The Experts below are selected from a list of 222 Experts worldwide ranked by ideXlab platform
Kazuo Umezawa - One of the best experts on this subject based on the ideXlab platform.
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inhibition of tumor angiogenesis by targeting endothelial surface atp synthase with Sangivamycin
Japanese Journal of Clinical Oncology, 2007Co-Authors: Yusuke Komi, Osamu Ohno, Kazuo Umezawa, Yasuhiro Suzuki, Mariko Shimamura, Kentaro Shimokado, Soichi KojimaAbstract:Background: Sangivamycin, an antibiotic with anti-tumor and anti-herpes virus activities by inhibiting both DNA/RNA synthesis and protein kinase C activity, was reported to suppress selectively DNA synthesis and growth of human umbilical vein endothelial cells and their tube formation in vitro. Here, to address the potential clinical use of Sangivamycin in future, we investigated its anti-angiogenic effect in in vivo chicken chorioallantoic membrane (CAM) and mouse dorsal air sac (DAS) assays, and investigated underlying mechanism. Methods: The effect of Sangivamycin on blood vessel formation in CAM was observed under the microscope after treating for two days. For DAS assays, chambers fulfilled with tumor cells were implanted beneath mouse dorsal skin. After the mice were administered with Sangivamycin, tumor-induced angiogenesis was observed under the microscope. The effect of Sangivamycin on ATP synthesis on the endothelial cell surface was assayed by measuring ATP production with bioluminescence assay. Results: Sangivamycin suppressed angiogenesis within CAM down to 94‐71%, which was partially blocked by simultaneous addition of a 40-fold excess of adenosine. Sangivamycin also inhibited tumor-angiogenesis in the DAS assay by 61%, and suppressed ATP production on the endothelial cell surface by 75%. Conclusion: Sangivamycin inhibits the in vivo angiogenesis within CAM and tumor-induced angiogenesis within mouse dorsal skin, at least in part via inhibiting endothelial cell surface ATP metabolism in addition to inhibition of DNA/RNA synthesis and/or protein kinase C activity, suggesting a potential clinical use of Sangivamycin as a novel anti-cancer reagent capable of targeting not only cancer cells but also endothelial cells.
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selective growth inhibition by Sangivamycin of human umbilical vein endothelial cells
International Journal of Oncology, 2001Co-Authors: Osamu Ohno, Yutaka Shima, Yoko Ikeda, Shinichi Kondo, Kuniki Kato, Kazuo UmezawaAbstract:: In the course of our screening for selective growth inhibitors of human umbilical vein endothelial cells (HUVECs), we isolated Sangivamycin from the culture filtrate of Streptomyces. It inhibited the growth of HUVECs at approximately 30 times lower concentration than that needed to inhibit the growth of WI-38 human fibroblasts. Structurally-related nucleosides, such as toyocamycin, tubercidin, and formycins A and B, did not show the differential inhibition. Although Sangivamycin is known to inhibit protein kinase C, other protein kinase C inhibitors did not inhibit the growth of HUVECs selectively. Sangivamycin effectively inhibited S-phase induction in HUVECs, like TNP-470 and LLnL, known selective inhibitors. However, unlike them Sangivamycin did not induce p21 expression. On the other hand, Sangivamycin was found to inhibit DNA synthesis selectively in HUVECs. Thus, Sangivamycin was shown to be a new selective growth inhibitor of HUVECs acting on DNA synthesis.
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Selective growth inhibition by Sangivamycin of human umbilical vein endothelial cells
International Journal of Oncology, 2001Co-Authors: Osamu Ohno, Yutaka Shima, Yoko Ikeda, Shinichi Kondo, Kuniki Kato, Kazuo UmezawaAbstract:In the course of our screening for selective growth inhibitors of human umbilical vein endothelial cells (HUVECs), we isolated Sangivamycin from the culture filtrate of Streptomyces. It inhibited the growth of HUVECs at ∼30 times lower concentration than that needed to inhibit the growth of WI-38 human fibroblasts. Structurally-related nucleosides, such as toyocamycin, tubercidin, and formycins A and B, did not show the differential inhibition. Although Sangivamycin is known to inhibit protein kinase C, other protein kinase C inhibitors did not inhibit the growth of HUVECs selectively. Sangivamycin effectively inhibited S-phase induction in HUVECs, like TNP-470 and LLnL, known selective inhibitors. However, unlike them Sangivamycin did not induce p21 expression. On the other hand, Sangivamycin was found to inhibit DNA synthesis selectively in HUVECs. Thus, Sangivamycin was shown to be a new selective growth inhibitor of HUVECs acting on DNA synthesis.
