inhibition of inosine monophosphate (IMP) dehydrogenase (63%) and an increase in IMP pools (&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. Tiazofurin (2-~-~-ribofuranosylthiazole-4-carboxamide, NSC-286193, 1) and Selenazofurin (2-p-D-ribofuranosylselenazole-4-carboxamide, NSC-340847,2) are two widely studied C-nucleosides endowed with several biological effects. These include effective antitumor activity both in vitro and in ~ivol~-~ and the ability to induce differentiation in neoplastic cells,2 to inhibit the G protein-mediated cellular signaling me~hanism,~ and to downregulate oncogene a~tivity.~ The biological effects of these nucleosides, which are structurally related to riba~irin,~ appear to be due to inhibition of inosine monophosphate dehydrogenase (IMPDH), which induces the shutdown of guanine nucleotide ~ynthesis.~~,~~~ ,~ In sensitive cells, tiazo- and Selenazofurin are converted into analogues of the cofactor nicotinamide adenine dinucleotide (NAD). These NAD analogues, called TAD (thiazole-4-carboxamide
Palmarisa Franchetti - One of the best experts on this subject based on the ideXlab platform.
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synthesis structure and antiproliferative activity of selenophenfurin an inosine 5 monophosphate dehydrogenase inhibitor analogue of Selenazofurin
1997Co-Authors: Palmarisa Franchetti, Loredana Cappellacci, Barry M. Goldstein, Hiremagalur N. Jayaram, Ghassan Abu Sheikha, V V Gurudutt, T Sint, Bryan P Schneider, William D Jones, G PerraAbstract:The synthesis and biological activity of selenophenfurin (5-β-d-ribofuranosylselenophene-3-carboxamide, 1), the selenophene analogue of Selenazofurin, are described. Glycosylation of ethyl selenophene-3-carboxylate (6) under stannic chloride-catalyzed conditions gave 2- and 5-glycosylated regioisomers, as a mixture of α- and β-anomers, and the β-2,5-diglycosylated derivative. Deprotected ethyl 5-β-d-ribofuranosylselenophene-3-carboxylate (12β) was converted into selenophenfurin by ammonolysis. The structure of 12β was determined by 1H- and 13C-NMR, crystallographic, and computational studies. Selenophenfurin proved to be antiproliferative against a number of leukemia, lymphoma, and solid tumor cell lines at concentrations similar to those of Selenazofurin but was more potent than the thiophene and thiazole analogues thiophenfurin and tiazofurin. Incubation of K562 cells with selenophenfurin resulted in inhibition of IMP dehydrogenase (IMPDH) (76%) and an increase in IMP pools (14.5-fold) with a concurrent...
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furanfurin and thiophenfurin two novel tiazofurin analogues synthesis structure antitumor activity and interactions with inosine monophosphate dehydrogenase
1995Co-Authors: Palmarisa Franchetti, Loredana Cappellacci, Mario Grifantini, Afsaneh Barzi, Giuseppe Nocentini, Hongyoan Yang, Ayrn Oconnor, Christopher J Carrell, Hiremagalur N. Jayaram, Barry M. GoldsteinAbstract:carboxylate (6) or ethyl 34hiophencarboxylate (18) with 1,2,3,5-tetra-O-acetyl-~-ribofuranose gave 2- and 5-glycosylated regioisomers, as a mixture of a- and 8-anomers, and the 8-2,5diglycosylated derivatives. Deprotection of ethyl 5-(2,3,5-tri-0-acetyl-B-~-ribofuranosyl)furan3-carboxylate (98) and ethyl 5-(2,3,5-tri-0-acetyl-~-~-ribofuranosyl)t~ophene-3-carboxyla~ (20,8) with sodium ethoxide afforded ethyl 5-~-~-ribofuranosylfuran-3-carboxylate (128) and ethyl 5-~-~-ribofuranosylthiophene-3-carboxylate (238) which were converted into 5-,8-D-ribofuranosylfuran-3-carboxamide (furanfurin, 4) and 5-~-~-ribofuranosylthiophene-3-carboxamide (thiophenfurin, 5) by reaction with ammonium hydroxide. The anomeric configuration and the site of glycosylation were established by lH-NMR and proton-proton nuclear Overhauser effect difference spectroscopy. The structure of compound 238 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 BDzFl mice inoculated with L1210 cells with a % T/C of 168 at 25 mgkg. K562 cells incubation with thiophenfurin resulted in inhibition of inosine monophosphate (IMP) dehydrogenase (63%) and an increase in IMP pools (&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. Tiazofurin (2-~-~-ribofuranosylthiazole-4-carboxamide, NSC-286193, 1) and Selenazofurin (2-p-D-ribofuranosylselenazole-4-carboxamide, NSC-340847,2) are two widely studied C-nucleosides endowed with several biological effects. These include effective antitumor activity both in vitro and in ~ivol~-~ and the ability to induce differentiation in neoplastic cells,2 to inhibit the G protein-mediated cellular signaling me~hanism,~ and to downregulate oncogene a~tivity.~ The biological effects of these nucleosides, which are structurally related to riba~irin,~ appear to be due to inhibition of inosine monophosphate dehydrogenase (IMPDH), which induces the shutdown of guanine nucleotide ~ynthesis.~~,~~~ ,~ In sensitive cells, tiazo- and Selenazofurin are converted into analogues of the cofactor nicotinamide adenine dinucleotide (NAD). These NAD analogues, called TAD (thiazole-4-carboxamide
G Perra - One of the best experts on this subject based on the ideXlab platform.
