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Combined Muta‐ and Semisynthesis: A Powerful Synthetic Hybrid Approach to Access Target Specific Antitumor Agents Based on Ansamitocin P3
Author(s) -
Taft Florian,
Harmrolfs Kirsten,
Nickeleit Irinia,
Heutling Anja,
Kiene Miriam,
Malek Nisar,
Sasse Florenz,
Kirschning Andreas
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201101640
Subject(s) - semisynthesis , chemistry , folate receptor , linker , stereochemistry , cell culture , biochemistry , cancer cell , combinatorial chemistry , biology , cancer , computer science , genetics , operating system
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 n M ) 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.