Total synthesis and antifungal evaluation of cyclic aminohexapeptides
The need for new therapies to treat systemic fungal infections continues to rise. Naturally occurring hexapeptide echinocandin B (1) has shown potent antifungal activity via its inhibition of the synthesis of beta-1,3 glucan, a key fungal cell wall component. Although this series of agents has been...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2000-07, Vol.8 (7), p.1677-1696 |
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| creator | KLEIN, L. L LEPING LI KISHORE, V LUNDELL, E. O WODKA, D MEULBROEK, J. A ALDER, J. D NILIUS, A. M LARTEY, P. A PLATTNER, J. J CHEN, H.-J CURTY, C. B DEGOEY, D. A GRAMPOVNIK, D. J LEONE, C. L THOMAS, S. A YEUNG, C. M FUNK, K. W |
| description | The need for new therapies to treat systemic fungal infections continues to rise. Naturally occurring hexapeptide echinocandin B (1) has shown potent antifungal activity via its inhibition of the synthesis of beta-1,3 glucan, a key fungal cell wall component. Although this series of agents has been limited thus far based on their physicochemical characteristics, we have found that the synthesis of analogues bearing an aminoproline residue in the 'northwest' position imparts greatly improved water solubility (> 5 mg/mL). The synthesis and structure-activity relationships (SAR) based on whole cell and upon in vivo activity of the series of compounds are reported. |
| doi_str_mv | 10.1016/S0968-0896(00)00097-3 |
| format | Article |
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L ; LEPING LI ; KISHORE, V ; LUNDELL, E. O ; WODKA, D ; MEULBROEK, J. A ; ALDER, J. D ; NILIUS, A. M ; LARTEY, P. A ; PLATTNER, J. J ; CHEN, H.-J ; CURTY, C. B ; DEGOEY, D. A ; GRAMPOVNIK, D. J ; LEONE, C. L ; THOMAS, S. A ; YEUNG, C. M ; FUNK, K. W</creator><creatorcontrib>KLEIN, L. L ; LEPING LI ; KISHORE, V ; LUNDELL, E. O ; WODKA, D ; MEULBROEK, J. A ; ALDER, J. D ; NILIUS, A. M ; LARTEY, P. A ; PLATTNER, J. J ; CHEN, H.-J ; CURTY, C. B ; DEGOEY, D. A ; GRAMPOVNIK, D. J ; LEONE, C. L ; THOMAS, S. A ; YEUNG, C. M ; FUNK, K. W</creatorcontrib><description>The need for new therapies to treat systemic fungal infections continues to rise. Naturally occurring hexapeptide echinocandin B (1) has shown potent antifungal activity via its inhibition of the synthesis of beta-1,3 glucan, a key fungal cell wall component. Although this series of agents has been limited thus far based on their physicochemical characteristics, we have found that the synthesis of analogues bearing an aminoproline residue in the 'northwest' position imparts greatly improved water solubility (> 5 mg/mL). The synthesis and structure-activity relationships (SAR) based on whole cell and upon in vivo activity of the series of compounds are reported.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/S0968-0896(00)00097-3</identifier><identifier>PMID: 10976515</identifier><language>eng</language><publisher>Oxford: Elsevier Science</publisher><subject>Acute Disease ; Amines - chemical synthesis ; Amines - chemistry ; Amines - pharmacology ; Amphotericin B - pharmacology ; Animals ; Anti-Bacterial Agents - chemical synthesis ; Anti-Bacterial Agents - chemistry ; Anti-Bacterial Agents - pharmacology ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antifungal agents ; Antifungal Agents - chemical synthesis ; Antifungal Agents - chemistry ; Antifungal Agents - pharmacology ; Biological and medical sciences ; Candida - drug effects ; Candidiasis, Vulvovaginal - drug therapy ; Candidiasis, Vulvovaginal - microbiology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Echinocandins ; Female ; Fungal Proteins ; Medical sciences ; Mice ; Microbial Sensitivity Tests ; Peptides ; Peptides, Cyclic - chemical synthesis ; Peptides, Cyclic - chemistry ; Peptides, Cyclic - pharmacology ; Pharmacology. 