Osamu Ohno - One of the best experts on this subject based on the ideXlab platform.
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inhibition of tumor angiogenesis by targeting endothelial surface atp synthase with Sangivamycin
Japanese Journal of Clinical Oncology, 2007Co-Authors: Yusuke Komi, Osamu Ohno, Kazuo Umezawa, Yasuhiro Suzuki, Mariko Shimamura, Kentaro Shimokado, Soichi KojimaAbstract:Background: Sangivamycin, an antibiotic with anti-tumor and anti-herpes virus activities by inhibiting both DNA/RNA synthesis and protein kinase C activity, was reported to suppress selectively DNA synthesis and growth of human umbilical vein endothelial cells and their tube formation in vitro. Here, to address the potential clinical use of Sangivamycin in future, we investigated its anti-angiogenic effect in in vivo chicken chorioallantoic membrane (CAM) and mouse dorsal air sac (DAS) assays, and investigated underlying mechanism. Methods: The effect of Sangivamycin on blood vessel formation in CAM was observed under the microscope after treating for two days. For DAS assays, chambers fulfilled with tumor cells were implanted beneath mouse dorsal skin. After the mice were administered with Sangivamycin, tumor-induced angiogenesis was observed under the microscope. The effect of Sangivamycin on ATP synthesis on the endothelial cell surface was assayed by measuring ATP production with bioluminescence assay. Results: Sangivamycin suppressed angiogenesis within CAM down to 94‐71%, which was partially blocked by simultaneous addition of a 40-fold excess of adenosine. Sangivamycin also inhibited tumor-angiogenesis in the DAS assay by 61%, and suppressed ATP production on the endothelial cell surface by 75%. Conclusion: Sangivamycin inhibits the in vivo angiogenesis within CAM and tumor-induced angiogenesis within mouse dorsal skin, at least in part via inhibiting endothelial cell surface ATP metabolism in addition to inhibition of DNA/RNA synthesis and/or protein kinase C activity, suggesting a potential clinical use of Sangivamycin as a novel anti-cancer reagent capable of targeting not only cancer cells but also endothelial cells.
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selective growth inhibition by Sangivamycin of human umbilical vein endothelial cells
International Journal of Oncology, 2001Co-Authors: Osamu Ohno, Yutaka Shima, Yoko Ikeda, Shinichi Kondo, Kuniki Kato, Kazuo UmezawaAbstract:: In the course of our screening for selective growth inhibitors of human umbilical vein endothelial cells (HUVECs), we isolated Sangivamycin from the culture filtrate of Streptomyces. It inhibited the growth of HUVECs at approximately 30 times lower concentration than that needed to inhibit the growth of WI-38 human fibroblasts. Structurally-related nucleosides, such as toyocamycin, tubercidin, and formycins A and B, did not show the differential inhibition. Although Sangivamycin is known to inhibit protein kinase C, other protein kinase C inhibitors did not inhibit the growth of HUVECs selectively. Sangivamycin effectively inhibited S-phase induction in HUVECs, like TNP-470 and LLnL, known selective inhibitors. However, unlike them Sangivamycin did not induce p21 expression. On the other hand, Sangivamycin was found to inhibit DNA synthesis selectively in HUVECs. Thus, Sangivamycin was shown to be a new selective growth inhibitor of HUVECs acting on DNA synthesis.
