Synthesis and biological evaluation of esterified and acylated derivatives of NH2-(AEEA)5-amphotericin B
Based on NH 2 -(AEEA) 5 -amphotericin B ( DMR005 ; AEEA is 8-amino-3,6-dioxaoctanoic acid), a series of novel esterified and acylated derivatives of DMR005 were synthesized. These derivatives were evaluated for their antifungal activities using the broth dilution method, for their hemolytic toxicity...
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| Veröffentlicht in: | Journal of antibiotics 2021-02, Vol.74 (2), p.133-142 |
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| creator | Zhang, Jinhua Dong, Yuanzhen Xu, Hongjiang Chen, Minwei Tang, Hanqing Shangguan, Wenwen Zhao, Wenjie Feng, Jun |
| description | Based on NH
2
-(AEEA)
5
-amphotericin B (
DMR005
; AEEA is 8-amino-3,6-dioxaoctanoic acid), a series of novel esterified and acylated derivatives of
DMR005
were synthesized. These derivatives were evaluated for their antifungal activities using the broth dilution method, for their hemolytic toxicity with sterile defibrinated sheep blood, and for their self-association through UV–visible spectroscopy. The preliminary screening tests indicated that NH
2
-(AEEA)
5
-amphotericin B methyl ester (
DMR031
) was an ideal compound. The results of minimum inhibitory concentration and time-kill assays showed that antifungal activities of
DMR031
(4 μg ml
−1
) against
Candida albicans
ATCC10231 and ATCC90028 were reduced by four times compared to these of amphotericin B (AmB) (1 μg ml
−1
).
DMR031
(142 ± 1 mg ml
−1
) significantly improved the water solubility of AmB as
DMR005
did. Preliminary safety assessments of
DMR031
were carried out via cell toxicity assay of HEK293T in vitro, which turned out to be much better than AmB. AmB had good efficacy in vivo at a dose of 1 mg ml
−1
. However,
DMR031
still had no efficacy in vivo even at a dose of 16 mg ml
−1
, merely prolonged the survival time of mice. |
| doi_str_mv | 10.1038/s41429-020-00365-3 |
| format | Article |
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2
-(AEEA)
5
-amphotericin B (
DMR005
; AEEA is 8-amino-3,6-dioxaoctanoic acid), a series of novel esterified and acylated derivatives of
DMR005
were synthesized. These derivatives were evaluated for their antifungal activities using the broth dilution method, for their hemolytic toxicity with sterile defibrinated sheep blood, and for their self-association through UV–visible spectroscopy. The preliminary screening tests indicated that NH
2
-(AEEA)
5
-amphotericin B methyl ester (
DMR031
) was an ideal compound. The results of minimum inhibitory concentration and time-kill assays showed that antifungal activities of
DMR031
(4 μg ml
−1
) against
Candida albicans
ATCC10231 and ATCC90028 were reduced by four times compared to these of amphotericin B (AmB) (1 μg ml
−1
).
DMR031
(142 ± 1 mg ml
−1
) significantly improved the water solubility of AmB as
DMR005
did. Preliminary safety assessments of
DMR031
were carried out via cell toxicity assay of HEK293T in vitro, which turned out to be much better than AmB. AmB had good efficacy in vivo at a dose of 1 mg ml
−1
. However,
DMR031
still had no efficacy in vivo even at a dose of 16 mg ml
−1
, merely prolonged the survival time of mice.</description><identifier>ISSN: 0021-8820</identifier><identifier>EISSN: 1881-1469</identifier><identifier>DOI: 10.1038/s41429-020-00365-3</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>101/58 ; 631/154/309/2144 ; 631/45/2783 ; 64/60 ; 82/16 ; Antibiotics ; Antifungal agents ; Bacteriology ; Biomedical and Life Sciences ; Bioorganic Chemistry ; Drug dosages ; Life Sciences ; Medicinal Chemistry ; Microbiology ; Organic Chemistry ; Reagents ; Toxicity</subject><ispartof>Journal of antibiotics, 2021-02, Vol.74 (2), p.133-142</ispartof><rights>The Author(s), under exclusive licence to the Japan Antibiotics Research Association 2020</rights><rights>The Author(s), under exclusive licence to the Japan Antibiotics Research Association 2020.