| Autor: |
Brütsch, Tobias M., Cotter, Etienne, Lucena‐Agell, Daniel, Redondo‐Horcajo, Mariano, Davies, Carolina, Pfeiffer, Bernhard, Pagani, Sandro, Berardozzi, Simone, Fernando Díaz, J., Miller, John H., Altmann, Karl‐Heinz |
| Předmět: |
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| Zdroj: |
Chemistry - A European Journal; 6/27/2023, Vol. 29 Issue 36, p1-13, 13p |
| Abstrakt: |
We describe the synthesis and biochemical and cellular profiling of five partially reduced or demethylated analogs of the marine macrolide (−)‐zampanolide (ZMP). These analogs were derived from 13‐desmethylene‐(−)‐zampanolide (DM‐ZMP), which is an equally potent cancer cell growth inhibitor as ZMP. Key steps in the synthesis of all compounds were the formation of the dioxabicyclo[15.3.1]heneicosane core by an intramolecular HWE reaction (67–95 % yield) and a stereoselective aza‐aldol reaction with an (S)‐BINOL‐derived sorbamide transfer complex, to establish the C(20) stereocenter (24–71 % yield). As the sole exception, for the 5‐desmethyl macrocycle, ring‐closure relied on macrolactonization; however, elaboration of the macrocyclization product into the corresponding zampanolide analog was unsuccessful. All modifications led to reduced cellular activity and lowered microtubule‐binding affinity compared to DM‐ZMP, albeit to a different extent. For compounds incorporating the reactive enone moiety of ZMP, IC50 values for cancer cell growth inhibition varied between 5 and 133 nM, compared to 1–12 nM for DM‐ZMP. Reduction of the enone double bond led to a several hundred‐fold loss in growth inhibition. The cellular potency of 2,3‐dihydro‐13‐desmethylene zampanolide, as the most potent analog identified, remained within a ninefold range of that of DM‐ZMP. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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