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synthesis structure and antiproliferative activity of selenophenfurin an inosine 5 monophosphate dehydrogenase inhibitor analogue of Selenazofurin
1997Co-Authors: Palmarisa Franchetti, Loredana Cappellacci, Barry M. Goldstein, Hiremagalur N. Jayaram, Ghassan Abu Sheikha, V V Gurudutt, T Sint, Bryan P Schneider, William D Jones, G PerraAbstract:The synthesis and biological activity of selenophenfurin (5-β-d-ribofuranosylselenophene-3-carboxamide, 1), the selenophene analogue of Selenazofurin, are described. Glycosylation of ethyl selenophene-3-carboxylate (6) under stannic chloride-catalyzed conditions gave 2- and 5-glycosylated regioisomers, as a mixture of α- and β-anomers, and the β-2,5-diglycosylated derivative. Deprotected ethyl 5-β-d-ribofuranosylselenophene-3-carboxylate (12β) was converted into selenophenfurin by ammonolysis. The structure of 12β was determined by 1H- and 13C-NMR, crystallographic, and computational studies. Selenophenfurin proved to be antiproliferative against a number of leukemia, lymphoma, and solid tumor cell lines at concentrations similar to those of Selenazofurin but was more potent than the thiophene and thiazole analogues thiophenfurin and tiazofurin. Incubation of K562 cells with selenophenfurin resulted in inhibition of IMP dehydrogenase (IMPDH) (76%) and an increase in IMP pools (14.5-fold) with a concurrent...
Kamran Gharehbaghi - One of the best experts on this subject based on the ideXlab platform.
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studies on the mechanism of action of benzamide riboside a novel inhibitor of imp dehydrogenase
2002Co-Authors: Kamran Gharehbaghi, Werner Grunberger, Hiremagalur N. JayaramAbstract:Benzamide is a well known inhibitor of poly(ADP-ribose)polymerase, an enzyme involved in DNA repair. However, benzamide exhibited neuotoxicity in animals and hence, in the hope of overcoming this problem, benzamide riboside (BR) was synthesized. Our mechanism of action studies on BR suggested that the agent was being metabolized to its 5'-monophosphate and then to its NAD analogue (BAD, benzamide adenine dinucleotide) that inhibits Inosine 5'-monophosphate dehydrogenase (IMPDH). IMPDH is the rate-limiting enzyme of the branched purine nucleotide synthetic pathway that provides guanylates including GTP and dGTP. There are two isoforms of IMPDH, type I that is constitutively present in all cells, and type II that is inducible and is present in highly proliferating cells such as cancer. Ongoing studies with BR analogues suggest that they are more selective in inhibiting IMPDH type II. Our studies have characterized the metabolites of BR, especially its NAD analogue, BAD, by synthesizing this active metabolite by enzymatic means, and identifying its structure by NMR and mass spectrometry. We have partially purified IMPDH from tumor cells and have examined the kinetics of inhibition of IMPDH by BAD. We have also compared biochemical and cytotoxic activities of BR with tiazofurin and Selenazofurin, that share similar mechanisms of action with BR. Our studies demonstrated that 2-3-fold more BAD is formed compared to TAD and SAD, the active metabolites of tiazofurin and Selenazofurin, respectively. BR has demonstrated potent cytotoxic activity in a diverse group of human tumor cells, specifically more active in sarcomas and CNS neoplasms compared to tiazofurin or Selenazofurin. Future in vivo animal studies should set a stage for determining its effectiveness in clinical Phase I studies.
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Comparison of biochemical parameters of benzamide riboside, a new inhibitor of IMP dehydrogenase, with tiazofurin and Selenazofurin
1994Co-Authors: Kamran Gharehbaghi, Ajay Sreenath, Zhang Hao, Kenneth D. Paull, Thomas Szekeres, David A. Cooney, Karsten Krohn, Hiremagalur N. JayaramAbstract:The biochemical and cytotoxic activities of the IMP dehydrogenase (IMPDH) inhibitors benzamide riboside, tiazofurin, and Selenazofurin were compared. These three C-nucleosides exert their cytotoxicity by forming an analogue of NAD, wherein nicotinamide is replaced by the C-nucleoside base. The antiproliferative activities of these three agents were compared in a panel of 60 human cancer cell lines. To examine the relationship of benzamide riboside and Selenazofurin to tiazofurin, COMPARE computer analysis was performed, and correlation coefficients of 0.761 and 0.815 were obtained for benzamide riboside and Selenazofurin, respectively. The biochemical activities of these agents were examined in human myelogenous leukemia K562 cells. Incubation of K562 cells for 4 hr with 10 microM each of benzamide riboside, Selenazofurin and tiazofurin resulted in a 49, 71, and 26% decrease in IMPDH activity with a concurrent increase in intracellular IMP pools. As a consequence of IMPDH inhibition, GTP and dGTP concentrations were curtailed. These studies demonstrated that Selenazofurin was the most potent of the three agents. To compare the cellular synthesis of NAD analogues of these agents, K562 cells were incubated with 10 microM each of benzamide riboside, tiazofurin and Selenazofurin after prelabeling the cells with [2,8-3H]adenosine. The results demonstrated that benzamide riboside produced 2- and 3-fold more of NAD analogue (BAD) than tiazofurin and Selenazofurin did. To elucidate the effects of the three compounds on other NAD-utilizing enzymes, the inhibitory activities of purified benzamide adenine dinucleotide (BAD), thiazole-4-carboxamide adenine dinucleotide (TAD) and selenazole-4-carboxamide adenine dinucleotide (SAD) were studied in commercially available purified preparations of lactate dehydrogenase, glutamate dehydrogenase and malate dehydrogenase. TAD and SAD did not inhibit these three dehydrogenases. Although BAD did not influence lactate and glutamate dehydrogenases, it selectively inhibited 50% of malate dehydrogenase activity at a 3.2 microM concentration. These studies demonstrate similarities and differences in the biochemical actions of the three C-nucleosides, even though they share similar mechanisms of action.