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Selective growth inhibition by Sangivamycin of human umbilical vein endothelial cells
International Journal of Oncology, 2001Co-Authors: Osamu Ohno, Yutaka Shima, Yoko Ikeda, Shinichi Kondo, Kuniki Kato, Kazuo UmezawaAbstract:In the course of our screening for selective growth inhibitors of human umbilical vein endothelial cells (HUVECs), we isolated Sangivamycin from the culture filtrate of Streptomyces. It inhibited the growth of HUVECs at ∼30 times lower concentration than that needed to inhibit the growth of WI-38 human fibroblasts. Structurally-related nucleosides, such as toyocamycin, tubercidin, and formycins A and B, did not show the differential inhibition. Although Sangivamycin is known to inhibit protein kinase C, other protein kinase C inhibitors did not inhibit the growth of HUVECs selectively. Sangivamycin effectively inhibited S-phase induction in HUVECs, like TNP-470 and LLnL, known selective inhibitors. However, unlike them Sangivamycin did not induce p21 expression. On the other hand, Sangivamycin was found to inhibit DNA synthesis selectively in HUVECs. Thus, Sangivamycin was shown to be a new selective growth inhibitor of HUVECs acting on DNA synthesis.
Leroy B Townsend - One of the best experts on this subject based on the ideXlab platform.
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Toyocamycin specifically inhibits auxin signaling mediated by SCFTIR1 pathway
Phytochemistry, 2009Co-Authors: Ken-ichiro Hayashi, Leroy B Townsend, Shuichi Kamio, Yutaka Oono, Hiroshi NozakiAbstract:Abstract The auxins, plant hormones, play a crucial role in many aspects of plant development by regulating cell division, elongation and differentiation. Toyocamycin, a nucleoside-type antibiotic, was identified as auxin signaling inhibitor in a screen of microbial extracts for inhibition of the auxin-inducible reporter gene assay. Toyocamycin specifically inhibited auxin-responsive gene expression, but did not affect other hormone-inducible gene expression. Toyocamycin also blocked auxin-enhanced degradation of the Aux/IAA repressor modulated by the SCF(TIR1) ubiquitin–proteasome pathway without inhibiting proteolytic activity of proteasome. Furthermore, toyocamycin inhibited auxin-induced lateral root formation and epinastic growth of cotyledon in the Arabidopsis thaliana plant. This evidence suggested that toyocamycin would act on the ubiquitination process regulated by SCF(TIR1) machineries. To address the structural requirements for the specific activity of toyocamycin on auxin signaling, the structure-activity relationships of nine toyocamycin-related compounds, including Sangivamycin and tubercidin, were investigated.
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synthesis of non nucleoside analogs of toyocamycin Sangivamycin and thioSangivamycin the effect of certain 4 and 4 6 substituents on the antiviral activity of pyrrolo 2 3 d pyrimidines
Journal of Medicinal Chemistry, 1996Co-Authors: Thomas E Renau, John C Drach, Christopher Kennedy, Roger G Ptak, Julie M Breitenbach, Leroy B TownsendAbstract:A number of 4-substituted 7-(ethoxymethyl)- and 7-[(2-methoxyethoxy)methyl]pyrrolo[2,3-d]-pyrimidine-5-carbonitrile and -5-thiocarboxamide derivatives and several 7-substituted 4,6-diaminopyrrolo[2,3-d]pyrimidine-5-carbonitrile, -5-carboxamide, and -5-thiocarboxamide analogs related to the nucleoside antibiotics toyocamycin and Sangivamycin were prepared and tested for activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1). Biologically, modifications at the 4-position were not well tolerated in cell culture, and in almost all cases no activity against HCMV or HSV-1 was observed. Furthermore, none of the compounds inhibited the growth of L1210 murine leukemic cells in vitro. In sharp contrast to the 4-substituted compounds, all of the 4,6-diamino 5-nitrile and the 5-thioamide analogs were active against HCMV, whereas the 5-carboxamides were inactive. The corresponding 4-amino 6-methylamino and 6-dimethylamino 5-nitrile analogs were inactive against HCMV, establishing that an amino group at both C-4 and C-6 is a likely requirement for antiviral activity. Overall, our results demonstrate that an amino group at C-4 and a thioamide moiety at C-5 of a 7-substituted pyrrolo[2,3-d]pyrimidine are essential for activity against HCMV, whereas a 4,6-diamino analog does not necessarily require a thioamide group at C-5 for activity against HCMV.
