Details
| Original language | English |
|---|---|
| Pages (from-to) | 880-886 |
| Number of pages | 7 |
| Journal | Chemistry - A European Journal |
| Volume | 18 |
| Issue number | 3 |
| Publication status | Published - 14 Dec 2011 |
Abstract
Access of four new tumor specific folic acid/ansamitocin conjugates is reported that relies on a synthetic strategy based on the combination of mutasynthesis and semisynthesis. Two bromo-ansamitocin derivatives were prepared by mutasynthesis or by a modified fermentation protocol, respectively, that served as starting point for the semisynthetic introduction of an allyl amine linker under Stille conditions. A sequence of standard coupling steps introduced the pteroic acid/glutamic acid/cysteine unit to the modified ansamitocins. All new derivatives, including those that are expected to be generated after internalization of the folic acid/ansamitocin conjugates into the cancer cell and reductive cleavage of the disulfide linkage showed good to strong antiproliferative activity (IC 50 <10 nM) for different cancer cell lines. Finally, the four conjugates were exposed to two cancer cell lines [cervix carcinoma, KB-3-1 (FR+) and lung carcinoma, A-459 (FR-)], the latter devoid of the membrane-bound folic acid receptor (FR-). All four conjugates showed strong antiproliferative activity for the FR+ cancer cell line but were inactive against the FR- cell line. The synthetic strategy pursued is based on the combination of mutasynthesis and semisynthesis and proved to be powerful for accessing new ansamitocin derivatives that are difficult to prepare by total synthesis. Synthetic power: Four novel folate-ansamitocin conjugates were prepared by a combined muta-/semisynthetic approach. They exert strong selectivity between cell lines that have expressed and that are devoid of folate receptors (FR). The study demonstrates both the power of target-specific chemotherapy with ansamitocins and reveals the diverse options mutasynthesis combined with semisynthesis provides.
Keywords
- ansamitocins, antitumor agents, folate-drug conjugates, mutasynthesis, semisynthesis, Stille reaction
ASJC Scopus subject areas
- Chemical Engineering(all)
- Catalysis
- Chemistry(all)
- Organic Chemistry
Sustainable Development Goals
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In: Chemistry - A European Journal, Vol. 18, No. 3, 14.12.2011, p. 880-886.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Combined muta- and semisynthesis
T2 - A powerful synthetic hybrid approach to access target specific antitumor agents based on ansamitocin P3
AU - Taft, Florian
AU - Harmrolfs, Kirsten
AU - Nickeleit, Irinia
AU - Heutling, Anja
AU - Kiene, Miriam
AU - Malek, Nisar
AU - Sasse, Florenz
AU - Kirschning, Andreas
PY - 2011/12/14
Y1 - 2011/12/14
N2 - Access of four new tumor specific folic acid/ansamitocin conjugates is reported that relies on a synthetic strategy based on the combination of mutasynthesis and semisynthesis. Two bromo-ansamitocin derivatives were prepared by mutasynthesis or by a modified fermentation protocol, respectively, that served as starting point for the semisynthetic introduction of an allyl amine linker under Stille conditions. A sequence of standard coupling steps introduced the pteroic acid/glutamic acid/cysteine unit to the modified ansamitocins. All new derivatives, including those that are expected to be generated after internalization of the folic acid/ansamitocin conjugates into the cancer cell and reductive cleavage of the disulfide linkage showed good to strong antiproliferative activity (IC 50 <10 nM) for different cancer cell lines. Finally, the four conjugates were exposed to two cancer cell lines [cervix carcinoma, KB-3-1 (FR+) and lung carcinoma, A-459 (FR-)], the latter devoid of the membrane-bound folic acid receptor (FR-). All four conjugates showed strong antiproliferative activity for the FR+ cancer cell line but were inactive against the FR- cell line. The synthetic strategy pursued is based on the combination of mutasynthesis and semisynthesis and proved to be powerful for accessing new ansamitocin derivatives that are difficult to prepare by total synthesis. Synthetic power: Four novel folate-ansamitocin conjugates were prepared by a combined muta-/semisynthetic approach. They exert strong selectivity between cell lines that have expressed and that are devoid of folate receptors (FR). The study demonstrates both the power of target-specific chemotherapy with ansamitocins and reveals the diverse options mutasynthesis combined with semisynthesis provides.
AB - Access of four new tumor specific folic acid/ansamitocin conjugates is reported that relies on a synthetic strategy based on the combination of mutasynthesis and semisynthesis. Two bromo-ansamitocin derivatives were prepared by mutasynthesis or by a modified fermentation protocol, respectively, that served as starting point for the semisynthetic introduction of an allyl amine linker under Stille conditions. A sequence of standard coupling steps introduced the pteroic acid/glutamic acid/cysteine unit to the modified ansamitocins. All new derivatives, including those that are expected to be generated after internalization of the folic acid/ansamitocin conjugates into the cancer cell and reductive cleavage of the disulfide linkage showed good to strong antiproliferative activity (IC 50 <10 nM) for different cancer cell lines. Finally, the four conjugates were exposed to two cancer cell lines [cervix carcinoma, KB-3-1 (FR+) and lung carcinoma, A-459 (FR-)], the latter devoid of the membrane-bound folic acid receptor (FR-). All four conjugates showed strong antiproliferative activity for the FR+ cancer cell line but were inactive against the FR- cell line. The synthetic strategy pursued is based on the combination of mutasynthesis and semisynthesis and proved to be powerful for accessing new ansamitocin derivatives that are difficult to prepare by total synthesis. Synthetic power: Four novel folate-ansamitocin conjugates were prepared by a combined muta-/semisynthetic approach. They exert strong selectivity between cell lines that have expressed and that are devoid of folate receptors (FR). The study demonstrates both the power of target-specific chemotherapy with ansamitocins and reveals the diverse options mutasynthesis combined with semisynthesis provides.
KW - ansamitocins
KW - antitumor agents
KW - folate-drug conjugates
KW - mutasynthesis
KW - semisynthesis
KW - Stille reaction
UR - http://www.scopus.com/inward/record.url?scp=84855698460&partnerID=8YFLogxK
U2 - 10.1002/chem.201101640
DO - 10.1002/chem.201101640
M3 - Article
C2 - 22170289
AN - SCOPUS:84855698460
VL - 18
SP - 880
EP - 886
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
SN - 0947-6539
IS - 3
ER -