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W</creatorcontrib><title>Total synthesis and antifungal evaluation of cyclic aminohexapeptides</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>The need for new therapies to treat systemic fungal infections continues to rise. Naturally occurring hexapeptide echinocandin B (1) has shown potent antifungal activity via its inhibition of the synthesis of beta-1,3 glucan, a key fungal cell wall component. Although this series of agents has been limited thus far based on their physicochemical characteristics, we have found that the synthesis of analogues bearing an aminoproline residue in the 'northwest' position imparts greatly improved water solubility (> 5 mg/mL). The synthesis and structure-activity relationships (SAR) based on whole cell and upon in vivo activity of the series of compounds are reported.</description><subject>Acute Disease</subject><subject>Amines - chemical synthesis</subject><subject>Amines - chemistry</subject><subject>Amines - pharmacology</subject><subject>Amphotericin B - pharmacology</subject><subject>Animals</subject><subject>Anti-Bacterial Agents - chemical synthesis</subject><subject>Anti-Bacterial Agents - chemistry</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antifungal agents</subject><subject>Antifungal Agents - chemical synthesis</subject><subject>Antifungal Agents - chemistry</subject><subject>Antifungal Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Candida - drug effects</subject><subject>Candidiasis, Vulvovaginal - drug therapy</subject><subject>Candidiasis, Vulvovaginal - microbiology</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>Echinocandins</subject><subject>Female</subject><subject>Fungal Proteins</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Microbial Sensitivity Tests</subject><subject>Peptides</subject><subject>Peptides, Cyclic - chemical synthesis</subject><subject>Peptides, Cyclic - chemistry</subject><subject>Peptides, Cyclic - pharmacology</subject><subject>Pharmacology. 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Antiparasitic agents</topic><topic>Antifungal agents</topic><topic>Antifungal Agents - chemical synthesis</topic><topic>Antifungal Agents - chemistry</topic><topic>Antifungal Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Candida - drug effects</topic><topic>Candidiasis, Vulvovaginal - drug therapy</topic><topic>Candidiasis, Vulvovaginal - microbiology</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>Echinocandins</topic><topic>Female</topic><topic>Fungal Proteins</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Microbial Sensitivity Tests</topic><topic>Peptides</topic><topic>Peptides, Cyclic - chemical synthesis</topic><topic>Peptides, Cyclic - chemistry</topic><topic>Peptides, Cyclic - pharmacology</topic><topic>Pharmacology. 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| identifier | ISSN: 0968-0896 |
| ispartof | Bioorganic & medicinal chemistry, 2000-07, Vol.8 (7), p.1677-1696 |
| issn | 0968-0896 1464-3391 |
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| subjects | Acute Disease Amines - chemical synthesis Amines - chemistry Amines - pharmacology Amphotericin B - pharmacology Animals Anti-Bacterial Agents - chemical synthesis Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Antibiotics. Antiinfectious agents. Antiparasitic agents Antifungal agents Antifungal Agents - chemical synthesis Antifungal Agents - chemistry Antifungal Agents - pharmacology Biological and medical sciences Candida - drug effects Candidiasis, Vulvovaginal - drug therapy Candidiasis, Vulvovaginal - microbiology Disease Models, Animal Dose-Response Relationship, Drug Echinocandins Female Fungal Proteins Medical sciences Mice Microbial Sensitivity Tests Peptides Peptides, Cyclic - chemical synthesis Peptides, Cyclic - chemistry Peptides, Cyclic - pharmacology Pharmacology. Drug treatments Proline - chemistry Solubility Structure-Activity Relationship Yeasts - drug effects |
| title | Total synthesis and antifungal evaluation of cyclic aminohexapeptides |
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