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RELATIONSHIP BETWEEN CYTOTOXICITY AND CONVERSION OF THIOSangivamycin ANALOGS TO TOYOCAMYCIN ANALOGS IN CELL CULTURE MEDIUM
Biochemical Pharmacology, 1994Co-Authors: Thomas E Renau, Leroy B Townsend, Linda L. Wotring, Christopher G. Young, John C DrachAbstract:Non-nucleoside analogs of the pyrrolopyrimidine nucleosides toyocamycin, Sangivamycin and thioSangivamycin have been synthesized and their cytotoxicity in mammalian cells determined. While studying the effects of Rhioamide-substituted analogs on cell growth, we observed an interesting phenomenon in which cells recovered spontaneously from growth inhibition during extended incubations. HPLC studies demonstrated that the 5-thioamide moiety of several structurally dissimilar 7-substituted 4-aminopyrrolo(2,3-djpyrimidines, including thioSangivamycin, is unstable in cell culture medium and is converted to the corresponding 5-nitrile with a half-life of approximately 48 hr. In contrast, different substituents at the 4-position of the heterocycle significantly affected the stability of the 5-thioamide moiety. Conversion of the thioamide to the nitrile was caused by components in the cell culture medium, not components of serum. The above observations demonstrate that caution should be exercised in interpreting biological data obtained in vitro for 5-thioamide pyrrolo(2,3-dlpyrimidines.
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design synthesis and activity against human cytomegalovirus of non phosphorylatable analogs of toyocamycin Sangivamycin and thioSangivamycin
Bioorganic & Medicinal Chemistry Letters, 1992Co-Authors: Thomas E Renau, John C Drach, Mary S Ludwig, Leroy B TownsendAbstract:Abstract A number of 7-alkyl 4-aminopyrrolo[2,3- d pyrimidine derivatives related to toyocamycin, Sangivamycin and thioSangivamycin have been prepared and tested for their activity against human cytomegalovirus (HCMV). Only the thioamide substituted derivatives demonstrated biological activity.
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Design, synthesis and activity against human cytomegalovirus of non-phosphorylatable analogs of toyocamycin, Sangivamycin and thioSangivamycin
Bioorganic & Medicinal Chemistry Letters, 1992Co-Authors: Thomas E Renau, John C Drach, Mary S Ludwig, Leroy B TownsendAbstract:A number of 7-alkyl 4-aminopyrrolo(2,3-glpyrimidine derivatives related to toyocamycin, Sangivamycin and thioSangivamycin have been prepared and tested for their activity against human cytomegalovirus (HCMV). Only the thioamide substituted derivatives demonstrated biological activity. Human cytomegalovirus (HCMV) infection is relatively benign in healthy individuals but can be debilitating or fatal to immunosuppressed individuals such as transplant recipients' and AIDS patients.2 The drugs currently approved for the treatment of HCMV are ganciclovir (GCV, DHPG)3 and foscarnet (PFA).4 The clinical use of these compounds is limited because of host toxicity. s-6 In addition, there have been recent report@ that strains of HCMV resistant to both drugs are emerging. Hence, there is a continued need to develop compounds which may circumvent the problems associated with the use of DHPG and PFA to treat HCMV infections. The naturally occurring pyrrolo(2,3-d)pyrimidine nucleosides toyocamycin (I), Sangivamycin (2) and a structurally related analog, thioSangivamycin (3), possess significant activity against HCMVg-lo
Soichi Kojima - One of the best experts on this subject based on the ideXlab platform.