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c2913-ab785206ed7707881bb0383a32823c7dada00be70d83c1a816bb58f2430d0d9a3</citedby><cites>FETCH-LOGICAL-c2913-ab785206ed7707881bb0383a32823c7dada00be70d83c1a816bb58f2430d0d9a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids></links><search><creatorcontrib>Zhang, Jinhua</creatorcontrib><creatorcontrib>Dong, Yuanzhen</creatorcontrib><creatorcontrib>Xu, Hongjiang</creatorcontrib><creatorcontrib>Chen, Minwei</creatorcontrib><creatorcontrib>Tang, Hanqing</creatorcontrib><creatorcontrib>Shangguan, Wenwen</creatorcontrib><creatorcontrib>Zhao, Wenjie</creatorcontrib><creatorcontrib>Feng, Jun</creatorcontrib><title>Synthesis and biological evaluation of esterified and acylated derivatives of NH2-(AEEA)5-amphotericin B</title><title>Journal of antibiotics</title><addtitle>J Antibiot</addtitle><description>Based on NH
2
-(AEEA)
5
-amphotericin B (
DMR005
; AEEA is 8-amino-3,6-dioxaoctanoic acid), a series of novel esterified and acylated derivatives of
DMR005
were synthesized. These derivatives were evaluated for their antifungal activities using the broth dilution method, for their hemolytic toxicity with sterile defibrinated sheep blood, and for their self-association through UV–visible spectroscopy. The preliminary screening tests indicated that NH
2
-(AEEA)
5
-amphotericin B methyl ester (
DMR031
) was an ideal compound. The results of minimum inhibitory concentration and time-kill assays showed that antifungal activities of
DMR031
(4 μg ml
−1
) against
Candida albicans
ATCC10231 and ATCC90028 were reduced by four times compared to these of amphotericin B (AmB) (1 μg ml
−1
).
DMR031
(142 ± 1 mg ml
−1
) significantly improved the water solubility of AmB as
DMR005
did. Preliminary safety assessments of
DMR031
were carried out via cell toxicity assay of HEK293T in vitro, which turned out to be much better than AmB. AmB had good efficacy in vivo at a dose of 1 mg ml
−1
. However,
DMR031
still had no efficacy in vivo even at a dose of 16 mg ml
−1
, merely prolonged the survival time of mice.</description><subject>101/58</subject><subject>631/154/309/2144</subject><subject>631/45/2783</subject><subject>64/60</subject><subject>82/16</subject><subject>Antibiotics</subject><subject>Antifungal agents</subject><subject>Bacteriology</subject><subject>Biomedical and Life Sciences</subject><subject>Bioorganic Chemistry</subject><subject>Drug dosages</subject><subject>Life Sciences</subject><subject>Medicinal Chemistry</subject><subject>Microbiology</subject><subject>Organic Chemistry</subject><subject>Reagents</subject><subject>Toxicity</subject><issn>0021-8820</issn><issn>1881-1469</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>BENPR</sourceid><recordid>eNp9kDFPwzAQhS0EEqXwB5giscBgONtJ7IwFFYpUwQDMlmM7ras0LnZaqf8et0FiYzrd6Xt39x5C1wTuCTDxEHOS0woDBQzAygKzEzQiQhBM8rI6RSMASrAQFM7RRYyrBHHGxQgtP_Zdv7TRxUx1Jqudb_3CadVmdqfareqd7zLfZDb2NrjGWXPklN63qk-NSdNdonY2HrC3GcW3k-l0cldgtd4s_UGlXZc9XqKzRrXRXv3WMfp6nn4-zfD8_eX1aTLHmlaEYVVzUVAoreEceDJQ18kfU4wKyjQ3yiiA2nIwgmmiBCnruhANzRkYMJViY3Qz7N0E_71Nb8uV34YunZQ050VJSF7wRNGB0sHHGGwjN8GtVdhLAvKQqBwSlSlReUxUsiRigygmuFvY8Lf6H9UPg7J4Cg</recordid><startdate>20210201</startdate><enddate>20210201</enddate><creator>Zhang, Jinhua</creator><creator>Dong, Yuanzhen</creator><creator>Xu, Hongjiang</creator><creator>Chen, Minwei</creator><creator>Tang, Hanqing</creator><creator>Shangguan, Wenwen</creator><creator>Zhao, Wenjie</creator><creator>Feng, Jun</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope></search><sort><creationdate>20210201</creationdate><title>Synthesis and biological evaluation of esterified and acylated derivatives of NH2-(AEEA)5-amphotericin