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inhibition of tumor angiogenesis by targeting endothelial surface atp synthase with Sangivamycin
Japanese Journal of Clinical Oncology, 2007Co-Authors: Yusuke Komi, Osamu Ohno, Kazuo Umezawa, Yasuhiro Suzuki, Mariko Shimamura, Kentaro Shimokado, Soichi KojimaAbstract:Background: Sangivamycin, an antibiotic with anti-tumor and anti-herpes virus activities by inhibiting both DNA/RNA synthesis and protein kinase C activity, was reported to suppress selectively DNA synthesis and growth of human umbilical vein endothelial cells and their tube formation in vitro. Here, to address the potential clinical use of Sangivamycin in future, we investigated its anti-angiogenic effect in in vivo chicken chorioallantoic membrane (CAM) and mouse dorsal air sac (DAS) assays, and investigated underlying mechanism. Methods: The effect of Sangivamycin on blood vessel formation in CAM was observed under the microscope after treating for two days. For DAS assays, chambers fulfilled with tumor cells were implanted beneath mouse dorsal skin. After the mice were administered with Sangivamycin, tumor-induced angiogenesis was observed under the microscope. The effect of Sangivamycin on ATP synthesis on the endothelial cell surface was assayed by measuring ATP production with bioluminescence assay. Results: Sangivamycin suppressed angiogenesis within CAM down to 94‐71%, which was partially blocked by simultaneous addition of a 40-fold excess of adenosine. Sangivamycin also inhibited tumor-angiogenesis in the DAS assay by 61%, and suppressed ATP production on the endothelial cell surface by 75%. Conclusion: Sangivamycin inhibits the in vivo angiogenesis within CAM and tumor-induced angiogenesis within mouse dorsal skin, at least in part via inhibiting endothelial cell surface ATP metabolism in addition to inhibition of DNA/RNA synthesis and/or protein kinase C activity, suggesting a potential clinical use of Sangivamycin as a novel anti-cancer reagent capable of targeting not only cancer cells but also endothelial cells.
John C Drach - One of the best experts on this subject based on the ideXlab platform.
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synthesis of non nucleoside analogs of toyocamycin Sangivamycin and thioSangivamycin the effect of certain 4 and 4 6 substituents on the antiviral activity of pyrrolo 2 3 d pyrimidines
Journal of Medicinal Chemistry, 1996Co-Authors: Thomas E Renau, John C Drach, Christopher Kennedy, Roger G Ptak, Julie M Breitenbach, Leroy B TownsendAbstract:A number of 4-substituted 7-(ethoxymethyl)- and 7-[(2-methoxyethoxy)methyl]pyrrolo[2,3-d]-pyrimidine-5-carbonitrile and -5-thiocarboxamide derivatives and several 7-substituted 4,6-diaminopyrrolo[2,3-d]pyrimidine-5-carbonitrile, -5-carboxamide, and -5-thiocarboxamide analogs related to the nucleoside antibiotics toyocamycin and Sangivamycin were prepared and tested for activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1). Biologically, modifications at the 4-position were not well tolerated in cell culture, and in almost all cases no activity against HCMV or HSV-1 was observed. Furthermore, none of the compounds inhibited the growth of L1210 murine leukemic cells in vitro. In sharp contrast to the 4-substituted compounds, all of the 4,6-diamino 5-nitrile and the 5-thioamide analogs were active against HCMV, whereas the 5-carboxamides were inactive. The corresponding 4-amino 6-methylamino and 6-dimethylamino 5-nitrile analogs were inactive against HCMV, establishing that an amino group at both C-4 and C-6 is a likely requirement for antiviral activity. Overall, our results demonstrate that an amino group at C-4 and a thioamide moiety at C-5 of a 7-substituted pyrrolo[2,3-d]pyrimidine are essential for activity against HCMV, whereas a 4,6-diamino analog does not necessarily require a thioamide group at C-5 for activity against HCMV.
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RELATIONSHIP BETWEEN CYTOTOXICITY AND CONVERSION OF THIOSangivamycin ANALOGS TO TOYOCAMYCIN ANALOGS IN CELL CULTURE MEDIUM
Biochemical Pharmacology, 1994Co-Authors: Thomas E Renau, Leroy B Townsend, Linda L. Wotring, Christopher G. Young, John C DrachAbstract:Non-nucleoside analogs of the pyrrolopyrimidine nucleosides toyocamycin, Sangivamycin and thioSangivamycin have been synthesized and their cytotoxicity in mammalian cells determined. While studying the effects of Rhioamide-substituted analogs on cell growth, we observed an interesting phenomenon in which cells recovered spontaneously from growth inhibition during extended incubations. HPLC studies demonstrated that the 5-thioamide moiety of several structurally dissimilar 7-substituted 4-aminopyrrolo(2,3-djpyrimidines, including thioSangivamycin, is unstable in cell culture medium and is converted to the corresponding 5-nitrile with a half-life of approximately 48 hr. In contrast, different substituents at the 4-position of the heterocycle significantly affected the stability of the 5-thioamide moiety. Conversion of the thioamide to the nitrile was caused by components in the cell culture medium, not components of serum. The above observations demonstrate that caution should be exercised in interpreting biological data obtained in vitro for 5-thioamide pyrrolo(2,3-dlpyrimidines.