B</title><author>Zhang, Jinhua ; Dong, Yuanzhen ; Xu, Hongjiang ; Chen, Minwei ; Tang, Hanqing ; Shangguan, Wenwen ; Zhao, Wenjie ; Feng, Jun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2913-ab785206ed7707881bb0383a32823c7dada00be70d83c1a816bb58f2430d0d9a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>101/58</topic><topic>631/154/309/2144</topic><topic>631/45/2783</topic><topic>64/60</topic><topic>82/16</topic><topic>Antibiotics</topic><topic>Antifungal agents</topic><topic>Bacteriology</topic><topic>Biomedical and Life Sciences</topic><topic>Bioorganic Chemistry</topic><topic>Drug dosages</topic><topic>Life Sciences</topic><topic>Medicinal Chemistry</topic><topic>Microbiology</topic><topic>Organic Chemistry</topic><topic>Reagents</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Jinhua</creatorcontrib><creatorcontrib>Dong, Yuanzhen</creatorcontrib><creatorcontrib>Xu, Hongjiang</creatorcontrib><creatorcontrib>Chen, Minwei</creatorcontrib><creatorcontrib>Tang, Hanqing</creatorcontrib><creatorcontrib>Shangguan, Wenwen</creatorcontrib><creatorcontrib>Zhao, Wenjie</creatorcontrib><creatorcontrib>Feng, Jun</creatorcontrib><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><jtitle>Journal of antibiotics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Jinhua</au><au>Dong, Yuanzhen</au><au>Xu, Hongjiang</au><au>Chen, Minwei</au><au>Tang, Hanqing</au><au>Shangguan, Wenwen</au><au>Zhao, Wenjie</au><au>Feng, Jun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and biological evaluation of esterified and acylated derivatives of NH2-(AEEA)5-amphotericin B</atitle><jtitle>Journal of antibiotics</jtitle><stitle>J Antibiot</stitle><date>2021-02-01</date><risdate>2021</risdate><volume>74</volume><issue>2</issue><spage>133</spage><epage>142</epage><pages>133-142</pages><issn>0021-8820</issn><eissn>1881-1469</eissn><abstract>Based on NH
2
-(AEEA)
5
-amphotericin B (
DMR005
; AEEA is 8-amino-3,6-dioxaoctanoic acid), a series of novel esterified and acylated derivatives of
DMR005
were synthesized. These derivatives were evaluated for their antifungal activities using the broth dilution method, for their hemolytic toxicity with sterile defibrinated sheep blood, and for their self-association through UV–visible spectroscopy. The preliminary screening tests indicated that NH
2
-(AEEA)
5
-amphotericin B methyl ester (
DMR031
) was an ideal compound. The results of minimum inhibitory concentration and time-kill assays showed that antifungal activities of
DMR031
(4 μg ml
−1
) against
Candida albicans
ATCC10231 and ATCC90028 were reduced by four times compared to these of amphotericin B (AmB) (1 μg ml
−1
).
DMR031
(142 ± 1 mg ml
−1
) significantly improved the water solubility of AmB as
DMR005
did. Preliminary safety assessments of
DMR031
were carried out via cell toxicity assay of HEK293T in vitro, which turned out to be much better than AmB. AmB had good efficacy in vivo at a dose of 1 mg ml
−1
. However,
DMR031
still had no efficacy in vivo even at a dose of 16 mg ml
−1
, merely prolonged the survival time of mice.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><doi>10.1038/s41429-020-00365-3</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0021-8820 |
| ispartof | Journal of antibiotics, 2021-02, Vol.74 (2), p.133-142 |
| issn | 0021-8820 1881-1469 |
| language | eng |
| recordid | cdi_proquest_journals_2475611457 |
| source | Alma/SFX Local Collection |
| subjects | 101/58 631/154/309/2144 631/45/2783 64/60 82/16 Antibiotics Antifungal agents Bacteriology Biomedical and Life Sciences Bioorganic Chemistry Drug dosages Life Sciences Medicinal Chemistry Microbiology Organic Chemistry Reagents Toxicity |
| title | Synthesis and biological evaluation of esterified and acylated derivatives of NH2-(AEEA)5-amphotericin B |
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