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design synthesis and activity against human cytomegalovirus of non phosphorylatable analogs of toyocamycin Sangivamycin and thioSangivamycin
Bioorganic & Medicinal Chemistry Letters, 1992Co-Authors: Thomas E Renau, John C Drach, Mary S Ludwig, Leroy B TownsendAbstract:Abstract A number of 7-alkyl 4-aminopyrrolo[2,3- d pyrimidine derivatives related to toyocamycin, Sangivamycin and thioSangivamycin have been prepared and tested for their activity against human cytomegalovirus (HCMV). Only the thioamide substituted derivatives demonstrated biological activity.
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Design, synthesis and activity against human cytomegalovirus of non-phosphorylatable analogs of toyocamycin, Sangivamycin and thioSangivamycin
Bioorganic & Medicinal Chemistry Letters, 1992Co-Authors: Thomas E Renau, John C Drach, Mary S Ludwig, Leroy B TownsendAbstract:A number of 7-alkyl 4-aminopyrrolo(2,3-glpyrimidine derivatives related to toyocamycin, Sangivamycin and thioSangivamycin have been prepared and tested for their activity against human cytomegalovirus (HCMV). Only the thioamide substituted derivatives demonstrated biological activity. Human cytomegalovirus (HCMV) infection is relatively benign in healthy individuals but can be debilitating or fatal to immunosuppressed individuals such as transplant recipients' and AIDS patients.2 The drugs currently approved for the treatment of HCMV are ganciclovir (GCV, DHPG)3 and foscarnet (PFA).4 The clinical use of these compounds is limited because of host toxicity. s-6 In addition, there have been recent report@ that strains of HCMV resistant to both drugs are emerging. Hence, there is a continued need to develop compounds which may circumvent the problems associated with the use of DHPG and PFA to treat HCMV infections. The naturally occurring pyrrolo(2,3-d)pyrimidine nucleosides toyocamycin (I), Sangivamycin (2) and a structurally related analog, thioSangivamycin (3), possess significant activity against HCMVg-lo
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synthesis antiproliferative and antiviral evaluation of certain acyclic 6 substituted pyrrolo 2 3 d pyrimidine nucleoside analogs related to Sangivamycin and toyocamycin
Nucleosides Nucleotides & Nucleic Acids, 1992Co-Authors: Eric E Swayze, John C Drach, Linda L. Wotring, William M Shannon, Robert W Buckheit, Leroy B TownsendAbstract:Abstract A number of 6-substituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine and 7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3-d]pyrimidine derivatives related to the nucleoside antibiotics toyocamycin and Sangivamycin were prepared and tested for their biological activity. Treatment of 2-amino-5-bromo-3,4-dicyanopyrrole (2) with triethylorthoformate, followed by alkylation via the sodium salt method with either 2-(acetoxyethoxy)methyl bromide or (1,3-diacetoxy-2-propoxy)methyl bromide, furnished the corresponding N-substituted pyrroles 3a and 3b. These compounds were then smoothly converted to the requisite deprotected 4-amino-6-bromopyrrolo[2,3-d]-pyrimidine-5-carbonitriles 5a and 5b (toyocamycin analogs) by methanolic ammonia. The 6-amino-derivatives were obtained by a displacement of the bromo group with liquid ammonia. Conventional functional group transformations involving the 5-cyano group furnished the 5-carboxamide (Sangivamycin) and 5-thioamide analogs. Compounds substituted at the 7-...
